News Topic genes

About these topic collections

I’ve been reporting on memory research for over ten years and these topic pages are simply collections of all the news items I have made on a particular topic. They do not pretend to be in any way exhaustive! I cover far too many areas within memory to come anywhere approaching that. What I aim to do is provide breadth, rather than depth. Outside my own area of cognitive psychology, it is difficult to know how much weight to give to any study (I urge you to read my blog post on what constitutes scientific evidence). That (among other reasons) is why my approach in my news reporting is based predominantly on replication and consistency. It's about the aggregate. So here is the aggregate of those reports I have at one point considered of sufficient interest to discuss. If you know of any research you would like to add to the collection, feel free to write about it in a comment (please provide a reference).

Genes for cognition

A very large genetic study has revealed that genetic differences have little effect on educational achievement. The study involved more than 125,000 people from the U.S., Australia, and 13 western European countries.

All told, genes explained about 2% of differences in educational attainment (as measured by years of schooling and college graduation), with the genetic variants with the strongest effects each explaining only 0.02% (in comparison, the gene variant with the largest effect on human height accounts for about 0.4%).

[3443] Rietveld, C. A., Medland S. E., Derringer J., Yang J., Esko T., Martin N. W., et al. (2013).  GWAS of 126,559 Individuals Identifies Genetic Variants Associated with Educational Attainment. Science.

Analysis of data from 418 older adults (70+) has found that carriers of the ‘Alzheimer’s gene’, APOEe4, were 58% more likely to develop mild cognitive impairment compared to non-carriers. However, ε4 carriers with MCI developed Alzheimer’s at the same rate as non-carriers. The finding turns prevailing thinking on its head: rather than the gene increasing the risk of developing Alzheimer’s, it appears that it increases the risk of MCI — and people with MCI are the main source of new Alzheimer’s diagnoses.

In this regard, it’s worth noting that the cognitive effects of this gene variant have been demonstrated in adults as young as the mid-20s.

The finding points to the benefit of genetic testing for assessing your likelihood of cognitive impairment rather than dementia — and using this knowledge to build habits that fight cognitive impairment.

[3370] Brainerd, C. J., Reyna V. F., Petersen R. C., Smith G. E., Kenney A. E., Gross C. J., et al. (2013).  The apolipoprotein E genotype predicts longitudinal transitions to mild cognitive impairment but not to Alzheimer's dementia: Findings from a nationally representative study. Neuropsychology. 27(1), 86 - 94.

A rat study has found that infant males have more of the Foxp2 protein (associated with language development) than females and that males also made significantly more distress calls than females. Increasing the protein level in females and reducing it in males reversed the gender differences in alarm calls.

A small pilot study with humans found that 4-year-old girls had more of the protein than boys. In both cases, it is the more communicative gender that has the higher level of Foxp2.

[3314] Bowers, M. J., Perez-Pouchoulen M., Edwards S. N., & McCarthy M. M. (2013).  Foxp2 Mediates Sex Differences in Ultrasonic Vocalization by Rat Pups and Directs Order of Maternal Retrieval. The Journal of Neuroscience. 33(8), 3276 - 3283.

A new study indicates that carrying the ‘Alzheimer’s gene’ may be a significant risk factor for women only.

While the ‘Alzheimer’s gene’ is relatively common — the ApoE4 mutation is present in around 15% of the population — having two copies of the mutation is, thankfully, much rarer, at around 2%. Having two copies is of course a major risk factor for developing Alzheimer’s, and it has been thought that having a single copy is also a significant (though lesser) risk factor. Certainly there is quite a lot of evidence linking ApoE4 carriers to various markers of cognitive impairment.

And yet, the evidence has not been entirely consistent. I have been puzzled by this myself, and now a new finding suggests a reason. It appears there are gender differences in responses to this gene variant.

The study involved 131 healthy older adults (median age 70), whose brains were scanned. The scans revealed that in older women with the E4 variant, brain activity showed the loss of synchronization that is typically seen in Alzheimer’s patients, with the precuneus (a major hub in the default mode network) out of sync with other brain regions. This was not observed in male carriers.

The finding was confirmed by a separate set of data, taken from the Alzheimer's Disease Neuroimaging Initiative database. Cerebrospinal fluid from 91 older adults (average age 75) revealed that female carriers had substantially higher levels of tau protein (a key Alzheimer’s biomarker) than male carriers or non-carriers.

It’s worth emphasizing that the participants in the first study were all cognitively normal — the loss of synchronization was starting to happen before visible Alzheimer’s symptoms appeared.

The findings suggest that men have less to worry about than women, as far as the presence of this gene is concerned. The study may also explain why more women than men get the disease (3 women to 2 men); it is not (although of course this is a factor) simply a consequence of women tending to live longer.

Whether or not these gender differences extend to carriers of two copies of the gene is another story.

People with a strong genetic risk of early-onset Alzheimer’s have revealed a progression of brain changes that begin 25 years before symptoms are evident.

A study involving those with a strong genetic risk of developing Alzheimer’s has found that the first signs of the disease can be detected 25 years before symptoms are evident. Whether this is also true of those who develop the disease without having such a strong genetic predisposition is not yet known.

The study involved 128 individuals with a 50% chance of inheriting one of three mutations that are certain to cause Alzheimer’s, often at an unusually young age. On the basis of participants’ parents’ medical history, an estimate of age of onset was calculated.

The first observable brain marker was a drop in cerebrospinal fluid levels of amyloid-beta proteins, and this could be detected 25 years before the anticipated age of onset. Amyloid plaques in the precuneus became visible on brain scans 15-20 years before memory problems become apparent; elevated cerebrospinal fluid levels of the tau protein 10-15 years, and brain atrophy in the hippocampus 15 years. Ten years before symptoms, the precuneus showed reduced use of glucose, and slight impairments in episodic memory (as measured in the delayed-recall part of the Wechsler’s Logical Memory subtest) were detectable. Global cognitive impairment (measured by the MMSE and the Clinical Dementia Rating scale) was detected 5 years before expected symptom onset, and patients met diagnostic criteria for dementia at an average of 3 years after expected symptom onset.

Family members without the risky genes showed none of these changes.

The risky genes are PSEN1 (present in 70 participants), PSEN2 (11), and APP (7) — note that together these account for 30-50% of early-onset familial Alzheimer’s, although only 0.5% of Alzheimer’s in general. The ‘Alzheimer’s gene’ APOe4 (which is a risk factor for sporadic, not familial, Alzheimer’s), was no more likely to be present in these carriers (25%) than noncarriers (22%), and there were no gender differences. The average parental age of symptom onset was 46 (note that this pushes back the first biomarker to 21! Can we speculate a connection to noncarriers having significantly more education than carriers — 15 years vs 13.9?).

The results paint a clear picture of how Alzheimer’s progresses, at least in this particular pathway. First come increases in the amyloid-beta protein, followed by amyloid pathology, tau pathology, brain atrophy, and decreased glucose metabolism. Following this biological cascade, cognitive impairment ensues.

The degree to which these findings apply to the far more common sporadic Alzheimer’s is not known, but evidence from other research is consistent with this progression.

It must be noted, however, that the findings are based on cross-sectional data — that is, pieced together from individuals at different ages and stages. A longitudinal study is needed to confirm.

The findings do suggest the importance of targeting the first step in the cascade — the over-production of amyloid-beta — at a very early stage.

Researchers encourage people with a family history of multiple generations of Alzheimer’s diagnosed before age 55 to register at, if they would like to be considered for inclusion in any research.

[2997] Bateman, R. J., Xiong C., Benzinger T. L. S., Fagan A. M., Goate A., Fox N. C., et al. (2012).  Clinical and Biomarker Changes in Dominantly Inherited Alzheimer's Disease. New England Journal of Medicine. 120723122607004 - 120723122607004.

New studies involving genetically-engineered mice and older adult humans support a connection between the immune system and cognitive impairment in old age.

A number of studies have come out in recent years linking age-related cognitive decline and dementia risk to inflammation and infection (put inflammation into the “Search this site” box at the top of the page and you’ll see what I mean). New research suggests one important mechanism.

In a mouse study, mice engineered to be deficient in receptors for the CCR2 gene — a crucial element in removing beta-amyloid and also important for neurogenesis — developed Alzheimer’s-like pathology more quickly. When these mice had CCR2 expression boosted, accumulation of beta-amyloid decreased and the mice’s memory improved.

In the human study, the expression levels of thousands of genes from 691 older adults (average age 73) in Italy (part of the long-running InCHIANTI study) were analyzed. Both cognitive performance and cognitive decline over 9 years (according to MMSE scores) were significantly associated with the expression of this same gene. That is, greater CCR2 activity was associated with lower cognitive scores and greater decline.

Expression of the CCR2 gene was also positively associated with the Alzheimer’s gene — meaning that those who carry the APOE4 variant are more likely to have higher CCR2 activity.

The finding adds yet more weight to the importance of preventing / treating inflammation and infection.

[2960] Harries, L. W., Bradley-Smith R. M., Llewellyn D. J., Pilling L. C., Fellows A., Henley W., et al. (2012).  Leukocyte CCR2 Expression Is Associated with Mini-Mental State Examination Score in Older Adults. Rejuvenation Research. 120518094735004 - 120518094735004.

Naert, G. & Rivest S. 2012. Hematopoietic CC-chemokine receptor 2-(CCR2) competent cells are protective for the cognitive impairments and amyloid pathology in a transgenic mouse model of Alzheimer's disease. Molecular Medicine, 18(1), 297-313.

El Khoury J, et al. 2007. Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease. Nature Medicine, 13, 432–8.

For those with the Alzheimer’s gene, higher blood pressure, even though within the normal range, is linked to greater brain shrinkage and reduced cognitive ability.

I’ve reported before on the evidence suggesting that carriers of the ‘Alzheimer’s gene’, APOE4, tend to have smaller brain volumes and perform worse on cognitive tests, despite being cognitively ‘normal’. However, the research hasn’t been consistent, and now a new study suggests the reason.

The e4 variant of the apolipoprotein (APOE) gene not only increases the risk of dementia, but also of cardiovascular disease. These effects are not unrelated. Apoliproprotein is involved in the transportation of cholesterol. In older adults, it has been shown that other vascular risk factors (such as elevated cholesterol, hypertension or diabetes) worsen the cognitive effects of having this gene variant.

This new study extends the finding, by looking at 72 healthy adults from a wide age range (19-77).

Participants were tested on various cognitive abilities known to be sensitive to aging and the effects of the e4 allele. Those abilities include speed of information processing, working memory and episodic memory. Blood pressure, brain scans, and of course genetic tests, were also performed.

There are a number of interesting findings:

  • The relationship between age and hippocampal volume was stronger for those carrying the e4 allele (shrinkage of this brain region occurs with age, and is significantly greater in those with MCI or dementia).
  • Higher systolic blood pressure was significantly associated with greater atrophy (i.e., smaller volumes), slower processing speed, and reduced working memory capacity — but only for those with the e4 variant.
  • Among those with the better and more common e3 variant, working memory was associated with lateral prefrontal cortex volume and with processing speed. Greater age was associated with higher systolic blood pressure, smaller volumes of the prefrontal cortex and prefrontal white matter, and slower processing. However, blood pressure was not itself associated with either brain atrophy or slower cognition.
  • For those with the Alzheimer’s variant (e4), older adults with higher blood pressure had smaller volumes of prefrontal white matter, and this in turn was associated with slower speed, which in turn linked to reduced working memory.

In other words, for those with the Alzheimer’s gene, age differences in working memory (which underpin so much of age-related cognitive impairment) were produced by higher blood pressure, reduced prefrontal white matter, and slower processing. For those without the gene, age differences in working memory were produced by reduced prefrontal cortex and prefrontal white matter.

Most importantly, these increases in blood pressure that we are talking about are well within the normal range (although at the higher end).

The researchers make an interesting point: that these findings are in line with “growing evidence that ‘normal’ should be viewed in the context of individual’s genetic predisposition”.

What it comes down to is this: those with the Alzheimer’s gene variant (and no doubt other genetic variants) have a greater vulnerability to some of the risk factors that commonly increase as we age. Those with a family history of dementia or serious cognitive impairment should therefore pay particular attention to controlling vascular risk factors, such as hypertension and diabetes.

This doesn’t mean that those without such a family history can safely ignore such conditions! When they get to the point of being clinically diagnosed as problems, then they are assuredly problems for your brain regardless of your genetics. What this study tells us is that these vascular issues appear to be problematic for Alzheimer’s gene carriers before they get to that point of clinical diagnosis.

New research indicates that the cognitive benefits of exercise depend on the gene variant you carry.

I’ve mentioned before that, for some few people, exercise doesn’t seem to have a benefit, and the benefits of exercise for fighting age-related cognitive decline may not apply to those carrying the Alzheimer’s gene.

New research suggests there is another gene variant that may impact on exercise’s effects. The new study follows on from earlier research that found that physical exercise during adolescence had more durable effects on object memory and BDNF levels than exercise during adulthood. In this study, 54 healthy but sedentary young adults (aged 18-36) were given an object recognition test before participating in either (a) a 4-week exercise program, with exercise on the final test day, (b) a 4-week exercise program, without exercise on the final test day, (c) a single bout of exercise on the final test day, or (d) remaining sedentary between test days.

Exercise both improved object recognition memory and reduced perceived stress — but only in one group: those who exercised for 4 weeks including the final day of testing. In other words, both regular exercise and recent exercise was needed to produce a memory benefit.

But there is one more factor — and this is where it gets really interesting — the benefit in this group didn’t happen for every member of the group. Only those carrying a specific genotype benefited from regular and recent exercise. This genotype has to do with the brain protein BDNF, which is involved in neurogenesis and synaptic plasticity, and which is increased by exercise. The BDNF gene comes in two flavors: Val and Met. Previous research has linked the less common Met variant to poorer memory and greater age-related cognitive decline.

In other words, it seems that the Met allele affects how much BDNF is released as a result of exercise, and this in turn affects cognitive benefits.

The object recognition test involved participants seeing a series of 50 images (previously selected as being highly recognizable and nameable), followed by a 15 minute filler task, before seeing 100 images (the previous 50 and 50 new images) and indicating which had been seen previously. The filler task involved surveys for state anxiety, perceived stress, and mood. On the first (pre-program) visit, a survey for trait anxiety was also completed.

Of the 54 participants, 31 carried two copies of the Val allele, and 23 had at least one Met allele (19 Val/Met; 4 Met/Met). The population frequency for carrying at least one Met allele is 50% for Asians, 30% in Caucasians, and 4% in African-Americans.

Although exercise decreased stress and increased positive mood, the cognitive benefits of exercise were not associated with mood or anxiety. Neither was genotype associated with mood or anxiety. However, some studies have found an association between depression and the Met variant, and this study is of course quite small.

A final note: this study is part of research looking at the benefits of exercise for children with ADHD. The findings suggest that genotyping would enable us to predict whether an individual — a child with ADHD or an older adult at risk of cognitive decline or impairment — would benefit from this treatment strategy.

A round-up of genetic news. Several genes are linked to smaller brain size and faster brain atrophy in middle- & old age. The main Alzheimer's gene is implicated in leaky blood vessels, and shown to interact with brain size, white matter lesions, and dementia risk. Some evidence suggests early-onset Alzheimer's is not so dissimilar to late-onset Alzheimer's.

Genetic analysis of 9,232 older adults (average age 67; range 56-84) has implicated four genes in how fast your hippocampus shrinks with age (rs7294919 at 12q24, rs17178006 at 12q14, rs6741949 at 2q24, rs7852872 at 9p33). The first of these (implicated in cell death) showed a particularly strong link to a reduced hippocampus volume — with average consequence being a hippocampus of the same size as that of a person 4-5 years older.

Faster atrophy in this crucial brain region would increase people’s risk of Alzheimer’s and cognitive decline, by reducing their cognitive reserve. Reduced hippocampal volume is also associated with schizophrenia, major depression, and some forms of epilepsy.

In addition to cell death, the genes linked to this faster atrophy are involved in oxidative stress, ubiquitination, diabetes, embryonic development and neuronal migration.

A younger cohort, of 7,794 normal and cognitively compromised people with an average age of 40, showed that these suspect gene variants were also linked to smaller hippocampus volume in this age group. A third cohort, comprised of 1,563 primarily older people, showed a significant association between the ASTN2 variant (linked to neuronal migration) and faster memory loss.

In another analysis, researchers looked at intracranial volume and brain volume in 8,175 elderly. While they found no genetic associations for brain volume (although there was one suggestive association), they did discover that intracranial volume (the space occupied by the fully developed brain within the skull — this remains unchanged with age, reflecting brain size at full maturity) was significantly associated with two gene variants (at loci rs4273712, on chromosome 6q22, and rs9915547, on 17q21). These associations were replicated in a different sample of 1,752 older adults. One of these genes is already known to play a unique evolutionary role in human development.

A meta-analysis of seven genome-wide association studies, involving 10,768 infants (average age 14.5 months), found two loci robustly associated with head circumference in infancy (rs7980687 on chromosome 12q24 and rs1042725 on chromosome 12q15). These loci have previously been associated with adult height, but these effects on infant head circumference were largely independent of height. A third variant (rs11655470 on chromosome 17q21 — note that this is the same chromosome implicated in the study of older adults) showed suggestive evidence of association with head circumference; this chromosome has also been implicated in Parkinson's disease and other neurodegenerative diseases.

Previous research has found an association between head size in infancy and later development of Alzheimer’s. It has been thought that this may have to do with cognitive reserve.

Interestingly, the analyses also revealed that a variant in a gene called HMGA2 (rs10784502 on 12q14.3) affected intelligence as well as brain size.

Why ‘Alzheimer’s gene’ increases Alzheimer’s risk

Investigation into the so-called ‘Alzheimer’s gene’ ApoE4 (those who carry two copies of this variant have roughly eight to 10 times the risk of getting Alzheimer’s disease) has found that ApoE4 causes an increase in cyclophilin A, which in turn causes a breakdown of the cells lining the blood vessels. Blood vessels become leaky, making it more likely that toxic substances will leak into the brain.

The study found that mice carrying the ApoE4 gene had five times as much cyclophilin A as normal, in cells crucial to maintaining the integrity of the blood-brain barrier. Blocking the action of cyclophilin A brought blood flow back to normal and reduced the leakage of toxic substances by 80%.

The finding is in keeping with the idea that vascular problems are at the heart of Alzheimer’s disease — although it should not be assumed from that, that other problems (such as amyloid-beta plaques and tau tangles) are not also important. However, one thing that does seem clear now is that there is not one single pathway to Alzheimer’s. This research suggests a possible treatment approach for those carrying this risky gene variant.

Note also that this gene variant is not only associated with Alzheimer’s risk, but also Down’s syndrome dementia, poor outcome following TBI, and age-related cognitive decline.

On which note, I’d like to point out recent findings from the long-running Nurses' Health Study, involving 16,514 older women (70-81), that suggest that effects of postmenopausal hormone therapy for cognition may depend on apolipoprotein E (APOE) status, with the fastest rate of decline being observed among HT users who carried the APOe4 variant (in general HT was associated with poorer cognitive performance).

It’s also interesting to note another recent finding: that intracranial volume modifies the effect of apoE4 and white matter lesions on dementia risk. The study, involving 104 demented and 135 nondemented 85-year-olds, found that smaller intracranial volume increased the risk of dementia, Alzheimer's disease, and vascular dementia in participants with white matter lesions. However, white matter lesions were not associated with increased dementia risk in those with the largest intracranial volume. But intracranial volume did not modify dementia risk in those with the apoE4 gene.

More genes involved in Alzheimer’s

More genome-wide association studies of Alzheimer's disease have now identified variants in BIN1, CLU, CR1 and PICALM genes that increase Alzheimer’s risk, although it is not yet known how these gene variants affect risk (the present study ruled out effects on the two biomarkers, amyloid-beta 42 and phosphorylated tau).

Same genes linked to early- and late-onset Alzheimer's

Traditionally, we’ve made a distinction between early-onset Alzheimer's disease, which is thought to be inherited, and the more common late-onset Alzheimer’s. New findings, however, suggest we should re-think that distinction. While the genetic case for early-onset might seem to be stronger, sporadic (non-familial) cases do occur, and familial cases occur with late-onset.

New DNA sequencing techniques applied to the APP (amyloid precursor protein) gene, and the PSEN1 and PSEN2 (presenilin) genes (the three genes linked to early-onset Alzheimer's) has found that rare variants in these genes are more common in families where four or more members were affected with late-onset Alzheimer’s, compared to normal individuals. Additionally, mutations in the MAPT (microtubule associated protein tau) gene and GRN (progranulin) gene (both linked to frontotemporal dementia) were also found in some Alzheimer's patients, suggesting they had been incorrectly diagnosed as having Alzheimer's disease when they instead had frontotemporal dementia.

Of the 439 patients in which at least four individuals per family had been diagnosed with Alzheimer's disease, rare variants in the 3 Alzheimer's-related genes were found in 60 (13.7%) of them. While not all of these variants are known to be pathogenic, the frequency of mutations in these genes is significantly higher than it is in the general population.

The researchers estimate that about 5% of those with late-onset Alzheimer's disease have changes in these genes. They suggest that, at least in some cases, the same causes may underlie both early- and late-onset disease. The difference being that those that develop it later have more protective factors.

Another gene identified in early-onset Alzheimer's

A study of the genes from 130 families suffering from early-onset Alzheimer's disease has found that 116 had mutations on genes already known to be involved (APP, PSEN1, PSEN2 — see below for some older reports on these genes), while five of the other 14 families all showed mutations on a new gene: SORL1.

I say ‘new gene’ because it hasn’t been implicated in early-onset Alzheimer’s before. However, it has been implicated in the more common late-onset Alzheimer’s, and last year a study reported that the gene was associated with differences in hippocampal volume in young, healthy adults.

The finding, then, provides more support for the idea that some cases of early-onset and late-onset Alzheimer’s have the same causes.

The SORL1 gene codes for a protein involved in the production of the beta-amyloid peptide, and the mutations seen in this study appear to cause an under-expression of SORL1, resulting in an increase in the production of the beta-amyloid peptide. Such mutations were not found in the 1500 ethnicity-matched controls.


Older news reports on these other early-onset genes (brought over from the old website):

New genetic cause of Alzheimer's disease

Amyloid protein originates when it is cut by enzymes from a larger precursor protein. In very rare cases, mutations appear in the amyloid precursor protein (APP), causing it to change shape and be cut differently. The amyloid protein that is formed now has different characteristics, causing it to begin to stick together and precipitate as amyloid plaques. A genetic study of Alzheimer's patients younger than 70 has found genetic variations in the promoter that increases the gene expression and thus the formation of the amyloid precursor protein. The higher the expression (up to 150% as in Down syndrome), the younger the patient (starting between 50 and 60 years of age). Thus, the amount of amyloid precursor protein is a genetic risk factor for Alzheimer's disease.

Theuns, J. et al. 2006. Promoter Mutations That Increase Amyloid Precursor-Protein Expression Are Associated with Alzheimer Disease. American Journal of Human Genetics, 78, 936-946.

Evidence that Alzheimer's protein switches on genes

Amyloid b-protein precursor (APP) is snipped apart by enzymes to produce three protein fragments. Two fragments remain outside the cell and one stays inside. When APP is produced in excessive quantities, one of the cleaved segments that remains outside the cell, called the amyloid b-peptides, clumps together to form amyloid plaques that kill brain cells and may lead to the development of Alzheimer’s disease. New research indicates that the short "tail" segment of APP that is trapped inside the cell might also contribute to Alzheimer’s disease, through a process called transcriptional activation - switching on genes within the cell. Researchers speculate that creation of amyloid plaque is a byproduct of a misregulation in normal APP processing.

[2866] Cao, X., & Südhof T. C. (2001).  A Transcriptively Active Complex of APP with Fe65 and Histone Acetyltransferase Tip60. Science. 293(5527), 115 - 120.

Inactivation of Alzheimer's genes in mice causes dementia and brain degeneration

Mutations in two related genes known as presenilins are the major cause of early onset, inherited forms of Alzheimer's disease, but how these mutations cause the disease has not been clear. Since presenilins are involved in the production of amyloid peptides (the major components of amyloid plaques), it was thought that such mutations might cause Alzheimer’s by increasing brain levels of amyloid peptides. Accordingly, much effort has gone into identifying compounds that could block presenilin function. Now, however, genetic engineering in mice has revealed that deletion of these genes causes memory loss and gradual death of nerve cells in the mouse brain, demonstrating that the protein products of these genes are essential for normal learning, memory and nerve cell survival.

Saura, C.A., Choi, S-Y., Beglopoulos, V., Malkani, S., Zhang, D., Shankaranarayana Rao, B.S., Chattarji, S., Kelleher, R.J.III, Kandel, E.R., Duff, K., Kirkwood, A. & Shen, J. 2004. Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration. Neuron, 42 (1), 23-36.

[2858] Consortium, E. N. I. G. M. - A.(E. N. I. G. M. A.), & Consortium C. H. A. R. G. E.(C. H. A. R. G. E.) (2012).  Common variants at 12q14 and 12q24 are associated with hippocampal volume. Nature Genetics. 44(5), 545 - 551.

[2909] Taal, R. H., Pourcain B. S., Thiering E., Das S., Mook-Kanamori D. O., Warrington N. M., et al. (2012).  Common variants at 12q15 and 12q24 are associated with infant head circumference. Nature Genetics. 44(5), 532 - 538.

[2859] Consortium, C. H. A. R. G. E.(C. H. A. R. G. E.), & Consortium E. G. G.(E. G. G.) (2012).  Common variants at 6q22 and 17q21 are associated with intracranial volume. Nature Genetics. 44(5), 539 - 544.

[2907] Stein, J. L., Medland S. E., Vasquez A. A., Hibar D. P., Senstad R. E., Winkler A. M., et al. (2012).  Identification of common variants associated with human hippocampal and intracranial volumes. Nature Genetics. 44(5), 552 - 561.

[2925] Bell, R. D., Winkler E. A., Singh I., Sagare A. P., Deane R., Wu Z., et al. (2012).  Apolipoprotein E controls cerebrovascular integrity via cyclophilin A. Nature.

Kang, J. H., & Grodstein F. (2012).  Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.

Skoog, I., Olesen P. J., Blennow K., Palmertz B., Johnson S. C., & Bigler E. D. (2012).  Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.

[2728] Cruchaga, C., Chakraverty S., Mayo K., Vallania F. L. M., Mitra R. D., Faber K., et al. (2012).  Rare Variants in APP, PSEN1 and PSEN2 Increase Risk for AD in Late-Onset Alzheimer's Disease Families. PLoS ONE. 7(2), e31039 - e31039.

Full text available at

[2897] Pottier, C., Hannequin D., Coutant S., Rovelet-Lecrux A., Wallon D., Rousseau S., et al. (2012).  High frequency of potentially pathogenic SORL1 mutations in autosomal dominant early-onset Alzheimer disease. Molecular Psychiatry.

McCarthy, J. J., Saith S., Linnertz C., Burke J. R., Hulette C. M., Welsh-Bohmer K. A., et al. (2012).  The Alzheimer's associated 5′ region of the SORL1 gene cis regulates SORL1 transcripts expression. Neurobiology of Aging. 33(7), 1485.e1-1485.e8 - 1485.e1-1485.e8

The protein associated with Alzheimer's disease appears to impair cognitive function many years before symptoms manifest. Higher levels of this protein are more likely in carriers of the Alzheimer’s gene, and such carriers may be more affected by the protein’s presence.

Another study adds to the evidence that changes in the brain that may lead eventually to Alzheimer’s begin many years before Alzheimer’s is diagnosed. The findings also add to the evidence that what we regard as “normal” age-related cognitive decline is really one end of a continuum of which the other end is dementia.

In the study, brain scans were taken of 137 highly educated people aged 30-89 (participants in the Dallas Lifespan Brain Study). The amount of amyloid-beta (characteristic of Alzheimer’s) was found to increase with age, and around a fifth of those over 60 had significantly elevated levels of the protein. These higher amounts were linked with worse performance on tests of working memory, reasoning and processing speed.

More specifically, across the whole sample, amyloid-beta levels affected processing speed and fluid intelligence (in a dose-dependent relationship — that is, as levels increased, these functions became more impaired), but not working memory, episodic memory, or crystallized intelligence. Among the elevated-levels group, increased amyloid-beta was significantly associated with poorer performance for processing speed, working memory, and fluid intelligence, but not episodic memory or crystallized intelligence. Among the group without elevated levels of the protein, increasing amyloid-beta only affected fluid intelligence.

These task differences aren’t surprising: processing speed, working memory, and fluid intelligence are the domains that show the most decline in normal aging.

Those with the Alzheimer’s gene APOE4 were significantly more likely to have elevated levels of amyloid-beta. While 38% of the group with high levels of the protein had the risky gene variant, only 15% of those who didn’t have high levels carried the gene.

Note that, while the prevalence of carriers of the gene variant matched population estimates (24%), the proportion was higher among those in the younger age group — 33% of those under 60, compared to 19.5% of those aged 60 or older. It seems likely that many older carriers have already developed MCI or Alzheimer’s, and thus been ineligible for the study.

The average age of the participants was 64, and the average years of education 16.4.

Amyloid deposits varied as a function of age and region: the precuneus, temporal cortex, anterior cingulate and posterior cingulate showed the greatest increase with age, while the dorsolateral prefrontal cortex, orbitofrontal cortex, parietal and occipital cortices showed smaller increases with age. However, when only those aged 60+ were analyzed, the effect of age was no longer significant. This is consistent with previous research, and adds to evidence that age-related cognitive impairment, including Alzheimer’s, has its roots in damage occurring earlier in life.

In another study, brain scans of 408 participants in the Mayo Clinic Study of Aging also found that higher levels of amyloid-beta were associated with poorer cognitive performance — but that this interacted with APOE status. Specifically, carriers of the Alzheimer’s gene variant were significantly more affected by having higher levels of the protein.

This may explain the inconsistent findings of previous research concerning whether or not amyloid-beta has significant effects on cognition in normal adults.

As the researchers of the first study point out, what’s needed is information on the long-term course of these brain changes, and they are planning to follow these participants.

In the meantime, all in all, the findings do provide more strength to the argument that your lifestyle in mid-life (and perhaps even younger) may have long-term consequences for your brain in old age — particularly for those with a genetic susceptibility to Alzheimer’s.

Iron-enriched baby formula improves cognitive development when infants have low iron levels, but harms development when iron levels are already high. Teenage iron levels are linked to white matter integrity in adulthood.

Iron deficiency is the world's single most common nutrient deficiency, and a well-known cause of impaired cognitive, language, and motor development. Many countries therefore routinely supplement infant foods with iron. However, a new study suggests that, while there is no doubt that such fortification has helped reduce iron deficiency, it may be that there is an optimal level of iron for infant development.

In 1992-94, 835 healthy, full-term infants living in urban areas in Chile, took part in a randomized trial to receive iron-fortified formula from 6 months of age to 12 months. A follow-up study has now assessed the cognitive functioning of 473 of these children at 10 years of age. Tests measured IQ, spatial memory, arithmetic achievement, visual-motor integration, visual perception and motor functioning.

Those who had received iron-fortified formula scored significantly lower than the non-fortified group on the spatial memory and visual-motor integration tests. Moreover, their performance on the other tests also tended to be worse, although these didn’t reach statistical significance.

There was no difference in iron level between these two groups (at age 10), and only one child had iron-deficiency anemia.

The crucial point, it seems, lies in the extent to which the infants needed additional iron. Children who had high iron levels at 6 months (5.5%, i.e. 26 infants) had lower scores at 10 years if they had received the iron-fortified formula, but those with low 6-month iron levels (18.4%; 87 infants) had higher scores at 10 years.

Further research is needed to confirm these findings, but the findings are not inconsistent with the idea that iron overload promotes neurodegenerative diseases.

In another longitudinal study, brain scans have revealed that teenage iron levels are associated with white matter fiber integrity.

The study first measured iron levels in 615 adolescent twins and siblings, and then scanned their brains when they were in their early twenties. Myelin (white matter) contains a lot of iron, so the strong correlation between teenage iron level and white matter integrity in young adulthood is not unexpected.

The correlation was stronger between identical twins that non-identical twins, suggesting a genetic contribution. Again, not unexpected — the transport of iron around the body is affected by several genes. One particular gene variant, in a gene that governs cellular absorption of transferrin-bound iron, was associated with both high iron levels and improved white matter integrity. This gene variant is found in about 12-15% of Caucasians.

The vital missing bit of information (because it wasn’t investigated) is whether this gene variant is associated with better cognitive performance. Further research will hopefully also investigate whether, while it might be better to have this variant earlier in life, it is detrimental in old age, given the suggestions that iron accumulation contributes to some neurodegenerative disorders (including Alzheimer’s).

Comparison of the brains of octogenarians whose memories match those of middle-aged people reveals important differences between their brains and those of cognitively-normal seniors.

A certain level of mental decline in the senior years is regarded as normal, but some fortunate few don’t suffer from any decline at all. The Northwestern University Super Aging Project has found seniors aged 80+ who match or better the average episodic memory performance of people in their fifties. Comparison of the brains of 12 super-agers, 10 cognitively-normal seniors of similar age, and 14 middle-aged adults (average age 58) now reveals that the brains of super-agers also look like those of the middle-aged. In contrast, brain scans of cognitively average octogenarians show significant thinning of the cortex.

The difference between the brains of super-agers and the others was particularly marked in the anterior cingulate cortex. Indeed, the super agers appeared to have a much thicker left anterior cingulate cortex than the middle-aged group as well. Moreover, the brain of a super-ager who died revealed that, although there were some plaques and tangles (characteristic, in much greater quantities, of Alzheimer’s) in the mediotemporal lobe, there were almost none in the anterior cingulate. (But note an earlier report from the researchers)

Why this region should be of special importance is somewhat mysterious, but the anterior cingulate is part of the attention network, and perhaps it is this role that underlies the superior abilities of these seniors. The anterior cingulate also plays a role error detection and motivation; it will be interesting to see if these attributes are also important.

While the precise reason for the anterior cingulate to be critical to retaining cognitive abilities might be mysterious, the lack of cortical atrophy, and the suggestion that super-agers’ brains have much reduced levels of the sort of pathological damage seen in most older brains, adds weight to the growing evidence that cognitive aging reflects clinical problems, which unfortunately are all too common.

Sadly, there are no obvious lifestyle factors involved here. The super agers don’t have a lifestyle any different from their ‘cognitively average’ counterparts. However, while genetics might be behind these people’s good fortune, that doesn’t mean that lifestyle choices don’t make a big difference to those of us not so genetically fortunate. It seems increasingly clear that for most of us, without ‘super-protective genes’, health problems largely resulting from lifestyle choices are behind much of the damage done to our brains.

It should be emphasized that these unpublished results are preliminary only. This conference presentation reported on data from only 12 of 48 subjects studied.

Harrison, T., Geula, C., Shi, J., Samimi, M., Weintraub, S., Mesulam, M. & Rogalski, E. 2011. Neuroanatomic and pathologic features of cognitive SuperAging. Presented at a poster session at the 2011 Society for Neuroscience conference.

New findings show the T variant of the KIBRA gene improves episodic memory through its effect on hippocampal activity. Another study finds the met variant of the BDNF gene is linked to greater age-related cognitive decline.

Previous research has found that carriers of the so-called KIBRA T allele have been shown to have better episodic memory than those who don’t carry that gene variant (this is a group difference; it doesn’t mean that any carrier will remember events better than any non-carrier). A large new study confirms and extends this finding.

The study involved 2,230 Swedish adults aged 35-95. Of these, 1040 did not have a T allele, 932 had one, and 258 had two.  Those who had at least one T allele performed significantly better on tests of immediate free recall of words (after hearing a list of 12 words, participants had to recall as many of them as they could, in any order; in some tests, there was a concurrent sorting task during presentation or testing).

There was no difference between those with one T allele and those with two. The effect increased with increasing age. There was no effect of gender. There was no significant effect on performance of delayed category cued recall tests or a visuospatial task, although a trend in the appropriate direction was evident.

It should also be noted that the effect on immediate recall, although statistically significant, was not large.

Brain activity was studied in a subset of this group, involving 83 adults aged 55-60, plus another 64 matched on sex, age, and performance on the scanner task. A further group of 113 65-75 year-olds were included for comparison purposes. While in the scanner, participants carried out a face-name association task. Having been presented with face-name pairs, participants were tested on their memory by being shown the faces with three letters, of which one was the initial letter of the name.

Performance on the scanner task was significantly higher for T carriers — but only for the 55-60 age group, not for the 65-75 age group. Activity in the hippocampus was significantly higher for younger T carriers during retrieval, but not encoding. No such difference was seen in the older group.

This finding is in contrast with an earlier, and much smaller, study involving 15 carriers and 15 non-carriers, which found higher activation of the hippocampus in non-T carriers. This was taken at the time to indicate some sort of compensatory activity. The present finding challenges that idea.

Although higher hippocampal activation during retrieval is generally associated with faster retrieval, the higher activity seen in T carriers was not fully accounted for by performance. It may be that such activity also reflects deeper processing.

KIBRA-T carriers were neither more nor less likely to carry other ‘memory genes’ — APOEe4; COMTval158met; BDNFval66met.

The findings, then, fail to support the idea that non-carriers engage compensatory mechanisms, but do indicate that the KIBRA-T gene helps episodic memory by improving the hippocampus function.

BDNF gene variation predicts rate of age-related decline in skilled performance

In another study, this time into the effects of the BDNF gene, performance on an airplane simulation task on three annual occasions was compared. The study involved 144 pilots, of whom all were healthy Caucasian males aged 40-69, and 55 (38%) of whom turned out to have at least one copy of a BDNF gene that contained the ‘met’ variant. This variant is less common, occurring in about one in three Asians, one in four Europeans and Americans, and about one in 200 sub-Saharan Africans.  

While performance dropped with age for both groups, the rate of decline was much steeper for those with the ‘met’ variant. Moreover, there was a significant inverse relationship between age and hippocampal size in the met carriers — and no significant correlation between age and hippocampal size in the non-met carriers.

Comparison over a longer time-period is now being undertaken.

The finding is more evidence for the value of physical exercise as you age — physical activity is known to increase BDNF levels in your brain. BDNF levels tend to decrease with age.

The met variant has been linked to higher likelihood of depression, stroke, anorexia nervosa, anxiety-related disorders, suicidal behavior and schizophrenia. It differs from the more common ‘val’ variant in having methionine rather than valine at position 66 on this gene. The BDNF gene has been remarkably conserved across evolutionary history (fish and mammalian BDNF have around 90% agreement), suggesting that mutations in this gene are not well tolerated.

A large-scale genome-wide analysis has confirmed that half the differences in intelligence between people of similar background can be attributed to genetic differences — but it’s an accumulation of hundreds of tiny differences.

There has been a lot of argument over the years concerning the role of genes in intelligence. The debate reflects the emotions involved more than the science. A lot of research has gone on, and it is indubitable that genes play a significant role. Most of the research however has come from studies involving twins and adopted children, so it is indirect evidence of genetic influence.

A new technique has now enabled researchers to directly examine 549,692 single nucleotide polymorphisms (SNPs — places where people have single-letter variations in their DNA) in each of 3511 unrelated people (aged 18-90, but mostly older adults). This analysis had produced an estimate of the size of the genetic contribution to individual differences in intelligence: 40% of the variation in crystallized intelligence and 51% of the variation in fluid intelligence. (See for a discussion of the difference)

The analysis also reveals that there is no ‘smoking gun’. Rather than looking for a handful of genes that govern intelligence, it seems that hundreds if not thousands of genes are involved, each in their own small way. That’s the trouble: each gene makes such a small contribution that no gene can be fingered as critical.

Discussions that involve genetics are always easily misunderstood. It needs to be emphasized that we are talking here about the differences between people. We are not saying that half of your IQ is down to your genes; we are saying that half the difference between you and another person (unrelated but with a similar background and education — study participants came from Scotland, England and Norway — that is, relatively homogenous populations) is due to your genes.

If the comparison was between, for example, a middle-class English person and someone from a poor Indian village, far less of any IQ difference would be due to genes. That is because the effects of environment would be so much greater.

These findings are consistent with the previous research using twins. The most important part of these findings is the confirmation it provides of something that earlier studies have hinted at: no single gene makes a significant contribution to variation in intelligence.

New genetic studies implicate myelin development, the immune system, inflammation, and lipid metabolism as critical pathways in the development of Alzheimer’s.

I commonly refer to ApoE4 as the ‘Alzheimer’s gene’, because it is the main genetic risk factor, tripling the risk for getting Alzheimer's. But it is not the only risky gene.

A mammoth genetic study has identified four new genes linked to late-onset Alzheimer's disease. The new genes are involved in inflammatory processes, lipid metabolism, and the movement of molecules within cells, pointing to three new pathways that are critically related to the disease.

Genetic analysis of more than 11,000 people with Alzheimer's and a nearly equal number of healthy older adults, plus additional data from another 32,000, has identified MS4A, CD2AP, CD33, and EPHA1 genes linked to Alzheimer’s risk, and confirmed two other genes, BIN1 and ABCA7.

A second meta-analysis of genetic data has also found another location within the MS4A gene cluster which is associated with Alzheimer's disease. Several of the 16 genes within the cluster are implicated in the activities of the immune system and are probably involved in allergies and autoimmune disease. The finding adds to evidence for a role of the immune system in the development of Alzheimer's.

Another study adds to our understanding of how one of the earlier-known gene factors works. A variant of the clusterin gene is known to increase the risk of Alzheimer’s by 16%. But unlike the ApoE4 gene, we didn’t know how, because we didn’t know what the CLU gene did. A new study has now found that the most common form of the gene, the C-allele, impairs the development of myelin.

The study involved 398 healthy adults in their twenties. Those carrying the CLU-C gene had poorer white-matter integrity in multiple brain regions. The finding is consistent with increasing evidence that degeneration of myelin in white-matter tracts is a key component of Alzheimer’s and another possible pathway to the disease. But this gene is damaging your brain (in ways only detectible on a brain scan) a good 50 years before any clinical symptoms are evident.

Moreover, this allele is present in 88% of Caucasians. So you could say it’s not so much that this gene variant is increasing your risk, as that having the other allele (T) is protective.

[2257] Naj, A. C., Jun G., Beecham G. W., Wang L. - S., Vardarajan B. N., Buros J., et al. (2011).  Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease. Nat Genet. 43(5), 436 - 441.

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at

[2254] Braskie, M. N., Jahanshad N., Stein J. L., Barysheva M., McMahon K. L., de Zubicaray G. I., et al. (2011).  Common Alzheimer's Disease Risk Variant Within the CLU Gene Affects White Matter Microstructure in Young Adults. The Journal of Neuroscience. 31(18), 6764 - 6770.

Three gene variants governing dopamine response in the prefrontal cortex and the striatum affect how likely we are to persist with inaccurate beliefs in the face of contradictory experience.

We learn from what we read and what people tell us, and we learn from our own experience. Although you would think that personal experience would easily trump other people’s advice, we in fact tend to favor abstract information against our own experience. This is seen in the way we commonly distort what we experience in ways that match what we already believe. But there is probably good reason for this tendency (reflected in confirmation bias), even if it sometimes goes wrong.

But of course individuals vary in the extent to which they persist with bad advice. A new study points to genes as a critical reason. Different brain regions are involved in the processing of these two information sources (advice vs experience): the prefrontal cortex and the striatum. Variants in the genes DARPP-32 and DRD2 affect the response to dopamine in the striatum. Variation in the gene COMT, on the other hand, affects dopamine response in the prefrontal cortex.

In the study, over 70 people performed a computerized learning task in which they had to pick the "correct" symbol, which they learned through trial and error. For some symbols, subjects were given advice, and sometimes that advice was wrong.

COMT gene variants were predictive of the degree to which participants persisted in responding in accordance with prior instructions even as evidence against their correctness grew. Variants in DARPP-32 and DRD2 predicted learning from positive and negative outcomes, and the degree to which such learning was overly inflated or neglected when outcomes were consistent or inconsistent with prior instructions.

A new study adds to growing evidence that having a mother with Alzheimer's disease is a greater risk factor than if your father suffered the disease.

A two-year study involving 53 older adults (60+) has found that those with a mother who had Alzheimer's disease had significantly more brain atrophy than those with a father or no parent with Alzheimer's disease. More specifically, they had twice as much gray matter shrinkage, and about one and a half times more whole brain shrinkage per year.

This atrophy was particularly concentrated in the precuneus and parahippocampal gyrus. Those with the APOE4 gene also had more atrophy in the frontal cortex than those who didn’t carry the ‘Alzheimer’s gene’.

This adds to evidence indicating that maternal history is a far greater risk factor for Alzheimer’s than paternal history. Eleven participants reported having a mother with Alzheimer's disease, 10 had a father with Alzheimer's disease and 32 had no family history of the disease. It has been estimated that people who have first-degree relatives with Alzheimer's disease are four to 10 times more likely to develop the disease.

Having the ‘Alzheimer’s gene’ and showing reduced brain activity during a mental task combined to correctly predict future cognitive decline in 80% of healthy elders.

In a study in which 78 healthy elders were given 5 different tests and then tested for cognitive performance 18 months later, two tests combined to correctly predict nearly 80% of those who developed significant cognitive decline. These tests were a blood test to identify presence of the ‘Alzheimer’s gene’ (APOE4), and a 5-minute fMRI imaging scan showing brain activity during mental tasks.

The gene test in itself correctly classified 61.5% of participants (aged 65-88; mean age 73), showing what a strong risk factor this is, but when taken with activity on the fMRI test, the two together correctly classified 78.9% of participants. Age, years of education, gender and family history of dementia were not accurate predictors of future cognitive decline. A smaller hippocampus was also associated with a greater risk of cognitive decline.

These two tests are readily available and not time-consuming, and may be useful in identifying those at risk of MCI and dementia.

Woodard, J.L.  et al. 2010. Prediction of Cognitive Decline in Healthy Older Adults using fMRI. Journal of Alzheimer’s Disease, 21 (3), 871-885.

A large study of very young twins confirms evidence that environment affects cognitive ability far more for those from poor homes, compared to those from better-off homes.

A study involving 750 sets of twins assessed at about 10 months and 2 years, found that at 10 months, there was no difference in how the children from different socioeconomic backgrounds performed on tests of early cognitive ability. However, by 2 years, children from high socioeconomic background scored significantly higher than those from low socioeconomic backgrounds. Among the 2-year-olds from poorer families, there was little difference between fraternal and identical twins, suggesting that genes were not the reason for the similarity in cognitive ability. However, among 2-year-olds from wealthier families, identical twins showed greater similarities in their cognitive performance than fraternal twins — genes accounted for about half of the variation in cognitive changes.

The findings are consistent with other recent research suggesting that individual differences in cognitive ability among children raised in socioeconomically advantaged homes are primarily due to genes, whereas environmental factors are more influential for children from disadvantaged homes.

While one twin study points to the common attribute of slow processing speed between those with ADHD and those with reading disabilities, another indicates a role for environment.

A twin study involving 457 pairs has found that ADHD on its own was associated with a reduced ability to inhibit responses to stimuli, while reading disabilities were associated independently with weaknesses on measures of phoneme awareness, verbal reasoning, and working memory. Both disorders were associated with a slow processing speed, and there was a significant genetic correlation between RD and ADHD.

However, just to remind us that genetics are rarely solely the answer, another twin study, involving 271 pairs of 10-year-old identical and fraternal twins, has found evidence that the associations between ADHD symptoms, reading outcomes and math outcomes are a product of both genetic and common environmental influences. The researchers speculate that such environmental influences may include aspects of the classroom and homework environment.

A small study suggests that physical activity may be of greater benefit to those carrying the Alzheimer’s gene in protecting against cognitive decline.

A study involving 68 healthy older adults (65-85) has compared brain activity among four groups, determined whether or not they carry the Alzheimer’s gene ApoE4 and whether their physical activity is reported to be high or low. The participants performed a task involving the discrimination of famous people, which engages 15 different functional regions of the brain. Among those carrying the gene, those with higher physical activity showed greater activation in many regions than those who were sedentary. Moreover, physically active people with the gene had greater brain activity than physically active people without the gene.

And adding to the evidence supporting the potential for exercise to lower the risk of dementia, another recent study has found that after ten years exercise (in terms of the number of different types of exercises performed and number of exercise sessions lasting at least 20 minutes) was inversely associated with the onset of cognitive impairment. The study used data from the National Long Term Care Survey.

A genome study has found a gene variant that leads to greater right-hand skill in dyslexics, but not others. The gene is implicated in embryonic development.

While brain laterality exists widely among animal species, the strong dominance of right-handedness in humans is something of an anomaly. As this implies a left-hemisphere dominance for motor function, it’s been suggested that the evolution of language (also mainly a function of the left hemisphere) may be behind the right-handed bias, leading to a search for a connection between hand preference and language disorders. To date, no convincing evidence has been found.

However, a genetic study of 192 dyslexic children has now revealed a strong link between a variant of a gene called PCSK6 and relative hand skill in these children. Specifically, those who carried the variant in PCSK6 were, on average, more skilled with their right hand compared to the left than those not carrying the variant. However, among the general population, this gene variant is associated with less right-hand skill.

The findings provide evidence for a link between brain lateralization and dyslexia. The gene’s protein is known to interact with another protein (NODAL) that plays a key role in establishing left-right asymmetry early in embryonic development, suggesting that the gene may affect the initial left-right patterning of the embryo, with consequences for cerebral lateralization.

An imaging study has found three different brain signatures discriminating children with autistic spectrum disorders, siblings of children with ASD, and other typically-developing children.

Last month I reported on a finding that toddlers with autism spectrum disorder showed a strong preference for looking at moving shapes rather than active people. This lower interest in people is supported by a new imaging study involving 62 children aged 4-17, of whom 25 were diagnosed with autistic spectrum disorder and 20 were siblings of children with ASD.

In the study, participants were shown point-light displays (videos created by placing lights on the major joints of a person and filming them moving in the dark). Those with ASD showed reduced activity in specific regions (right amygdala, ventromedial prefrontal cortex, right posterior superior temporal sulcus, left ventrolateral prefrontal cortex, and the fusiform gyri) when they were watching a point-light display of biological motion compared with a display of moving dots. These same regions have also been implicated in previous research with adults with ASD.

Moreover, the severity of social deficits correlated with degrees of activity in the right pSTS specifically. More surprisingly, other brain regions (left dorsolateral prefrontal cortex, right inferior temporal gyrus, and a different part of the fusiform gyri) showed reduced activity in both the siblings group and the ASD group compared to controls. The sibling group also showed signs of compensatory activity, with some regions (right posterior temporal sulcus and a different part of the ventromedial prefrontal cortex) working harder than normal.

The implications of this will be somewhat controversial, and more research will be needed to verify these findings.

[1987] Kaiser, M. D., Hudac C. M., Shultz S., Lee S. M., Cheung C., Berken A. M., et al. (2010).  Neural signatures of autism. Proceedings of the National Academy of Sciences.

Full text available at

An imaging study has revealed how one of the many genes implicated in autism is associated with an atypical pattern of connectivity between the hemispheres and within and from the frontal lobe.

Many genes have been implicated in autism; one of them is the CNTNAP2 gene. This gene (which is also implicated in specific language disorder) is most active during brain development in the frontal lobe. An imaging study involving 32 children, half of whom had autism, has revealed that regardless of their diagnosis, the children carrying the risk variant showed communication problems within and with the frontal lobe. The frontal lobe was over-connected to itself and poorly connected to the rest of the brain, particularly the back of the brain.

There were also differences in connectivity between the left and right sides of the brain — in those with the non-risk gene, communication pathways in the frontal lobe linked more strongly to the left side of the brain (which is more strongly involved in language), but in those with the risk variant, the communications pathways connected more broadly to both sides of the brain.

The findings could lead to earlier detection of autism, and new interventions to strengthen connections between the frontal lobe and left side of the brain. But it should be emphasized that the autistic spectrum disorders probably encompass a number of different genetic patterns associated with different variants of ASD.

It should also be emphasized that this gene variant, although it increases the risk of various neurodevelopmental disorders (such as specific language impairment, which has also been associated with this gene), is found among a third of the population. So the pattern of connectivity, although not ‘normal’ (i.e., the majority position), is not abnormal. It would be interesting to explore whether other, more subtle, cognitive differences correlate with this genetic difference.

Scott-Van Zeeland., A.A. et al. 2010. Altered Functional Connectivity in Frontal Lobe Circuits Is Associated with Variation in the Autism Risk Gene CNTNAP2. Science Translational Medicine, 2 (56), DOI: 10.1126/scitranslmed.3001344

Research with genetically engineered mice shows why the apoE4 gene is so strongly associated with Alzheimer’s, and points to strategies for countering its effects.

Carriers of the so-called ‘Alzheimer’s gene’ (apoE4) comprise 65% of all Alzheimer's cases. A new study helps us understand why that’s true. Genetically engineered mice reveal that apoE4 is associated with the loss of GABAergic interneurons in the hippocampus. This is consistent with low levels of GABA (produced by these neurons) typically found in Alzheimer’s brains. This loss was associated with cognitive impairment in the absence of amyloid beta accumulation, demonstrating it is an independent factor in the development of this disease.

The relationship with the other major characteristic of the Alzheimer’s brain, tau tangles, was not independent. When the mice’s tau protein was genetically eliminated, the mice stopped losing GABAergic interneurons, and did not develop cognitive deficits. Previous research has shown that suppressing tau protein can also prevent amyloid beta from causing memory deficits.

Excitingly, daily injections of pentobarbital, a compound that enhances GABA action, restored cognitive function in the mice.

The findings suggest that increasing GABA signaling and reducing tau are potential strategies to treat or prevent apoE4-related Alzheimer's disease.

It seems that prosopagnosia can be, along with perfect pitch and eidetic memory, an example of what happens when your brain can’t abstract the core concept.

‘Face-blindness’ — prosopagnosia — is a condition I find fascinating, perhaps because I myself have a touch of it (it’s now recognized that this condition represents the end of a continuum rather than being an either/or proposition). The intriguing thing about this inability to recognize faces is that, in its extreme form, it can nevertheless exist side-by-side with quite normal recognition of other objects.

Prosopagnosia that is not the result of brain damage often runs in families, and a study of three family members with this condition has revealed that in some cases at least, the inability to remember faces has to do with failing to form a mental representation that abstracts the essence of the face, sans context. That is, despite being fully able to read facial expressions, attractiveness and gender from the face (indeed one of the family members is an artist who has no trouble portraying fully detailed faces), they couldn’t cope with changes in lighting conditions and viewing angles.

I’m reminded of the phenomenon of perfect pitch, which is characterized by an inability to generalize across acoustically similar tones, so an A in a different key is a completely different note. Interestingly, like prosopagnosia, perfect pitch is now thought to be more common than has been thought (recognition of it is of course limited by the fact that some musical expertise is generally needed to reveal it). This inability to abstract or generalize is also a phenomenon of eidetic memory, and I have spoken before of the perils of this.

(Note: A fascinating account of what it is like to be face-blind, from a person with the condition, can be found at:

A large American study of middle- and high-school students has found lower academic performance in core subjects was associated with three dopamine gene variants

Analysis of DNA and lifestyle data from a representative group of 2,500 U.S. middle- and high-school students tracked from 1994 to 2008 in the National Longitudinal Study of Adolescent Health has revealed that lower academic performance was associated with three dopamine gene variants. Having more of the dopamine gene variants (three rather than one, say) was associated with a significantly lower GPA.

Moreover, each of the dopamine genes (on its own) was linked to specific deficits: there was a marginally significant negative effect on English grades for students with a specific variant in the DAT1 gene, but no apparent effect on math, history or science; a specific variant in the DRD2 gene was correlated with a markedly negative effect on grades in all four subjects; those with the deleterious DRD4 variant had significantly lower grades in English and math, but only marginally lower grades in history and science.

Precisely why these specific genes might impact academic performance isn’t known with any surety, but they have previously been linked to such factors as adolescent delinquency, working memory, intelligence and cognitive abilities, and ADHD, among others.

The discovery that the mutated NF1 gene inhibits working memory through too much GABA in the prefrontal cortex offers hope for an effective therapy for those with the most common learning disability.

Neurofibromatosis type 1 (NF1) is the most common cause of learning disabilities, caused by a mutation in a gene that makes a protein called neurofibromin. Mouse research has now revealed that these mutations are associated with higher levels of the inhibitory neurotransmitter GABA in the medial prefrontal cortex. Brain imaging in humans with NF1 similarly showed reduced activity in the prefrontal cortex when performing a working memory task, with the levels of activity correlating with task performance. It seems, therefore, that this type of learning disability is a result of too much GABA in the prefrontal cortex inhibiting the activity of working memory. Potentially they could be corrected with a drug that normalizes the excess GABA's effect. The researchers are currently studying the effect of the drug lovastatin on NF1 patients.

New evidence suggests that Down syndrome, Alzheimer's, diabetes, and cardiovascular disease, all share a common disease mechanism.

It’s been suggested before that Down syndrome and Alzheimer's are connected. Similarly, there has been evidence for connections between diabetes and Alzheimer’s, and cardiovascular disease and Alzheimer’s. Now new evidence shows that all of these share a common disease mechanism. According to animal and cell-culture studies, it seems all Alzheimer's disease patients harbor some cells with three copies of chromosome 21, known as trisomy 21, instead of the usual two. Trisomy 21 is characteristic of all the cells in people with Down syndrome. By age 30 to 40, all people with Down syndrome develop the same brain pathology seen in Alzheimer's. It now appears that amyloid protein is interfering with the microtubule transport system inside cells, essentially creating holes in the roads that move everything, including chromosomes, around inside the cells. Incorrect transportation of chromosomes when cells divide produces new cells with the wrong number of chromosomes and an abnormal assortment of genes. The beta amyloid gene is on chromosome 21; thus, having three copies produces extra beta amyloid. The damage to the microtubule network also interferes with the receptor needed to pull low-density lipoprotein (LDL — the ‘bad’ cholesterol) out of circulation, thus (probably) allowing bad cholesterol to build up (note that the ‘Alzheimer’s gene’ governs the low-density lipoprotein receptor). It is also likely that insulin receptors are unable to function properly, leading to diabetes.

Providing support for a modular concept of the brain, a twin study has found that face recognition is heritable, and that it is inherited separately from IQ.

No surprise to me (I’m hopeless at faces), but a twin study has found that face recognition is heritable, and that it is inherited separately from IQ. The findings provide support for a modular concept of the brain, suggesting that some cognitive abilities, like face recognition, are shaped by specialist genes rather than generalist genes. The study used 102 pairs of identical twins and 71 pairs of fraternal twins aged 7 to 19 from Beijing schools to calculate that 39% of the variance between individuals on a face recognition task is attributable to genetic effects. In an independent sample of 321 students, the researchers found that face recognition ability was not correlated with IQ.

Zhu, Q. et al. 2010. Heritability of the specific cognitive ability of face perception. Current Biology, 20 (2), 137-142.

A brain scanning study adds to evidence that having a mother with Alzheimer’s is a greater risk factor than having a father with Alzheimer’s.

A brain scanning study using Pittsburgh Compound B, involving 42 healthy individuals (aged 50-80), of whom 14 had mothers who developed Alzheimer's, 14 had fathers with Alzheimer's, and 14 had no family history of the disease, has found that those with a maternal history had 15% more amyloid-beta plaques than those with a paternal history, and 20% more than those with no family history. The findings add to evidence that having a mother with Alzheimer’s is a greater risk factor than having a father with Alzheimer’s. The groups did not differ in age, gender, education, or apolipoprotein E (ApoE) status.

New analysis reveals the most important factors for predicting whether amnestic-MCI would develop into Alzheimer’s within 2 years were hyperglycemia, female gender and having the Alzheimer's gene.

An analysis technique using artificial neural networks has revealed that the most important factors for predicting whether amnestic mild cognitive impairment (MCI-A) would develop into Alzheimer’s within 2 years were hyperglycemia, female gender and having the APOE4 gene (in that order). These were followed by the scores on attentional and short memory tests.

Tabaton, M. et al. 2010. Artificial Neural Networks Identify the Predictive Values of Risk Factors on the Conversion of Amnestic Mild Cognitive Impairment. Journal of Alzheimer's Disease, 19 (3), 1035-1040.

Another gene has been identified that appears to increase risk of Alzheimer’s. The gene is involved in influencing the body's levels of homocysteine (high levels are known to be a strong risk factor), and have also been implicated in coronary artery disease.

Another gene has been identified that appears to increase risk of Alzheimer’s. The gene, MTHFD1L, is located on chromosome six. Comparison of the genomes of 2,269 people with late-onset Alzheimer's disease and 3,107 people without the disease found those with a particular variation in this gene were almost twice as likely to develop Alzheimer's disease as those people without the variation. The gene is involved in influencing the body's levels of homocysteine (high levels are known to be a strong risk factor), and have also been implicated in coronary artery disease.

The results were presented at the American Academy of Neurology's 62nd Annual Meeting in Toronto, April 10–17, 2010.

A new study reveals that having the 'Alzheimer's gene' doesn't simply increase your risk of developing Alzheimer's, but affects how the brain is damaged.

A comprehensive study reveals how the ‘Alzheimer's gene’ (APOE ε4) affects the nature of the disease. It is not simply that those with the gene variant tend to be more impaired (in terms of both memory loss and brain damage) than those without. Different parts of the brain (and thus different functions) tend to be differentially affected, depending on whether the individual is a carrier of the gene or not. Carriers displayed significantly greater impairment on tests of memory retention, while noncarriers were more impaired on tests of working memory, executive control, and lexical access. Consistent with this, carriers showed greater atrophy in the mediotemporal lobe, and noncarriers greater atrophy in the frontoparietal area. The findings have implications both for diagnosis and treatment.

The role of the dopamine-regulating COMT gene in cognitive function has been the subject of debate. Now a large study of older adults has revealed that the Met variant of the COMT gene was linked to a greater decline in cognitive function. This effect was more pronounced for African-Americans.

The role of the catechol-O-methyltransferase (COMT) gene in cognitive function has been the subject of some debate. The gene, which affects dopamine, comes in two flavors: Val and Met. One recent study found no difference between healthy carriers of these two gene variants in terms of cognitive performance, but did find differences in terms of neural activity. Another found that, although the gene did not affect Alzheimer’s risk in its own, it acted synergistically with the Alzheimer’s gene variant to do so. Now an eight-year study of nearly 3000 adults in their 70s has revealed that the Met variant of the COMT gene was linked to a greater decline in cognitive function. This effect was more pronounced for African-Americans. This is interesting because it has been the Val genotype that in other research has been shown to have a detrimental effect. It seems likely that this genotype must be considered in its context (age, race, gender, and ApoE status have all been implicated in research).

A variant of a gene called the fat mass and obesity associated (FTO) gene causes people to gain weight and puts them at risk for obesity. Now a new study suggests that this gene variant is also associated with loss of brain tissue, in that, if you have this gene variant, your weight is associated with neuron loss, and if you don't, it isn’t.

A variant of a gene called the fat mass and obesity associated (FTO) gene causes people to gain weight and puts them at risk for obesity. The gene variant is found in nearly half of all people in the U.S. with European ancestry, around one-quarter of U.S. Hispanics, 15 percent of African Americans and 15 percent of Asian Americans. A new study involving 206 healthy elderly subjects from around the U.S. now suggests that this gene variant is also associated with loss of brain tissue. It’s not clear why, but the gene is highly expressed in the brain. Those with the "bad" version of the FTO gene had an average of 8% less tissue in the frontal lobes, and 12% less in the occipital lobes. The brain differences could not be directly attributed to other obesity-related factors (cholesterol levels, hypertension, or the volume of white matter hyperintensities), which didn’t vary between carriers and non-carriers. But if you have this gene variant, your weight is associated with neuron loss, and if you don't, it isn’t. The finding emphasizes the need for those with the gene to fight weight gain (and brain loss) by exercising and eating healthily.

Two studies have come out in favor of a diet rich in foods containing vitamin E to help protect against Alzheimer's disease. One study involved 815 Chicago residents age 65 and older with no initial symptoms of mental decline, who were questioned about their eating habits and followed for an average of about four years. When factors like age and education were taken into account, those eating the most vitamin E-rich foods had a lower risk of developing Alzheimer’s, provided they did not have the ApoE e4 allele. This was not true when vitamin E was taken as a supplement. Intake of vitamin C and beta carotene appeared protective, but not at a statistically significant level. The other study involved 5,395 people in the Netherlands age 55 and older who were followed for an average of six years. Those with high intakes of vitamins E and C were less likely to become afflicted with Alzheimer's, regardless of whether they had the gene variation. This association was most pronounced for current smokers, for whom beta carotene also seemed to be protective. A number of clinical trials are underway to further investigate these links.

Engelhart, M.J., Geerlings, M.I., Ruitenberg, A., van Swieten, J.C., Hofman, A., Witteman, J.C.M. & Breteler, M.M.B. 2002. Dietary Intake of Antioxidants and Risk of Alzheimer Disease. JAMA, 287, 3223-3229.
Morris, M.C., Evans, D.A., Bienias, J.L., Tangney, C.C., Bennett, D.A., Aggarwal, N., Wilson, R.S. & Scherr, P.A. 2002. Dietary Intake of Antioxidant Nutrients and the Risk of Incident Alzheimer Disease in a Biracial Community Study. JAMA, 287, 3230-3237.

Older news items (pre-2010) brought over from the old website

‘Memory gene’ impacts driving performance

People with a particular variant (“met”) of the COMT gene performed more than 20% worse on a driving test than people without it. About 30% of Americans have the variant, which limits the availability of the vital protein BDNF during activity. Previous studies have shown that in people with the variant, episodic (event) memory is poorer, and a smaller portion of the brain is stimulated when doing a task. The study involved 29 people, of whom 7 had the gene variant, driving 15 laps on a simulator that required them to learn the nuances of a track programmed to have difficult curves and turns. The test was repeated 4 days later. Those with the variant did worse on both tests than the other participants, and they remembered less the second time. However, the gene isn’t all bad — although carriers don't recover as well after a stroke, they retain their mental sharpness longer in the case of neurodegenerative disease.

[1283] McHughen, S. A., Rodriguez P. F., Kleim J. A., Kleim E. D., Crespo L. M., Procaccio V., et al. (2010).  BDNF Val66Met Polymorphism Influences Motor System Function in the Human Brain. Cereb. Cortex. 20(5), 1254 - 1262.

Two studies help explain the spacing effect

I talked about the spacing effect in my last newsletter. Now it seems we can point to the neurology that produces it. Not only that, but the study has found a way of modifying it, to improve learning. It’s a protein called SHP-2 phosphatase that controls the spacing effect by determining how long resting intervals between learning sessions need to last so that long-lasting memories can form. The discovery happened because more than 50% of those with a learning disorder called Noonan's disease have mutations in a gene called PTP11, which encodes the SHP-2 phosphatase protein. These mutations boost the activity levels of SHP-2 phosphatase, which, in genetically modified fruit flies, disturbs the spacing effect by increasing the interval before a new chemical signal can occur (it is the repeated formation and decay of these signals that produces memory). Accordingly, those with the mutation need longer periods between repetitions to establish long-term memory.

[1433] Pagani, M. R., Oishi K., Gelb B. D., & Zhong Y. (2009).  The Phosphatase SHP2 Regulates the Spacing Effect for Long-Term Memory Induction. Cell. 139(1), 186 - 198.

A study involving Aplysia (often used as a model for learning because of its simplicity and the large size of its neural connections) reveals that spaced and massed training lead to different types of memory formation. The changes at the synapses that underlie learning are controlled by the release of the neurotransmitter serotonin. Four to five spaced applications of serotonin generated long-term changes in the strength of the synapse and less activation of the enzyme Protein kinase C Apl II, leading to stronger connections between neurons. However, when the application of serotonin was continuous (as in massed learning), there was much more activation of PKC Apl II, suggesting that activation of this enzyme may block the mechanisms for generating long-term memory, while retaining mechanisms for short-term memory.

[1504] Villareal, G., Li Q., Cai D., Fink A. E., Lim T., Bougie J. K., et al. (2009).  Role of Protein Kinase C in the Induction and Maintenance of Serotonin-Dependent Enhancement of the Glutamate Response in Isolated Siphon Motor Neurons of Aplysia californica. J. Neurosci.. 29(16), 5100 - 5107.

Smart gene helps brain cells communicate

For the second time, scientists have created a smarter rat by making their brains over-express CaMKII, a protein that acts as a promoter and signaling molecule for the NR2B subunit of the NMDA receptor. Over-expressing the gene lets brain cells communicate a fraction of a second longer. The research indicates that it plays a crucial role in initiating long-term potentiation. The NR2B subunit is more common in juvenile brains; after puberty the NR2A becomes more common. This is one reason why young people tend to learn and remember better — because the NR2B keeps communication between brain cells open maybe just a hundred milliseconds longer than the NR2A. Although this genetic modification is not something that could probably be replicated in humans, it does validate NR2B as a drug target for improving memory in healthy individuals as well as those struggling with Alzheimer's or mild dementia.

[599] Wang, D., Cui Z., Zeng Q., Kuang H., Wang P. L., Tsien J. Z., et al. (2009).  Genetic Enhancement of Memory and Long-Term Potentiation but Not CA1 Long-Term Depression in NR2B Transgenic Rats. PLoS ONE. 4(10), e7486 - e7486.

Full text at

Common variation in gene linked to structural changes in the brain

Variations in the regions of the gene MECP2, previously associated with Retts Syndrome, autism, and mental retardation, has been found to be associated with changes in brain structure in both healthy individuals and patients with neurological and psychiatric disorders. The study used data from 289 healthy and psychotic subjects (the TOP study), and 655 healthy and demented patients (mostly Alzheimer's; from the ADNI study). The most significant genetic variation resulted in reduced surface area in the cortex (in particular in the cuneus, fusiform gyrus, pars triangularis), and was specific to males.

[297] Schork, N. J., Andreassen O. A., Dale A. M., Joyner A. H., J. C. R., Bloss C. S., et al. (2009).  A common MECP2 haplotype associates with reduced cortical surface area in humans in two independent populations. Proceedings of the National Academy of Sciences. 106(36), 15483 - 15488.

Genes more important for IQ as children get older

Data from six studies carried out in the US, the UK, Australia and the Netherlands, involving a total of 11,000 pairs of twins, has revealed that genes become more important for intelligence as we get older. The researchers calculated that genes accounted for some 41% of the variation in intelligence in 9 year olds, rising to 55% in 12 year olds, and 66% in 17 year olds. It was suggested that as they get older, children get better at controlling (or perhaps are allowed to have more control over) their environment, which they do in a way that accentuates their ‘natural’ abilities — bright children feed their abilities; less bright children choose activities and friends that are less challenging.

Haworth, C.M.A. et al. 2009. R Plomin The heritability of general cognitive ability increases linearly from childhood to young adulthood. Molecular Psychiatry, advance online publication 2 June 2009; doi: 10.1038/mp.2009.55

Early maternal experience can affect memory in her offspring

A study of pre-adolescent mice with a genetically-created defect in memory has found that a mere two weeks exposure to a stimulating environment resulted in a reversal of the memory defect. But most surprisingly, it was also found that this effect was passed on to the next generation, even though they had the same genetic defect and even though they had no such experience themselves, and even when they were reared by other mice (not their mothers). It’s worth emphasizing that the enrichment occurs for the mother long before she’s fertile, yet still benefits her offspring. The finding adds to many recent studies showing that genes are more malleable than we thought.

[1434] Arai, J. A., Li S., Hartley D. M., & Feig L. A. (2009).  Transgenerational Rescue of a Genetic Defect in Long-Term Potentiation and Memory Formation by Juvenile Enrichment. J. Neurosci.. 29(5), 1496 - 1502.

A gene that influences intelligence

A study involving more than 2000 people from 200 families has found a link between the gene CHRM2, that activates multiple signaling pathways in the brain involved in learning, memory and other higher brain functions, and performance IQ. Researchers found that several variations within the CHRM2 gene (which is on chromosome 7) could be correlated with slight differences in performance IQ scores, which measure a person's visual-motor coordination, logical and sequential reasoning, spatial perception and abstract problem solving skills, and when people had more than one positive variation in the gene, the improvements in performance IQ were cumulative. Intelligence is a complex attribute that results from a combination of many genetic and environmental factors, so don’t interpret this finding to mean we’ve found a gene for intelligence.

[1173] Edenberg, H., Porjesz B., Begleiter H., Hesselbrock V., Goate A., Bierut L., et al. (2007).  Association of CHRM2 with IQ: Converging Evidence for a Gene Influencing Intelligence. Behavior Genetics. 37(2), 265 - 272.

Common gene version optimizes thinking but carries a risk

On the same subject, another study has found that the most common version of DARPP-32, a gene that shapes and controls a circuit between the striatum and prefrontal cortex, optimizes information filtering by the prefrontal cortex, thus improving working memory capacity and executive control (and thus, intelligence). However, the same version was also more prevalent among people who developed schizophrenia, suggesting that a beneficial gene variant may translate into a disadvantage if the prefrontal cortex is impaired. In other words, one of the things that make humans more intelligent as a species may also make us more vulnerable to schizophrenia.

[864] Kolachana, B., Kleinman J. E., Weinberger D. R., Meyer-Lindenberg A., Straub R. E., Lipska B. K., et al. (2007).  Genetic evidence implicating DARPP-32 in human frontostriatal structure, function, and cognition. Journal of Clinical Investigation. 117(3), 672 - 682.

Genetic cause for word-finding disease

Primary Progressive Aphasia is a little-known form of dementia in which people lose the ability to express themselves and understand speech. People can begin to show symptoms of PPA as early as in their 40's and 50's. A new study has found has discovered a gene mutation in two unrelated families in which nearly all the siblings suffered from PPA. The mutations were not observed in the healthy siblings or in more than 200 controls.

[1164] Hutton, M. L., Graff-Radford N. R., Mesulam M. Marsel, Johnson N., Krefft T. A., Gass J. M., et al. (2007).  Progranulin Mutations in Primary Progressive Aphasia: The PPA1 and PPA3 Families. Arch Neurol. 64(1), 43 - 47.

Longevity gene also helps retain cognitive function

The Longevity Genes Project has studied 158 people of Ashkenazi, or Eastern European Jewish, descent who were 95 years of age or older. Those who passed a common test of mental function were two to three times more likely to have a common variant of a gene associated with longevity (the CETP gene) than those who did not. When the researchers studied another 124 Ashkenazi Jews between 75 and 85 years of age, those subjects who passed the test of mental function were five times more likely to have this gene variant than their counterparts. The gene variant makes cholesterol particles in the blood larger than normal.

[916] Barzilai, N., Atzmon G., Derby C. A., Bauman J. M., & Lipton R. B. (2006).  A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 67(12), 2170 - 2175.

'Memory gene' identified

Analysis of the human genome has revealed a gene associated with memory performance. The gene is called Kibra, and is expressed in the hippocampus. According to brain scans, people with the version of the gene related to poorer memory potential had to tax their brains harder to remember the same amount of information.

[2658] Papassotiropoulos, A., Stephan D. A., Huentelman M. J., Hoerndli F. J., Craig D. W., Pearson J. V., et al. (2006).  Common Kibra Alleles Are Associated with Human Memory Performance. Science. 314(5798), 475 - 478.

Protein found to inhibit conversion to long-term memory

In a study using genetically engineered mice, researchers have found that mice without a protein called GCN2 acquire new information that doesn’t fade as easily as it does in normal mice. After weak training on the Morris water maze, their spatial memory was enhanced, but it was impaired after more intense training. The researchers concluded that GCN2 may prevent new information from being stored in long-term memory, suggesting the conversion of new information into long-term memory requires both the activation of molecules that facilitate memory storage, and the silencing of proteins such as GCN2 that inhibit memory storage.

[949] Yoshida, M., Imataka H., Cuello C. A., Seidah N., Sossin W., Lacaille J. - C., et al. (2005).  Translational control of hippocampal synaptic plasticity and memory by the eIF2[alpha] kinase GCN2. Nature. 436(7054), 1166 - 1173.

Closing in on the genes involved in human intelligence

A genetic study claims to have identified two regions of the human genome that appear to explain variation in IQ. Previous research has suggested that between 40% and 80% of variation in human intelligence (as measured by IQ tests) can be attributed to genetic factors, but research has so far failed to identify these genes. The new study has identified specific locations on Chromosomes 2 and 6 as being highly influential in determining IQ, using data from 634 sibling pairs. The region on Chromosome 2 that shows significant links to performance IQ overlaps a region associated with autism. The region on Chromosome 6 that showed strong links with both full-scale and verbal IQ marginally overlapped a region implicated in reading disability and dyslexia.

[382] Posthuma, D., Luciano M., Geus E., Wright M., Slagboom P., Montgomery G., et al. (2005).  A Genomewide Scan for Intelligence Identifies Quantitative Trait Loci on 2q and 6p. The American Journal of Human Genetics. 77(2), 318 - 326.

Human cerebellum and cortex age in very different ways

Analysis of gene expression in five different regions of the brain's cortex has found that brain changes with aging were pronounced and consistent across the cortex, but changes in gene expression in the cerebellum were smaller and less coordinated. Researchers were surprised both by the homogeneity of aging within the cortex and by the dramatic differences between cortex and cerebellum. They also found that chimpanzees' brains age very differently from human brains; the findings cast doubt on the effectiveness of using rodents to model various types of neurodegenerative disease.

[951] Fraser, H. B., Khaitovich P., Plotkin J. B., Pääbo S., & Eisen M. B. (2005).  Aging and Gene Expression in the Primate Brain. PLoS Biol. 3(9), e274 - e274.

More light on a common developmental disorder

Chromosome 22q11.2 deletion syndrome is the most common genetic deletion syndrome, and causes symptoms such as heart defects, cleft palate, abnormal immune responses and cognitive impairments. Two related studies have recently cast more light on these cognitive impairments. Previously it was known that numerical abilities were impaired more than verbal skills. The new study found children with the chromosome deletion performed more poorly on experiments designed to test visual attention orienting, enumerating, and judging numerical magnitudes. All three tasks relate to how the children mentally represent objects and the spatial relationships among them, supporting previous arguments that such visual-spatial skills are a fundamental foundation to the later learning of counting and mathematics. The second study found that such children had changes in the shape, size and position of the corpus callosum, the main bridge between the two hemispheres.

[1139] Simon, T. J., Bearden C. E., Mc-Ginn D. M. D., & Zackai E. (2005).  Visuospatial and Numerical Cognitive Deficits in Children with Chromosome 22Q11.2 Deletion Syndrome. Cortex. 41(2), 145 - 155.

[812] Simon, T. J., Ding L., Bish J. P., McDonald-McGinn D. M., Zackai E. H., & Gee J. (2005).  Volumetric, connective, and morphologic changes in the brains of children with chromosome 22q11.2 deletion syndrome: an integrative study. NeuroImage. 25(1), 169 - 180.

Closing in on the genes involved in context learning

A study involving the worm C. elegans (whose genome has been completely sequenced) has demonstrated that even such simple animals demonstrate memory that is sensitive to context. In the study, the worms were trained in a salt medium to associate a particular smell with starvation. When placed in a different salt medium, the worms didn’t respond to the smell, but showed distaste when experiencing the smell in the context of the salt medium in which they were trained. More importantly, use of this animal has enabled the researchers to identify a genetic mutation that affects this type of memory. The next step will be to identify the specific gene involved in processing environmental cues.

[1072] Law, E., Nuttley W. M., & van der Kooy D. (2004).  Contextual Taste Cues Modulate Olfactory Learning in C. elegans by an Occasion-Setting Mechanism. Current Biology. 14(14), 1303 - 1308.

Some brains age more rapidly than others

Investigation of the patterns of gene expression in post-mortem brain tissue has revealed two groups of genes with significantly altered expression levels in the brains of older individuals. The most significantly affected were mostly those related to learning and memory. One of the most interesting, and potentially useful, findings, is that patterns of gene expression were quite similar in the brains of younger adults. Very old adults also showed similar patterns, although the similarity was less. But the greatest degree of individual variation occurred in those aged between 40 and 70. Some of these adults showed gene patterns that looked more like the young group, whereas others showed gene patterns that looked more like the old group. It appears that gene changes start around 40 in some people, but not in others. It also appears that those genes that are affected by age are unusually vulnerable to damage from agents such as free radicals and toxins in the environment, suggesting that lifestyle in young adults may play a part in deciding rate and degree of cognitive decline in later years.

[1335] Lu, T., Pan Y., Kao S. - Y., Li C., Kohane I., Chan J., et al. (2004).  Gene regulation and DNA damage in the ageing human brain. Nature. 429(6994), 883 - 891.

Could memory performance and spatial learning be genetically based?

A new rat study provides evidence that individual differences in some cognitive functions (specifically spatial navigation, in this experiment) may have a genetic basis.

[1267] Ruiz-Opazo, N., & Tonkiss J. (2004).  X-linked loci influence spatial navigation performance in Dahl rats. Physiological Genomics. 16(3), 329 - 333.

Gene essential for development of normal brain connections discovered

After birth, learning and experience change the architecture of the brain dramatically. The structure of individual neurons, or nerve cells, changes during learning to accommodate new connections between neurons. Neuroscientists believe these structural changes are initiated when neurons are activated, causing calcium ions to flow into cells and alter the activity of genes. Now the first gene, CREST, known to mediate these changes in the structure of neurons in response to calcium, has been discovered. In the study, it was found that mice lacking this gene didn’t develop normally in response to sensory experience, and their brains, while normal at birth, later showed far less interconnectivity between neurons. The gene produces a protein that, in adult humans, is produced in the hippocampus. It is therefore speculated that the protein may be necessary for learning and memory storage. The discovery of this gene may have implications for certain types of learning disorders in humans.

[915] Aizawa, H., Hu S. - C., Bobb K., Balakrishnan K., Ince G., Gurevich I., et al. (2004).  Dendrite development regulated by CREST, a calcium-regulated transcriptional activator. Science (New York, N.Y.). 303(5655), 197 - 202.

Brain protein affecting learning and memory discovered

A significant new brain protein has been identified. Cypin is found throughout the body, but in the brain it now appears that it regulates neuron branching in the hippocampus. Such branching is thought to increase when learning occurs, and a reduction in branching is associated with certain neurological diseases. Discovery of this protein opens the possibility of new drug therapies for treating neurological disorders, and perhaps even memory-enhancing drugs.

[696] Akum, B. F., Chen M., Gunderson S. I., Riefler G. M., Scerri-Hansen M. M., & Firestein B. L. (2004).  Cypin regulates dendrite patterning in hippocampal neurons by promoting microtubule assembly. Nat Neurosci. 7(2), 145 - 152.

Amphetamine helps or hinders cognitive function depending on your genes

Everyone inherits two copies of the catecho-O-methyltransferase (COMT) gene, that codes for the enzyme that metabolizes neurotransmitters like dopamine and norepinephrine. It comes in two common versions. One version, met, contains the amino acid methionine at a point in its chemical sequence where the other version, val, contains a valine. Depending on the mix of variants inherited, a person's COMT genes can be typed met/met, val/val, or val/met. People with the val/val variant appear to have reduced prefrontal dopamine activity and less efficient prefrontal information processing, along with slightly increased risk for schizophrenia. People with val/met have more efficient prefrontal function, and people with met/met the most efficient.
In a recent imaging study, 27 volunteers (10 val/val, 11 val/met, and 6 met/met) performed a variety of cognitive tasks that involved working memory and executive functioning, after taking either amphetamine or a placebo. Since amphetamine boosts dopamine activity in the prefrontal cortex, the researchers predicted that the drug would enable val/val types to boost their low level of dopamine and perform better on cognitive tasks that depend on the prefrontal cortex. On the other hand, those with met/met should be hindered by amphetamine. The study confirmed these predictions - val/val subjects on amphetamine performed comparably to met/met types in normal conditions, while met/met subjects on amphetamine performed worse than subjects with val/val types in normal conditions.
Amphetamines and other drugs that affect prefrontal dopamine systems are used to treat Attention Deficit Hyperactivity Disorder (ADHD), and other psychiatric illnesses, and some people respond better than others to these medications. About 15-20% of individuals in populations of European ancestry have the met/met COMT gene type.

[1292] Mattay, V. S., Goldberg T. E., Fera F., Hariri A. R., Tessitore A., Egan M. F., et al. (2003).  Catechol O-methyltransferase val158-met genotype and individual variation in the brain response to amphetamine. Proceedings of the National Academy of Sciences of the United States of America. 100(10), 6186 - 6191.

Gene linked to poor episodic memory

Brain derived neurotrophic factor (BDNF) plays a key role in neuron growth and survival and, it now appears, memory. We inherit two copies of the BDNF gene - one from each parent - in either of two versions. Slightly more than a third inherit at least one copy of a version nicknamed "met," which the researchers have now linked to poorer memory. Those who inherit the “met” gene appear significantly worse at remembering events that have happened to them, probably as a result of the gene’s effect on hippocampal function. Most notably, those who had two copies of the “met” gene scored only 40% on a test of episodic (event) memory, while those who had two copies of the other version scored 70%. Other types of memory did not appear to be affected. It is speculated that having the “met” gene might also increase the risk of disorders such as Alzheimer’s and Parkinson's.

[1039] Dean, M., Egan M. F., Kojima M., Callicott J. H., Goldberg T. E., Kolachana B. S., et al. (2003).  The BDNF val66met Polymorphism Affects Activity-Dependent Secretion of BDNF and Human Memory and Hippocampal Function. Cell. 112(2), 257 - 269.

Evolution of the brain

A new finding points to brain reorganization, rather than brain size, as the driver in primate brain evolution. Data from 17 anthropoid primate species (including humans) across 40 million years has found that around three quarters of differences between the brains of species of monkeys and apes are due to internal reorganization that is independent of size. The prefrontal cortex in particular appears to have played the biggest role in explaining the evolutionary changes in primate brains.

[3366] Smaers, J. B., & Soligo C. (2013).  Brain reorganization, not relative brain size, primarily characterizes anthropoid brain evolution. Proceedings of the Royal Society B: Biological Sciences. 280(1759), 

More evidence for the importance of glia, previously regarded as mere ‘support cells’ in the brain, comes from a mouse study — which also indicates the role of astrocytes in the evolution of the human brain. The study found that mice that received transplants of human glial progenitor cells learned much more quickly than normal mice.

The study follows on from recent findings that human astrocytes are very different from those found in mouse and rat brains. The study also points to one particular aspect of human astrocytes as being crucial: greater increases in the release of a cytokine called TNFa. When this was blocked, learning was reduced.

[3318] Han, X., Chen M., Wang F., Windrem M., Wang S., Shanz S., et al. (2013).  Forebrain Engraftment by Human Glial Progenitor Cells Enhances Synaptic Plasticity and Learning in Adult Mice. Cell Stem Cell. 12(3), 342 - 353.

Two recent studies comparing gene expression in the brains of human and other animals reveal a key protein for brain size and others for connectivity and regulation.

Genetic comparisons have pinpointed a specific protein as crucial for brain size, both between and within species. Another shows how genetic regulation in the frontal lobes distinguishes the human brain from that of closely related species, and points to two genes in particular as critical.

The protein determining brain size

Comparison of genome sequences from humans and other animals has revealed what may be a crucial protein in the development of the human brain. The analysis found that humans have more than 270 copies of a protein called DUF1220 — more than any other animal studied — and that the number of copies in a species seems to match how close they are to us. Chimpanzees, for example, have 125, and gorillas 99, while marmosets have only 30, and mice just one.

Moreover, comparison of humans with microcephaly and macrocephaly reveals that those with microcephaly (“small brain”) have lower numbers of this protein than normal for humans, and those with macrocephaly (“large brain”) have higher numbers. Copy numbers of the protein were also correlated with gray matter volume in humans without these brain disorders.

In other words, evidence from three lines of inquiry converge on DUF1220 copy number being associated with brain size.

Differences in gene expression and connectivity

But the development of the human brain is not only about size. The human brain is more complex, more connected, than the brains of most other animals. Another genetic analysis has been comparing gene activity in humans, chimpanzees and rhesus macaques, using post-mortem brain tissue of three regions in particular – the frontal cortex, hippocampus and striatum.

Gene expression in the frontal lobe of humans showed a striking increase in molecular complexity, with much more elaborate regulation and connection. The biggest differences occurred in the expression of human genes involved in plasticity.

One gene in particular stood out as behaving differently in the human brain. This gene — called CLOCK, for obvious reasons — is thought to be the master regulator of our body’s clocks. The finding suggests it has influence beyond this role. Interestingly, this gene is often disrupted in mood disorders such as depression and bipolar syndrome.

A second important distinction was how many more connections there were in human brains among networks that included the language genes FOXP1 and FOXP2.

In comparison to all this, gene expression in the caudate nucleus was very similar across all three species.

The findings point to the role of learning (the genes involved in plasticity) and language in driving human brain evolution. They also highlight the need to find out more about the CLOCK gene.

Chimpanzee brains don’t shrink with age as humans’ do. It may be that cognitive impairment and even dementia are our lot because we work our brains too hard for too long.

Comparison of 99 chimpanzee brains ranging from 10-51 years of age with 87 human brains ranging from 22-88 years of age has revealed that, unlike the humans, chimpanzee brains showed no sign of shrinkage with age. But the answer may be simple: we live much longer. In the wild, chimps rarely live past 45, and although human brains start shrinking as early as 25 (as soon as they reach maturity, basically!), it doesn’t become significant until around 50.

The answer suggests one reason why humans are uniquely vulnerable to Alzheimer’s disease — it’s all down to our combination of large brain and long life. There are other animals that experience some cognitive impairment and brain atrophy as they age, but nothing as extreme as that found in humans (a 10-15% decline in volume over the life-span). (Elephants and whales have the same two attributes as humans — large brains and long lives — but we lack information on how their brains change with age.)

The problem may lie in the fact that our brains use so much more energy than chimps’ (being more than three times larger than theirs) and thus produce a great deal more damaging oxidation. Over a longer life-span, this accumulates until it significantly damages the brain.

If that’s true, it reinforces the value of a diet high in antioxidants.

[2500] Sherwood, C. C., Gordon A. D., Allen J. S., Phillips K. A., Erwin J. M., Hof P. R., et al. (2011).  Aging of the cerebral cortex differs between humans and chimpanzees. Proceedings of the National Academy of Sciences. 108(32), 13029 - 13034.

High-tech X-ray scans of ancient fossil skulls have revealed that the increase in brain size that began with the first mammals was driven by improvements in smell and touch.

190-million-year-old fossil skulls of Morganucodon and Hadrocodium, two of the earliest known mammal species, has revealed that even at this early stage of mammalian evolution, mammals had larger brains than would be expected for their body size. High-resolution CT scans of the skulls have now shown that this increase in brain size can be attributed to an increase in those regions dealing with smell and touch (mammals have a uniquely well developed ability to sense touch through their fur).

Comparison of these fossils with seven fossils of early reptiles (close relatives of the first mammals), 27 other primitive mammals, and 270 living mammals, has further revealed that the size of the mammalian brain evolved in three major stages. First, an initial increase in the olfactory bulb and related areas (including the cerebellum) by 190 million years ago; then another jump in the size of these regions shortly after that time; and finally an increase in those regions that control neuromuscular coordination by integrating different senses by 65 million years ago.

It’s speculated that the initial increase in smell and touch was driven by early mammals being nocturnal — dinosaurs being active during the day.

[2301] Rowe, T. B., Macrini T. E., & Luo Z. - X. (2011).  Fossil Evidence on Origin of the Mammalian Brain. Science. 332(6032), 955 - 957.

More support for the theory that bigger brains were a response to living in social groups comes from a wide-ranging comparison of 511 mammalian species, but a comparison of wasp brains over time points to the importance of parasitism.

A comparison of the brain and body size of over 500 species of living and fossilised mammals has found that the brains of monkeys grew the most over 60 million years, followed by horses, dolphins, camels and dogs. Those with relatively bigger brains tend to live in stable social groups. The brains of more solitary mammals, such as cats, deer and rhino, grew much more slowly during the same period.

On the other hand, a new study comparing wasp brains over time has revealed that the mushroom bodies (neural clusters responsible for processing and remembering smells and sights) of parasitic wasps are consistently larger and more complex than those of nonparasitic wasps, which represent the very oldest form of wasp.

Previously, findings that social insects tend to have larger mushroom bodies than solitary ones have lead researchers to believe that the transition from solitary to social living was behind the larger brain regions. These new findings suggest that it is parasitism (which evolved 90 million years before social insects appear) that is behind the growth in size. That may be because well-developed mushroom bodies help parasitic wasps better locate hosts for their larvae.

Of course, this doesn’t rule out the possibility that sociality lead to another boost in size and complexity, and indeed the researchers suggest that these neurological developments may have been a crucial precursor for central place foraging. This behavior is widespread in this group of insects (the Aculeata), requires extensive spatial learning, and may have contributed to the various developments of social behavior. A comparison of the brains of social worker bees and those of parasitic wasps would be helpful.

New research shows that many old bees, like many older humans, have trouble replacing out-of-date knowledge with new memories.

I love cognitive studies on bees. The whole notion that those teeny-tiny brains are capable of the navigation and communication feats bees demonstrate is so wonderful. Now a new study finds that, just like us, aging bees find it hard to remember the location of a new home.

The study builds on early lab research that demonstrated that old bees find it harder to learn floral odors. In this new study, researchers trained bees to a new nest box while their former nest was closed off. Groups composed of mature and old bees were given several days in which to learn the new home location and to extinguish the bees' memory of their unusable former nest box. The new home was then disassembled, and groups of mixed-age bees were given three alternative nest locations to choose from (including the former nest box). Some old bees (those with symptoms of senescence) preferentially went to the former nest site, despite the experience that should have told them that it was unusable.

The findings demonstrate that memory problems and increasing inflexibility with age are not problems confined to mammals.

Comparison of marsupial and placental mammal brains reveals that maternal investment is a critical factor in evolving a large brain, and primates benefit from two approaches.

Analysis of the brain sizes of 197 marsupial and 457 placental mammals has found that marsupial mammals (e.g. kangaroos, possums), had relative brain sizes that are at least as big as placental mammals. Previous belief that marsupials have relatively smaller brains appears to be produced by the inclusion of the one outlier group — primates. In both placental and marsupial groups, big brains were correlated to length of maternal care (i.e. lactation). Basal metabolic rate (the energy an animal expends at rest), although correlated with brain size in placental mammals, did not correlate with marsupial brain size. Because brain tissue uses so much energy, it has been assumed that a high metabolism was a prerequisite for a big brain.

The new findings indicate that maternal investment is a more critical factor than metabolic rate. It may also be that primates have been especially advantaged by combining both methods of increasing brain size: fast growth in the womb with the help of the mother’s high metabolic rate (placental method), and slower but lengthy growth after birth with the help of extended lactation (marsupial method).

[1895] Weisbecker, V., & Goswami A. (2010).  Brain size, life history, and metabolism at the marsupial/placental dichotomy. Proceedings of the National Academy of Sciences. 107(37), 16216 - 16221.

New technology shows that the structure of the mammalian brain is not as special as we thought it was -- an area of the chicken brain shows the same structure.

For a long time, it has been assumed that mammals have different (better!) brains than other animals — partly because of the highly convoluted neocortex. Specifically, the mammalian neocortex features layers of cells (lamination) connected by radially arrayed columns of other cells, forming functional modules characterized by neuronal types and specific connections. Early studies of homologous regions in nonmammalian brains found no similar arrangement. Now new technology has revealed that a part of the chicken brain that handles auditory information is also composed of laminated layers of cells linked by narrow, radial columns of different types of cells with extensive interconnections that form microcircuits that are virtually identical to those found in the mammalian cortex. The finding suggests that the distinct structure of the mammalian neocortex has evolved from circuitry dating back at least 300 million years. The findings also indicate that mammalian and bird brains are more alike than we thought.

[1637] Wang, Y., Brzozowska-Prechtl A., & Karten H. J. (2010).  Laminar and columnar auditory cortex in avian brain. Proceedings of the National Academy of Sciences. 107(28), 12676 - 12681.

The first comparison of the brain sizes of social and non-social individuals of the same species provides more support for the social brain hypothesis (we evolved our big brains to deal with social groups).

The first comparison of the brain sizes of social and non-social individuals of the same species provides more support for the social brain hypothesis (we evolved our big brains to deal with social groups). The tropical sweat bee species, Megalopta genalis, have two sorts of queen: solitary ones, who themselves go out from the nest to forage for food, or social ones — who stay at home and sends out her daughters. Although even the social queens don't have bigger brains overall, the area associated with learning and memory (the mushroom body) was more developed in the social queens than in the solitary bees (and also the social daughters — suggesting dominance is also a factor).

Perhaps we should start thinking of language less as some specialized process and more as a particular approach to thought. A study involving native signers of American Sign Language adds to the increasing body of evidence that we process words in the same way as we do the concepts represented by the words; speaking (or reading) is, neutrally speaking, the same as doing.

Perhaps we should start thinking of language less as some specialized process and more as one approach to thought. A study involving native signers of American Sign Language (which has the helpful characteristic that subject-object relationships can be expressed in either of the two ways languages usually use: word order or inflection) has revealed that there are distinct regions of the brain that are used to process the two types of sentences: those in which word order determined the relationships between the sentence elements, and those in which inflection was providing the information. These brain regions are the ones designed to accomplish tasks that relate to the type of sentence they are trying to interpret. Word order sentences activated areas involved in working memory and lexical access, including the dorsolateral prefrontal cortex, the inferior frontal gyrus, the inferior parietal lobe, and the middle temporal gyrus. Inflectional sentences activated areas involved in building and analyzing combinatorial structure, including bilateral inferior frontal and anterior temporal regions as well as the basal ganglia and medial temporal/limbic areas. In other words, as an increasing body of evidence tells us, we process words in the same way as we do the concepts represented by the words; speaking (or reading) is, neutrally speaking, the same as doing.

[453] Newman, A. J., Supalla T., Hauser P., Newport E. L., & Bavelier D. (2010).  Dissociating neural subsystems for grammar by contrasting word order and inflection. Proceedings of the National Academy of Sciences. 107(16), 7539 - 7544.

Older news items (pre-2010) brought over from the old website

Humans aren’t the only ones to think about what they know

As we get smarter about designing experiments and working out how to ask the right questions, the gap between human and non-human cognition keeps closing. Now a rat study has found evidence that rats can think about whether they know something or not. The study involved offering rats rewards for classifying a brief tone as either short or long. A right answer led to a large food reward; a wrong one, nothing. But on some tests runs, before starting, the rats were given a chance to back out of the test, in which case they got a small reward anyway. In some of the tests, the signal lengths were very different, making the discrimination very easy. But in others the difference was a lot harder to discern. In such a case, if the rats realized they couldn’t be sure of the answer, they would be better to forego the test and get the small, but guaranteed prize. Which was what was found.

[387] Foote, A. L., & Crystal J. D. (2007).  Metacognition in the Rat. Current Biology. 17(6), 551 - 555.

Size of brain areas does matter -- but bigger isn't necessarily better

In a fascinating mouse study that overturns our simplistic notion that, when it comes to the brain, bigger is better, researchers have found that there is an optimal size for regions within the brain. The study found that if areas of the cortex involved in body sensations and motor control are either smaller or larger than normal, mice couldn’t run an obstacle course, keep from falling off a rotating rod, or perform other tactile and motor behaviors that require balance and coordination as well as mice with normal-sized areas could. It now seems that the best size in one that is best tuned to the context of the neural system within which that area functions — which is not really so surprising when you consider that every brain region acts as part of a network, in conjunction with other regions. This study builds upon a previous discovery by the same researchers, that a gene controls how the cortex in mice is divided during embryonic development into its functionally specialized areas. Different levels of the protein expressed by this gene changes the size of the sensorimotor areas of the cortex. It is known that significant variability in cortical area size exists in humans, and this may explain at least in part variability in human performance.

[334] Leingärtner, A., Thuret S., Kroll T. T., Chou S. - J., Leasure L. J., Gage F. H., et al. (2007).  Cortical area size dictates performance at modality-specific behaviors. Proceedings of the National Academy of Sciences. 104(10), 4153 - 4158.

Full text is available at

Neurons targeted by dementing illness may have evolved for complex social cognition

Special elongated nerve cells called spindle neurons, also known as Von Economo neurons (VENs), are found in two parts of the cerebral cortex known to be associated with social behavior, consciousness, and emotion (the anterior cingulate and fronto-insular cortex). They have only been found in humans and great apes, and, recently, whales. Because of this link with social behavior, and because these brain regions are targeted by frontotemporal dementia, a recent study investigated whether VENs play a role in this type of dementia that causes people to lose inhibition in social situations. Autopsies revealed that among FTD sufferers, the anterior cingulate cortex had a dramatic reduction in the number of VENs compared to controls. In contrast, Alzheimer's patients had only a small and statistically insignificant reduction.

[668] Seeley, W. W., Carlin D. A., Allman J. M., Macedo M. N., Bush C., Miller B. L., et al. (2006).  Early frontotemporal dementia targets neurons unique to apes and humans. Annals of Neurology. 60(6), 660 - 667.

A cognitive strategy shared by human infants and our great-ape kin

There are two basic strategies for remembering the location of something: either remembering the features of the item (it was a tree, a stone, etc.), or knowing the spatial placement (left, right, middle, etc.). All animal species tested so far seem to employ both strategies, but some species (e.g. fish, rats and dogs) have a preference for locational strategies, while others (e.g. toads, chickens and children) favor those which use distinctive features. A comparison of the cognitive strategies of humans, chimpanzees, bonobos, gorillas, and orangutans, has revealed that all non-human great apes and 1-year-old human infants prefer a locational strategy, even when an object strategy would be more efficient. This suggests that the common ancestor of all great apes enacted a similar strategy preference in employing spatial memory. However, 3-year-old human children in these circumstances chose the more efficient strategy.

[1007] Haun, D. B. M., Call J., Janzen G., & Levinson S. C. (2006).  Evolutionary Psychology of Spatial Representations in the Hominidae. Current Biology. 16(17), 1736 - 1740.

Genetic variations that may be key to the evolution of the human brain

It has been thought that most genetic variations between people and between species are due to small changes in the sequence of DNA lettering, but a new idea that’s becoming popular is that the number of copies of genes is an important source of variation that may be driving evolution. Comparison of the DNA sequences of humans, chimpanzees and monkeys, has now revealed that a gene that codes for a piece of protein called DUF1220 exists in 212 copies in humans, but only 37 in chimpanzees and 30 in monkeys. Mice and rats have only one. The protein is found in the heart, spleen, skeletal muscle, and small intestine, and particularly in brain regions associated with higher cognitive function.

[643] Popesco, M. C., MacLaren E. J., Hopkins J., Dumas L., Cox M., Meltesen L., et al. (2006).  Human Lineage-Specific Amplification, Selection, and Neuronal Expression of DUF1220 Domains. Science. 313(5791), 1304 - 1307.

An exploration of those 49 areas of the genome that have changed most between human and chimpanzee has revealed one area that's changed dramatically in a relatively short period of time. The gene is found only in mammals and birds, and hasn’t changed much in other animals — between a chimp and a chicken, there are only two differences in the 118 letters of DNA code that make up HAR1 (human accelerated region 1). But there are 18 differences in that one gene between human and chimp. That is a lot of change to happen in five million years. HAR1 is part of two overlapping genes -- both the rare RNA genes, not genes that code for proteins -- one of which (HAR1F) is active in nerve cells that appear early in embryonic development and play a critical role in the formation of the layered structure of the human cerebral cortex. The other also appears to be involved in cortical development.

[420] Siepel, A., Kern A. D., Dehay C., Igel H., Ares M., Vanderhaeghen P., et al. (2006).  An RNA gene expressed during cortical development evolved rapidly in humans. Nature. 443(7108), 167 - 172.

Avoiding predators may be the reason for our large brains

A study of predators in Africa and South America suggests a new theory for why we evolved big brains. Apparently predators prefer prey with smaller brains, suggesting that more smarts help you outwit your enemies. A popular theory has been that the complexities of being social pushed the increase in brain size, and it does seem that this is also a factor, but predation is probably behind this as well — living in a group protects against predators, because group mates help keep an eye out for danger. However, the study found that while predators did prefer less sociable prey, the strongest pattern was for predators to prefer prey with relatively small brains. The researchers suggest that the need for a larger brain was strengthened when our primate ancestors came down out of the trees, and entered a much more dangerous environment.

[1325] Shultz, S., & Dunbar R. I. M. (2006).  Chimpanzee and felid diet composition is influenced by prey brain size. Biology Letters. 2(4), 505 - 508.,,1835615,00.html

Bigger brains associated with domain-general intelligence

Analysis of hundreds of studies testing the cognitive abilities of non-human primates provides support for a general intelligence, and confirms that the great apes are more intelligent than monkeys and prosimians. Individual studies have always been criticized for not clearly ensuring that one species wasn’t out-performing another simply because the particular testing situation was more suited to them. However, by looking at so many varied tests, the researchers have overcome this criticism. Although there were a few cases where one species performed better than another one in one task and reversed places in a different task, overall, some species truly outperformed others. The smartest species were clearly the great apes — orangutans, chimpanzees, and gorillas. Moreover, there was no evidence that any species performed especially well within a particular paradigm, contradicting the theory that species differences in intelligence only exist for narrow, specialized skills. Instead, the results argue that some species possess a broad, domain-general type of intelligence that allows them to succeed in a variety of situations.

Deaner, R.O., van Schaik, C.P. & Johnson, V. 2006. Do some taxa have better domain-general cognition than others? A meta-analysis of nonhuman primate studies. Evolutionary Psychology, 4, 149-196.

Full-text available at

Asymmetrical brains let fish multitask

A fish study provides support for a theory that lateralized brains allow animals to better handle multiple activities, explaining why vertebrate brains evolved to function asymmetrically. The minnow study found that nonlateralized minnows were as good as those bred to be lateralized (enabling it to favor one or other eye) at catching shrimp. However, when the minnows also had to look out for a sunfish (a minnow predator), the nonlateralized minnows took nearly twice as long to catch 10 shrimp as the lateralized fish.

[737] Dadda, M., & Bisazza A. (2006).  Does brain asymmetry allow efficient performance of simultaneous tasks?. Animal Behaviour. 72(3), 523 - 529.

Primates take weather into account when searching for fruits

In recent times, a popular hypothesis for why primates, and especially humans, have more strongly developed cognitive skills than other mammals, is that they result from the need for complex social skills. There is quite a lot of support for this argument. But it is not the only possibility and a recent study has looked at an alternative: that it evolved to deal with ecological problems, such as foraging for food. Researchers followed a group of wild gray-cheeked mangabeys from dawn to dusk over 210 days in their natural rainforest habitat, obtaining an almost complete record of their foraging decisions in relation to their preferred food, figs. The findings are consistent with the idea that monkeys make foraging decisions on the basis of episodic ("event-based") memories of whether or not a tree previously carried fruit, combined with knowledge of recent and present weather conditions and a more generalized understanding of the relationship between temperature and solar radiation and the maturation rate of fruit and insect larvae.

[493] Janmaat, K., Byrne R., & Zuberbuhler K. (2006).  Primates Take Weather into Account when Searching for Fruits. Current Biology. 16(12), 1232 - 1237.

'Perception' gene tracked humanity's evolution

A gene thought to influence perception and susceptibility to drug dependence is expressed more readily in human beings than in other primates, and this difference coincides with the evolution of our species. The gene encodes prodynorphin, an opium-like protein implicated in the anticipation and experience of pain, social attachment and bonding, as well as learning and memory. Although the protein prodynorphin is identical in humans and chimps, in the gene's promoter sequence (that controls how much of the protein is expressed) some 10% is different (this compares to the overall 1 to 1.5% difference between human and chimpanzee genes). There is high genetic variation in the prodynorphin promoter among humans, but not among other primates. Variants have been tentatively linked to schizophrenia, cocaine addiction, and epilepsy. The report supports a growing consensus among evolutionary anthropologists that hominid divergence from the other great apes was fueled not by the origin of new genes, but by the quickening (or slowing) of the expression of existing genes.

[732] Rockman, M. V., Hahn M. W., Soranzo N., Zimprich F., Goldstein D. B., & Wray G. A. (2005).  Ancient and Recent Positive Selection Transformed Opioid cis-Regulation in Humans. PLoS Biol. 3(12), e387 - e387.

Full text available at

Human brains still evolving

Two genes active in the brain — Microcephalin and ASPM — have now been sequenced. Both regulate brain size. The sequencing has revealed a distinctive mutation in both genes, both of which change the protein the gene codes for. For the Microcephalin gene, the mutation is now in the brains of about 70% of humans, and half of this group carry completely identical versions of the gene, suggesting the mutation arose recently (between 60,000 and 14,000 years ago) and spread quickly through the human species due to selection pressure, rather than accumulating random changes through neutral genetic drift. The new variant of ASPM appeared in humans even more recently — somewhere between 14,000 and 500 years ago — and is already present in about a quarter of people alive today.

[381] Evans, P. D., Gilbert S. L., Mekel-Bobrov N., Vallender E. J., Anderson J. R., Vaez-Azizi L. M., et al. (2005).  Microcephalin, a Gene Regulating Brain Size, Continues to Evolve Adaptively in Humans. Science. 309(5741), 1717 - 1720.

[684] Mekel-Bobrov, N., Gilbert S. L., Evans P. D., Vallender E. J., Anderson J. R., Hudson R. R., et al. (2005).  Ongoing Adaptive Evolution of ASPM, a Brain Size Determinant in Homo sapiens. Science. 309(5741), 1720 - 1722.

New light on speech evolution in humans

A new monkey study challenges thinking that speech developed as a result of new structures that evolved in the human brain. A distinct brain region that controls jaw movements in macaque monkeys has been found in the same area and with the same anatomical characteristics as Broca's area. The discovery suggests that this area of the brain evolved originally to perform high-order control over the mouth and the jaw, and that as humans evolved this area came to control the movements necessary for speech.

[1333] Petrides, M., Cadoret G., & Mackey S. (2005).  Orofacial somatomotor responses in the macaque monkey homologue of Broca's area. Nature. 435(7046), 1235 - 1238.

Primitive brain learns faster than the "thinking" part of our brain

A study of monkeys has revealed that a primitive region of the brain known as the basal ganglia learns rules first, then “trains” the prefrontal cortex, which learns more slowly. The findings turn our thinking about how rules are learned on its head — it has been assumed that the smarter areas of our brain work things out; instead it seems that primitive brain structures might be driving even our most high-level learning.

[722] Pasupathy, A., & Miller E. K. (2005).  Different time courses of learning-related activity in the prefrontal cortex and striatum. Nature. 433(7028), 873 - 876.

Another clue to the evolution of the human brain

A new study suggests that the birth of a gene that fueled neurotransmission may have been a key advance in the evolution of the hominoid brain. GLUD2, a gene gene involved in glutamate metabolism, is found in humans and apes, but not in Old World monkeys, indicating that the gene appeared after monkeys and hominoids went their separate ways (some 23 million years ago), but before the gibbon lineage split from humans and great apes around 18 million years ago. Over time, GLUD2 acquired two amino acid changes that increased glutamate flux, possibly enhancing cognitive function in the hominoid brain.

[1277] Burki, F., & Kaessmann H. (2004).  Birth and adaptive evolution of a hominoid gene that supports high neurotransmitter flux. Nat Genet. 36(10), 1061 - 1063.

More support for social skill theory of brain evolution

Why do we have such large brains? Brains are very costly — they require a lot of energy. Gaining credence in recent years has been the idea that the advantage of our brain has been through the complex social skills it allows. Evidence supporting this has come from a study of records of primates deceiving each other for personal gain. The bigger the neocortex, it seems, the more likely a primate is to practice deception. The researchers gathered instances of deception across 18 species of primate and found no link with overall brain size, but a clear match between devious deeds and neocortex volume.

[838] Byrne, R. W., & Corp N. (2004).  Neocortex size predicts deception rate in primates.. Proceedings of the Royal Society B: Biological Sciences. 271(1549), 1693 - 1699.,12978,1250723,00.html

More complex brain may have pre-dated Homo genus

New research supports Raymond Dart’s suggestion (in 1925) that the human brain started evolving its unique characteristics much earlier than has previously been supposed. One of the differences between human and ape brains is the position of the primary visual striate cortex (PVC), an area of the brain devoted exclusively to vision. In the ape brain, this is situated further forward than it is in human brains, making the PVC larger. It has been claimed that the PVC only decreased in size once the brain had grown substantially in size – when big-brained Homo (the hominid group that includes humans) appeared around 2.4 million years ago. However, new examination of an endocast of the brain of an Australopithecus africanus (Australopithecines pre-dated Homo, and their brains were similar in size to those of chimpanzees) has found evidence of a decreased PVC. This suggests an increase in the region lying in front of the PVC - the posterior parietal cerebral cortex, which is associated in humans with a variety of complex behaviors such as the appreciation of objects and their qualities, facial recognition and social communication.

[1379] Holloway, R. L., Clarke R. J., & Tobias P. V. (2004).  Posterior lunate sulcus in Australopithecus africanus: was Dart right?. Comptes Rendus Palevol. 3(4), 287 - 293.

Gene may be key to evolution of larger human brain

Researchers have now identified a gene that appears to have played a significant role in the expansion of the human brain's cerebral cortex. The gene is called the Abnormal Spindle-Like Microcephaly Associated (ASPM) gene, and dysfunction in this gene is linked to human microcephaly — a severe reduction in the size of the cerebral cortex. Comparison of the gene sequence in humans with that of 6 other primates (progressively less related to humans) revealed that the ASPM gene showed clear evidence of changes accelerated by evolutionary pressure in the lineage leading to humans, and the acceleration was most prominent in recent human evolution after humans diverged from chimpanzees (our closest primate relative) some five million years ago. A massive population-wide genetic change in the gene seems to have occurred in the human lineage every 300,000 to 400,000 years since then, with the last such change occurring between 200,000 and 500,000 years ago. Such strong evidence of evolutionary change is most unusual. No such change was found when other (non-primate) mammals were investigated.

[1199] Evans, P. D., Anderson J. R., Vallender E. J., Gilbert S. L., Malcom C. M., Dorus S., et al. (2004).  Adaptive evolution of ASPM, a major determinant of cerebral cortical size in humans. Hum. Mol. Genet.. 13(5), 489 - 494.

Evolution of the mammalian brain

Two recent studies cast light on the evolution of the mammalian brain. A study of the brains of cetaceans, has found that that the cortex of a killer whale is dramatically more “folded” than that of an Amazon River dolphin (the deep and complex folding, or gyrification, of the cortex surface is what allows the human brain to have far more informational capacity than would be expected from its mass). The whales’ brain was particularly convoluted in the area of the corpus callosum, the main “bridge” between the hemispheres. In other comparative study of mammalian brains, it was found that the larger the brain, the larger the mean diameter of the axons. Axons were also less densely packed and more heavily myelinated. Across all species studied, fast cross-brain conduction times were maintained at 1-2 milliseconds.

Research presented at the 2003 annual meeting of the Society for Neuroscience, held November 8–12 in New Orleans, LA

Human frontal cortex not proportionately larger compared to great apes

Humans are widely considered to have a disproportionately large frontal cortex compared to other animals, and the disparity in cognitive capabilities is partly attributed to this difference. However, a comparison of the relative size of the frontal cortex in humans versus other great apes reveals that human frontal cortices are not disproportionately large in comparison to those of the great apes. The authors suggest that the human advantage may be due to differences in individual cortical areas and to a richer interconnectivity, rather than an overall size difference.

[955] Semendeferi, K., Lu A., Schenker N., & Damasio H. (2002).  Humans and great apes share a large frontal cortex. Nat Neurosci. 5(3), 272 - 276.

Living in large groups could give you a better memory

A study into the brains of songbirds found that birds living in large groups have more new neurons and probably a better memory than those living alone. Does this have relevance for humans? We don't know yet, but it has been observed that social animals such as elephants tend to have better memories than loners.

[774] Lipkind, D., Nottebohm F., Rado R., & Barnea A. (2002).  Social change affects the survival of new neurons in the forebrain of adult songbirds. Behavioural Brain Research. 133(1), 31 - 43.

Manipulating a signaling protein in a developing mouse brain caused radical changes in the cortex and may provide a clue about how the cerebral cortex changes in evolution

Using a newly developed technique, University of Chicago researchers have manipulated one of the signaling proteins in the developing mouse brain and found such manipulations cause radical changes in the cortex. Fibroblast Growth Factor 8 (FGF8), a member of a family of signaling proteins involved in forming other structures in the embryo, is normally found near the front of the developing cortex. Using a new microsurgical technique, the researchers were able to manipulate the amount and position of this signaling protein in the embryo and look for changes in the cortical pattern much later. The researchers increased the amount of the signaling protein in its normal position, decreased it by inserting a gene for a receptor able to soak up the protein, or expressed it in a new position. Each manipulation profoundly affected cortical area pattern. "Most dramatic, when a new source of the signaling protein was generated close to the back of the embryonic cortex, the whole program changed." The generation of a new cortical area by a molecular manipulation has not been seen before and may provide a clue about how the cerebral cortex changes in evolution. One way that evolution seems to generate more functionally complex brains is by adding new areas to the cortex.

[498] Fukuchi-Shimogori, T., & Grove E. A. (2001).  Neocortex Patterning by the Secreted Signaling Molecule FGF8. Science. 294(5544), 1071 - 1074.

Add comment

  • Web page addresses and e-mail addresses turn into links automatically.
  • Allowed HTML tags: <a> <em> <strong> <cite> <code> <ul> <ol> <li> <dl> <dt> <dd>
  • Lines and paragraphs break automatically.

More information about formatting options

By submitting this form, you accept the Mollom privacy policy.