genes

Alzheimer’s biomarkers present decades before symptoms

July, 2012
  • 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 http://www.DIANXR.org/, if they would like to be considered for inclusion in any research.

Reference: 

[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.

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Immune system may protect against Alzheimer's

July, 2012

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.

Reference: 

[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.

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Effect of blood pressure on the aging brain depends on genetics

July, 2012
  • 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.

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How exercise affects the brain, and who it benefits

June, 2012

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.

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Genes, brain size, brain atrophy, and Alzheimer’s risk

May, 2012

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.

http://www.eurekalert.org/pub_releases/2006-04/vfii-rda041906.php

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.

http://www.eurekalert.org/pub_releases/2001-07/aaft-eta070201.php

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.

http://www.eurekalert.org/pub_releases/2004-04/cp-ioa032904.php

Reference: 

[2858] Consortium, E N I G M-A(ENIGMA)., & Cohorts Heart Aging Research Genomic Epidemiology(charge)
(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] Cohorts Heart Aging Research Genomic Epidemiology,(charge), & Consortium E G G(EGG).
(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 http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039

[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

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Alzheimer's protein may impair mental function even in healthy adults

March, 2012

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.

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Genes

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.

http://www.sciencedaily.com/releases/2009/10/091028134637.htm
http://www.miller-mccune.com/news/are-you-a-bad-driver-it-may-not-be-your-fault-1577
http://www.eurekalert.org/pub_releases/2009-10/uoc--bdm102809.php

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.

http://www.eurekalert.org/pub_releases/2009-10/cshl-csi092809.php

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.

http://www.eurekalert.org/pub_releases/2009-10/mu-wow100109.php

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 http://dx.plos.org/10.1371/journal.pone.0007486

http://www.eurekalert.org/pub_releases/2009-10/mcog-sr101909.php

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., Roddey J. Cooper, 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.

http://www.eurekalert.org/pub_releases/2009-08/uoc--cvi081709.php
http://www.eurekalert.org/pub_releases/2009-08/sri-sru081809.php

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

http://www.newscientist.com/article/mg20327174.600-genes-drive-iq-more-as-kids-get-older.html

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.

http://www.physorg.com/news152905156.html
http://www.eurekalert.org/pub_releases/2009-02/rumc-wym020209.php
http://www.eurekalert.org/pub_releases/2009-02/tuhs-dyk012909.php

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.

http://www.eurekalert.org/pub_releases/2007-02/wuso-gag022607.php

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.

http://www.sciencedaily.com/releases/2007/02/070208230059.htm
http://www.eurekalert.org/pub_releases/2007-02/niom-cgv020707.php

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.

http://www.eurekalert.org/pub_releases/2007-01/nu-rdg011507.php

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.

http://tinyurl.com/yrf5s4
http://www.eurekalert.org/pub_releases/2006-12/aaon-lga121906.php

'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.

http://www.eurekalert.org/pub_releases/2006-10/ttgr-rti101906.php

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.

http://www.eurekalert.org/pub_releases/2005-08/uom-mrp082905.php

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.

http://www.qimr.edu.au/news/index.html

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.

http://www.eurekalert.org/pub_releases/2005-08/hu-hca072805.php

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 MD., & 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.

http://www.eurekalert.org/pub_releases/2005-03/chop-lbt030205.php

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.

http://www.eurekalert.org/pub_releases/2004-07/uot-eil072704.php

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.

http://www.eurekalert.org/pub_releases/2004-06/chb-dgi060204.php

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.

http://www.eurekalert.org/pub_releases/2004-02/aps-cmp020404.php

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.

http://www.eurekalert.org/pub_releases/2004-01/uoc--gef010804.php

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.

http://www.eurekalert.org/pub_releases/2004-01/rtsu-rsd011204.php
http://news.independent.co.uk/world/science_medical/story.jsp?story=482567

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.

http://www.eurekalert.org/pub_releases/2003-05/niom-gep050703.php

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.

http://www.nih.gov/news/pr/jan2003/nimh-23.htm
http://www.eurekalert.org/pub_releases/2003-01/niom-hga012203.php
http://news.bbc.co.uk/1/hi/health/2687267.stm

tags memworks: 

Intelligence

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

Aerobic fitness boosts IQ in teenage boys

Data from the 1.2 million Swedish men born between 1950 and 1976 who enlisted for mandatory military service at the age of 18 has revealed that on every measure of cognitive performance, average test scores increased according to aerobic fitness — but not muscle strength. The link was strongest for logical thinking and verbal comprehension, and the association was restricted to cardiovascular fitness. The results of the study also underline the importance of getting healthier between the ages of 15 and 18 while the brain is still changing — those who improved their cardiovascular health between 15 and 18 showed significantly greater intelligence scores than those who became less healthy over the same time period. Those who were fittest at 18 were also more likely to go to college. Although association doesn’t prove cause, the fact that the association was only with cardiovascular fitness and not strength supports a cardiovascular effect on brain function. Results from over 260,000 full-sibling pairs, over 3,000 sets of twins, and more than 1,400 sets of identical twins, also supports a causal relationship.

[1486] Åberg, M AI., Pedersen N. L., Torén K., Svartengren M., Bäckstrand B., Johnsson T., et al.
(2009).  Cardiovascular fitness is associated with cognition in young adulthood.
Proceedings of the National Academy of Sciences. 106(49), 20906 - 20911.

http://www.physorg.com/news179415275.html
http://www.telegraph.co.uk/science/science-news/6692474/Physical-health-leads-to-mental-health.html

Confidence as important as IQ in exam success

I’ve talked repeatedly about the effects of self-belief on memory and cognition. One important area in which this is true is that of academic achievement. Evidence indicates that your perceived abilities matter, just as much? more than? your actual abilities. It has been assumed that self perceived abilities, self-confidence if you will, is a product mainly of nurture. Now a new twin study provides evidence that nurture / environment may only provide half the story; the other half may lie in the genes. The study involved 1966 pairs of identical twins and 1877 pairs of fraternal twins. The next step is to tease out which of these genes are related to IQ and which to personality variables.

[1080] Greven, C. U., Harlaar N., Kovas Y., Chamorro-Premuzic T., & Plomin R.
(2009).  More Than Just IQ: School Achievement Is Predicted by Self-Perceived Abilities—But for Genetic Rather Than Environmental Reasons.
Psychological Science. 20(6), 753 - 762.

http://www.newscientist.com/article/dn17187-confidence-as-important-as-iq-in-exam-success.html

Children of older fathers perform less well in intelligence tests during infancy

Reanalysis of a dataset of over 33,000 children born between 1959 and 1965 and tested at 8 months, 4 years, and 7 years, has revealed that the older the father, the more likely the child was to have lower scores on the various tests used to measure the ability to think and reason, including concentration, learning, memory, speaking and reading skills. In contrast, the older the mother, the higher the scores of the child in the cognitive tests.

[1447] Saha, S., Barnett A. G., Foldi C., Burne T. H., Eyles D. W., Buka S. L., et al.
(2009).  Advanced Paternal Age Is Associated with Impaired Neurocognitive Outcomes during Infancy and Childhood.
PLoS Med. 6(3), e1000040 - e1000040.

Full text available at http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pmed.1000040

http://www.eurekalert.org/pub_releases/2009-03/plos-coo030309.php

Brain-training to improve working memory boosts fluid intelligence

General intelligence is often separated into "fluid" and "crystalline" components, of which fluid intelligence is considered more reflective of “pure” intelligence (for more on this, see my article), and largely resistant to training and learning effects. However, in a new study in which participants were given a series of training exercises designed to improve their working memory, fluid intelligence was found to have significantly improved, with the amount of improvement increasing with time spent training. The small study contradicts decades of research showing that improving on one kind of cognitive task does not improve performance on other kinds, so has been regarded with some skepticism by other researchers. More research is definitely needed, but the memory task did differ from previous studies, engaging executive functions such as those that inhibit irrelevant items, monitor performance, manage two tasks simultaneously, and update memory.

[1183] Jaeggi, S. M., Buschkuehl M., Jonides J., & Perrig W. J.
(2008).  From the Cover: Improving fluid intelligence with training on working memory.
Proceedings of the National Academy of Sciences. 105(19), 6829 - 6833.

http://www.physorg.com/news128699895.html
http://www.sciam.com/article.cfm?id=study-shows-brain-power-can-be-bolstered

Effect of schooling on achievement gaps within racial groups

Analysis of data from a national sample (U.S.) of 8,060 students, collected at four points in time, starting in kindergarten and ending in the spring of fifth grade, has found evidence that education has an impact in closing the achievement gap for substantial numbers of children. High-performing groups in reading were found among all races. About 30% of European Americans, 26% of African Americans and 45% of Asian Americans were in high-achieving groups by the spring of fifth grade — these groups included approximately 23% of African American children and 36% of Asian children who caught up with the initial group of high achievers over time. Only around 4% of European American students were in catch-up groups, because a higher percentage of European Americans started kindergarten as high achievers in reading. The situation was different for Hispanic students, however.  By the end of fifth grade, just over 5% of Hispanic children were high achievers in reading, while the remainder tested in the middle range. There were no low achievers and no catch-up groups. A different pattern was found in math. Only 17% of European American students were high-achievers in math by the end of fifth grade, including 13% who started kindergarten at a lower achievement level and caught up over time.  About 18% of Asian Americans were high-achievers at the end of fifth grade (11% catch-up). Only 0.3% of African Americans were high achievers at the end of fifth grade, and 26% were medium-high achievers. But about 16% of Hispanics were high achievers in math. There were no catch-up groups for either the African Americans or the Hispanics. This suggests that current schooling doesn't have as strong an impact on math achievement as it does in reading.

The study was presented in Washington, D.C. at the 2008 annual meeting of the Society for Research on Educational Effectiveness.

http://www.physorg.com/news123859991.html

Autism non-verbal not unintelligent

New findings suggest that the association of autism with low intelligence is a product of their language difficulties. Testing autistic kids and normal kids on two popular IQ tests — the WISC (which relies heavily on language) and Raven's Progressive Matrices (considered the best test of "fluid intelligence", and a test that doesn't require much language) found that while not a single autistic child scored in the "high intelligence" range of the WISC, a third did on the Raven's. A third of the autistics had WISC scores in the mentally retarded range, but only one in 20 scored that low on the Raven's test. The non-autistic children scored similarly on both tests. The same results occurred when the experiment was run on autistic and normal adults.

[580] Dawson, M., Soulières I., Gernsbacher M A., & Mottron L.
(2007).  The level and nature of autistic intelligence.
Psychological Science: A Journal of the American Psychological Society / APS. 18(8), 657 - 662.

http://www.physorg.com/news105376203.html
http://www.eurekalert.org/pub_releases/2007-08/afps-tmo080307.php

Being treated as oldest linked to IQ

The question of whether there is an IQ advantage to being the first-born has long been debated. Now analysis of IQ test results of 241,310 Norwegians drafted into the armed forces between 1967 and 1976 has revealed that the average IQ of first-born men was 103.2 while second-born men averaged 101.2 and third-borns, 100.0. However, second-born men whose older sibling died in infancy scored 102.9, and if both older siblings died young, the third-born score rose to 102.6. This suggests the advantage lies in the social rank in the family and not birth order as such.

[589] Kristensen, P., & Bjerkedal T.
(2007).  Explaining the Relation Between Birth Order and Intelligence.
Science. 316(5832), 1717 - 1717.

http://www.nature.com/news/2007/070618/full/070618-14.html

Executive function as important as IQ for math success

A study of 141 preschoolers from low-income homes has found that a child whose IQ and executive functioning were both above average was three times more likely to succeed in math than a child who simply had a high IQ. The parts of executive function that appear to be particularly linked to math ability in preschoolers are working memory and inhibitory control. In this context, working memory may be thought of as the ability to keep information or rules in mind while performing mental tasks. Inhibitory control is the ability to halt automatic impulses and focus on the problem at hand. Inhibitory control was also important for reading ability. The finding offers the hope that training to improve executive function will improve academic performance.

[1256] Blair, C., & Razza R P.
(2007).  Relating Effortful Control, Executive Function, and False Belief Understanding to Emerging Math and Literacy Ability in Kindergarten.
Child Development. 78(2), 647 - 663.

http://www.sciam.com/article.cfm?articleID=90377FAE-E7F2-99DF-3A1204FC5F2BF0F7

Students who believe intelligence can be developed perform better

Research with 12-year-olds has found that, although all students began the study with equivalent achievement levels in math, over a two year period, those who believed that intelligence was malleable increasingly did better than those who believed their intelligence was fixed. Another study found that, when students showing declines in their math grades were taught that intelligence could be increased, they reversed their decline and showed significantly higher math grades than others who weren’t taught that.

[1123] Blackwell, L. S., Trzesniewski K. H., & Dweck C S.
(2007).  Implicit Theories of Intelligence Predict Achievement across an Adolescent Transition: A Longitudinal Study and an Intervention.
Child Development. 78(1), 246 - 263.

http://www.eurekalert.org/pub_releases/2007-02/sfri-swb013107.php

Implicit stereotypes and gender identification may affect female math performance

Relatedly, another study has come out showing that women enrolled in an introductory calculus course who possessed strong implicit gender stereotypes, (for example, automatically associating "male" more than "female" with math ability and math professions) and were likely to identify themselves as feminine, performed worse relative to their female counterparts who did not possess such stereotypes and who were less likely to identify with traditionally female characteristics. Strikingly, a majority of the women participating in the study explicitly expressed disagreement with the idea that men have superior math ability, suggesting that even when consciously disavowing stereotypes, female math students are still susceptible to negative perceptions of their ability.

[969] Kiefer, A. K., & Sekaquaptewa D.
(2007).  Implicit stereotypes, gender identification, and math-related outcomes: a prospective study of female college students.
Psychological Science: A Journal of the American Psychological Society / APS. 18(1), 13 - 18.

http://www.eurekalert.org/pub_releases/2007-01/afps-isa012407.php

Reducing the racial achievement gap

And staying with the same theme, a study that came out six months ago, and recently reviewed on the excellent new Scientific American Mind Matters blog, revealed that a single, 15-minute intervention erased almost half the racial achievement gap between African American and white students. The intervention involved writing a brief paragraph about which value, from a list of values, was most important to them and why. The intervention improved subsequent academic performance for some 70% of the African American students, but none of the Caucasians. The study was repeated the following year with the same results. It is thought that the effect of the intervention was to protect against the negative stereotypes regarding the intelligence and academic capabilities of African Americans.

[1082] Cohen, G. L., Garcia J., Apfel N., & Master A.
(2006).  Reducing the Racial Achievement Gap: A Social-Psychological Intervention.
Science. 313(5791), 1307 - 1310.

Fitness and childhood IQ indicators of cognitive ability in old age

Data from the Scottish Mental Survey of 1932 has revealed that physical fitness contributed more than 3% of the differences in cognitive ability in old age. The study involved 460 men and women, who were tested using the same cognitive test at age 79 that they had undergone at age 11. Physical fitness was defined by time to walk six meters, grip strength and lung function. Childhood IQ was also significantly related to lung function at age 79, perhaps because people with higher intelligence might respond more favorably to health messages about staying fit. But physical fitness was more important for cognitive ability in old age than childhood IQ. People in more professional occupations and with more education also had better fitness and higher cognitive test scores at 79.

[770] Deary, I. J., Whalley L. J., Batty D. G., & Starr J. M.
(2006).  Physical fitness and lifetime cognitive change.
Neurology. 67(7), 1195 - 1200.

http://www.eurekalert.org/pub_releases/2006-10/aaon-fac100306.php

Black-white IQ gap has narrowed

Data now available suggests that Black Americans have gained an average of .18 IQ points a year on White Americans from 1972 to 2002 for a total gain of 5.4 IQ points.

[929] Dickens, W. T., & Flynn J. R.
(2006).  Black Americans reduce the racial IQ gap: evidence from standardization samples.
Psychological Science: A Journal of the American Psychological Society / APS. 17(10), 913 - 920.

http://www.eurekalert.org/pub_releases/2006-09/afps-big091206.php

Does IQ drop with age or does something else impact intelligence?

As people grow older, their IQ scores drop. But is it really that they lose intelligence? A study has found that if college students had to perform under conditions that mimic the perception deficits many older people have, their IQ scores would also take a drop.

[234] Gilmore, G. C., Spinks R. A., & Thomas C. W.
(2006).  Age effects in coding tasks: componential analysis and test of the sensory deficit hypothesis.
Psychology and Aging. 21(1), 7 - 18.

http://www.eurekalert.org/pub_releases/2006-05/cwru-did050106.php

Smarter kids may live longer

A prospective study that recruited 897 individuals who scored 135 or higher on the Stanford-Binet IQ test in 1922 has found that higher IQs were associated with longevity, with the survival advantage leveling off after a childhood IQ of 163. The association was independent of childhood social position (as measured by father’s occupation). The study confirms earlier research suggesting an association between IQ and mortality, and provides the new finding of where the cut-off point (when high IQ no longer brought additional health benefits) appears — the cutoff of 163 was much higher than expected. Suggested reasons for the association (all of which may well be valid) include: greater tendency to adopt healthy habits and avoid bad ones; increased probability of better jobs; better skills for managing their health and the health-care system.

[690] Martin, L. T., & Kubzansky L. D.
(2005).  Childhood Cognitive Performance and Risk of Mortality: A Prospective Cohort Study of Gifted Individuals.
Am. J. Epidemiol.. 162(9), 887 - 890.

http://health.yahoo.com/news/126478

Growing up in a chaotic home may impair child's cognitive development

An association between disorganized, noisy and cramped homes and lower childhood intelligence has been observed before, but the reasons for the association have never been clear. Now a study of some 8000 3- and 4-year-old twins has perhaps disentangled the variables, and has found that chaos had an influence on cognitive skills independent of socioeconomic status. The findings also suggest that when the environment is more stressful, intelligence is more likely to be constrained by genes.

[570] Petrill, S. A., Pike A., Price T., & Plomin R.
(Submitted).  Chaos in the home and socioeconomic status are associated with cognitive development in early childhood: Environmental mediators identified in a genetic design.
Intelligence. 32(5), 445 - 460.

http://www.newscientist.com/news/news.jsp?id=ns99996323

Early music instruction raises child’s IQ

A new study confirms earlier research supporting the benefits of early music instruction. The study involved 144 children, 6 years old at the start of the study. They were given free weekly voice or piano lessons at the Royal Conservatory of Music. Another group of 6-year-olds was given free training in weekly drama classes, while a fourth group received no extra classes during the study period. Before any classes were given, all the children were tested using the full Weschler intelligence test. At the end of the school year (their first school year), the children were retested. All had an IQ increase of at least 4.3 points on average (a consequence of going to school). Children who took drama lessons scored no higher than those who had no extra lessons, but those who took music lessons scored on average 2.7 points higher than the children who did not take music lessons. Those in the drama group did however show substantial improvement in adaptive social behavior.

[1009] Schellenberg, E. Glenn
(2004).  Music lessons enhance IQ.
Psychological Science: A Journal of the American Psychological Society / APS. 15(8), 511 - 514.

http://www.sciencentral.com/articles/view.htm3?article_id=218392326

Knowledge-based IQ test predicts work performance as well as school

A meta-analysis of 127 studies supports the view that the Miller Analogies Test (MAT) — a knowledge-based test used for admissions decisions into U.S. graduate schools as well as in hiring and promotion decisions in the workplace since 1926 — is predictive of performance in both the academic and workplace environments. Specifically, MAT was a valid predictor of seven of the eight measures of graduate student performance, five of the six school-to-work transition performance criteria, and all four of the work performance criteria. MAT is assumed to measure “g”, the oft-debated “general intelligence” factor.

[1109] Kuncel, N. R., Hezlett S. A., & Ones D. S.
(2004).  Academic Performance, Career Potential, Creativity, and Job Performance: Can One Construct Predict Them All?.
Journal of Personality and Social Psychology. 86(1), 148 - 161.

Support for "general intelligence" factor

Researchers into intelligence and memory have always concentrated on verbal abilities — for the good reason that they are considerably easier to test. New research suggests that strong visuospatial skills and working memory may be at least as good as verbal skills and working memory as indicators of general intelligence. The study, involving 167 subjects, found a clear relationship between being good at complex visuospatial tasks, and being good at tasks involving the so-called “central executive” (which coordinates tasks, sets goals, etc). The study lends support both to the view that intelligence has both discrete components and a general aspect, and that this “general intelligence” may be related to executive functioning.

[1152] Miyake, A., Friedman N. P., Rettinger D. A., Shah P., & Hegarty M.
(2001).  How are visuospatial working memory, executive functioning, and spatial abilities related? A latent-variable analysis.
Journal of Experimental Psychology. General. 130(4), 621 - 640.

http://www.eurekalert.org/pub_releases/2001-12/apa-npo121001.php

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For the brain, iron levels may need to be just right

January, 2012

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).

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Why a select group of seniors retain their cognitive abilities

December, 2011
  • 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.

Reference: 

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.

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