Latest Research News
Data from 1,215 older adults, of whom 173 (14%) were African-American, has found that, although brain scans showed no significant differences between black and white participants, cerebrospinal fluid (CSF) showed significantly lower levels of the brain protein tau in African-Americans.
While both groups showed the same (expected) pattern of higher tau levels being associated with greater chance of cognitive impairment, the absolute amounts of tau protein were consistently lower in African-Americans.
However, when APOE status was taken into account, it was found that those who held the low-risk variants of the “Alzheimer’s gene” had similar levels of tau, regardless of race. It was only African-Americans with the APOE4 gene variant that showed lower levels of tau.
This suggests that the APOE4 risk factor has different effects in African-Americans compared to non-Hispanic white Americans, and points to the need for more investigation into how Alzheimer’s develops in various populations.
Interestingly, another study, using data from 1798 patients (of whom 1690 were white), found that there was a strong gender difference in the association between APOE status and tau levels in the CSF.
Previous research has shown that the link between APOE4 and Alzheimer's is stronger in women than men. This study points to a connection with tau levels, as there was no gender difference in the association between APOE and amyloid-beta levels, amyloid plaques, or tau tangles.
Morris JC, Schindler SE, McCue LM, et al. Assessment of Racial Disparities in Biomarkers for Alzheimer Disease. JAMA Neurol. Published online January 07, 2019. doi:10.1001/jamaneurol.2018.4249
Understanding a protein's role in familial Alzheimer's disease
Genetic engineering of human induced pluripotent stem cells has revealed very specifically how a key mutated protein is involved in familial Alzheimer's. Familial Alzheimer’s is a subset of early-onset Alzheimer's disease that is caused by inherited gene mutations.
The study looked at presenilin 1 (PS1), a protein that catalyzes gamma-secretase, an enzyme that splits amyloid precursor protein (APP), creating amyloid-beta. About 20% of the time, these cuts result in potentially harmful amyloid-beta fragments. What this study has found is that mutations in PS1 double the frequency of these bad cuts. Such PS1 mutations are the most common cause of familial Alzheimer’s disease.
Rare genomic mutations linked to familial Alzheimer's
Mutations in three genes – amyloid precursor protein (APP) and presenilins 1 and 2 – account for around half of all cases of early-onset familial Alzheimer's. A new study has now implicated 10 copy-number variants (duplications or deletions creating a change in the number of copies of a gene), which were found in affected members of 10 families with early-onset Alzheimer's. Notably, different genomic changes were identified in each family.
Genetic data from 261 families with at least one member who developed Alzheimer's before the age of 65 found that two families had CNVs that included the well-established APP gene, but 10 others had CNVs not previously associated with Alzheimer's (although two, CHMP2B and MAPT, have been associated with frontotemporal dementia).
CNVs are now thought to have a greater impact on genomic diversity than do single-nucleotide changes (single-nucleotide polymorphisms, SNPs, are the most common type of genetic variation, involving a change in a single nucleotide: A, G, T, C).
A brain imaging study of 162 healthy babies (2-25 months) has found that those who carried the ApoE4 gene (60 of the 162) tended to have increased brain growth in areas in the frontal lobe, and decreased growth in several areas in the middle and rear of the brain (precuneus, posterior/middle cingulate, lateral temporal, and medial occipitotemporal regions) — areas that tend to be affected in Alzheimer’s disease.
While this does not mean that those children are destined to develop Alzheimer’s, the findings do suggest brains of ApoE4 carriers tend to develop differently from those of non-carriers, and perhaps these early changes provide a “foothold” for the development of Alzheimer’s pathologies.
A gene linked to Alzheimer's has been linked to brain changes in childhood. This gene, SORL1, has two connections to Alzheimer’s: it carries the code for the sortilin-like receptor, which is involved in recycling some molecules before they develop into amyloid-beta; it is also involved in lipid metabolism, putting it at the heart of the vascular risk pathway.
Brain imaging of 186 healthy individuals (aged 8-86) found that, even among the youngest, those with a specific variant of SORL1 showed a reduction in white matter connections. Post-mortem brain tissue from 269 individuals (aged 0-92) without Alzheimer's disease, found that the same SORL1 variant was linked to a disruption in the process by which the gene translated its code to become the sortilin-like receptor, and this was most prominent during childhood and adolescence. Another set of post-mortem brains from 710 individuals (aged 66-108), of whom the majority had mild cognitive impairment or Alzheimer's, found that the SORL1 risk gene was linked with the presence of amyloid-beta.
It may be that, for those carrying this gene variant, lifestyle interventions may be of greatest value early in life.
Analysis of data from more than 8,000 people, most of them older than 60, has revealed that, among the 5,000 people initially tested cognitively normal, carrying one copy of the “Alzheimer’s gene” (ApoE4) only slightly increased men’s risk of developing MCI or Alzheimer’s — but nearly doubled women’s risk (healthy men with APOE4 were 27% more likely to develop MCI or Alzheimer’s compared to those without the gene, while female carriers had an 81% greater risk).
Among the 2,200 who were initially diagnosed with mild cognitive impairment, women were more likely to progress to Alzheimer’s (116% greater risk vs 64% for men), but the difference wasn’t significant. However, it was significant when only comparing carriers of 2 copies of the common ApoE3 variant with carriers of one ApoE3 copy and one ApoE4 copy (there are three variants of the ApoE gene: E3 is the most common; E4 is the ‘bad’ one; E2 is actually protective). Analysis of imaging and biomarker data from 1,000 patients confirmed the gender difference.
A gender difference was first suggested in a 1997 paper, but the research had never been followed up until recently. The current study was preceded by a 2012 imaging study, that found that female ApoE4 carriers had brain connectivity significantly different from normal, while male carriers’ brains were little different than normal.
While it’s not known why there should be such differences, biomarkers suggested that the increased female risk has something to do with tau pathology. Previous research has also indicated that ApoE4 interacts with estrogen.
The finding suggests why Alzheimer’s is so much more common in women — not just because they tend to live longer, but because they are, indeed, more at risk. It also tells us that research referencing the ApoE gene should separate by gender.
Analysis of 700 subjects from the Alzheimer's Disease Neuroimaging Initiative has revealed a genetic mutation (rs4728029) that’s associated with people who develop Alzheimer’s pathology but don’t show clinical symptoms in their lifetime. The gene appears to be related to an inflammatory response in the presence of phosphorylated tau. In other words, some people’s brains react to phosphorylated tau with a ‘bad’ inflammatory response, while others don’t.
A new discovery helps explain why the “Alzheimer’s gene” ApoE4 is such a risk factor. It appears that ApoE4 causes a dramatic reduction in SirT1, an "anti-aging protein" that is targeted by resveratrol (present in red wine). This reduction in SirT1 was associated with a change in the way the amyloid precursor protein (APP) was processed. Moreover, there was evidence that ‘bad’ tau and amyloid-beta could be prevented by increasing SirT1.
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%).
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Postmenopausal hormone therapy, timing of initiation, APOE and cognitive decline. Neurobiology of Aging. 33(7), 1129 - 1137.(2012).
Head size may modify the impact of white matter lesions on dementia. Neurobiology of Aging. 33(7), 1186 - 1193.(2012).
Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0031039
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(2012).
Why ‘Alzheimer’s gene’ increases Alzheimer’s risk: http://www.futurity.org/health-medicine/alzheimers-gene-opens-floodgate-in-brain/
More genes involved in Alzheimer’s: Full text available at http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0015918
Same genes linked to early- and late-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-02/wuso-sgl020112.php
Another gene identified in early-onset Alzheimer's: http://www.eurekalert.org/pub_releases/2012-04/ind-ang040412.php
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 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).
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.
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.
Full text is available at http://www.nature.com/tp/journal/v1/n10/full/tp201147a.html
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 http://www.memory-key.com/memory/individual/wm-intelligence 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.
http://www.edweek.org/ew/articles/2011/08/09/446822_ap.html (registration required)
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.
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 http://genomemedicine.com/content/3/5/33/abstract
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 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.
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.
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 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.
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.
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.
Full text available at http://www.pnas.org/content/early/2010/11/05/1010412107.full.pdf+html
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 http://stm.sciencemag.org/content/2/56/56ra80.abstract
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.
‘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: http://www.choisser.com/faceblind/)
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.
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.
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.
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 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.
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, 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 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 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. 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.
Full text is available at http://www.pnas.org/content/107/18/8404.abstract?sid=d95d84c7-f052-4d50-...
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.
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.
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.
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.
Full text at http://dx.plos.org/10.1371/journal.pone.0007486
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.
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.
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.
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.
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.
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.
'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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.