genes

Memory genes vary in protecting against age-related cognitive decline

November, 2011

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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Many genes are behind human intelligence

August, 2011

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

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

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

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Discovery of more risky genes reveals more about the paths to Alzheimer’s

June, 2011

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

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

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

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

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

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

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

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

Reference: 

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

Antunez, C. et al. 2011. The membrane-spanning 4-domains, subfamily A (MS4A) gene cluster contains a common variant associated with Alzheimer's disease. Genome Medicine,  3:33 doi:10.1186/gm249
Full text available at http://genomemedicine.com/content/3/5/33/abstract

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

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Advice vs. experience: Genes predict learning style

May, 2011

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

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

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

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

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

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More evidence that Alzheimer's disease may be inherited from your mother

March, 2011
  • A new study adds to growing evidence that having a mother with Alzheimer's disease is a greater risk factor than if your father suffered the disease.

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

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

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

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Poverty suppresses children's genetic potential

January, 2011

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

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

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

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Twin studies shed light on relationship among ADHD, reading, math

January, 2011

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

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

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

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Importance of exercise for Alzheimer's gene carriers

January, 2011

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

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

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

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Link between handedness and dyslexia

January, 2011

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

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

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

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

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Children with autism have distinctive patterns of brain activity

December, 2010

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

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

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

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

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

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

Full text available at http://www.pnas.org/content/early/2010/11/05/1010412107.full.pdf+html

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