Five new risk genes for Alzheimer's disease
Genetic data from more than 94,000 individuals has revealed five new risk genes for Alzheimer's disease, and confirmed 20 known others. The new genes are: IQCK, ACE, ADAM10, ADAMTS1 and WWOX.
The findings support developing evidence that groups of genes associated with specific biological processes, such as cell trafficking, lipid transport, inflammation and the immune response, are "genetic hubs" that are an important part of the disease process.
The study also suggests that variants affecting APP and amyloid beta protein processing are associated with both early-onset autosomal dominant Alzheimer's and with late onset Alzheimer's. In addition, for the first time, the study implicated a genetic link to tau binding proteins.
The findings follow on from a 2013 report.
Gene variant found that protects against Alzheimer's
A large study involving families that had a large number of resilient individuals (those who carried the APOE4 gene but remained healthy into advanced age) has found that the resilient subjects shared a variant in the RAB10 gene while those who got the disease did not share that genetic variant.
Gene linked to Alzheimer's gene affects age-related cognitive decline
TOMM40 and APOE genes are adjacent to each other on chromosome 19, and have sometimes been used as proxies for one another in genetic studies. TOMM40 has largely been thought of as a “sidekick” to ApoE4. But new research suggests it may have a stronger role.
Data from two large surveys — the U.S. Health and Retirement Study and the English Longitudinal Study of Ageing — found that verbal recall score was significantly affected by TOMM40 genotype.
The researchers examined 1.2 million gene variations across the human genome. TOMM40 was the only one with a strong link to declines in immediate recall and level of delayed recall. APOE4 also was linked but not as strongly.
To test immediate recall, an interviewer read a list of 10 nouns and then asked the participant to repeat the words back immediately. For delayed recall, the interviewer waited five minutes and then asked the participant to recall the list. Test scores ranged from 0 to 10. The average score for immediate recall was 5.7 words out of 10, and the delayed recall scoring average was 4.5 words out of 10. A large gap between the two sets of scores can signal the development of Alzheimer's or some other form of dementia.
Those who had received a likely diagnosis of dementia or a dementia-like condition were excluded from the study.
Family history of Alzheimer's may alter gene that increases risk
There have been conflicting findings about whether the gene, TOMM40 (Translocase of Outer Mitochondrial Membrane-40kD) increases the risk for Alzheimer's. A new study, however, has found that its impact on memory and dementia risk depends on two other factors: parental history of Alzheimer's, and the length of a specific section of the gene.
In the study, late middle-aged people with a family history (parent with Alzheimer’s) and longer version of the gene had twice as much memory loss up to 10 years later as someone with a family history and a short version of the gene. A similar but stronger finding was seen in a group of older adults.
Multiple genetic markers combine to estimate Alzheimer's risk
Genotype data from three very large studies has enabled researchers to construct a test that can be used to calculate any individual’s yearly risk for onset of Alzheimer's. The polygenic hazard score (PHS) is based on 31 genetic markers.
Those with the highest PHS (top 10%) were more than three times more likely to develop Alzheimer's than those with the lowest PHS, and to do so more than 10 years earlier.
In people with the high-risk version of ApoE, those ranked in the top 10% of risk on the new test got Alzheimer’s at an average age of 84 years, compared with 95 years for those ranked in the lowest 10%.
The study also demonstrates that, aside from ApoE, there are thousands of background genetic variations that each have a tiny influence on Alzheimer’s risk, but whose cumulative influence is substantial.
But note that this doesn’t tell us that it’s all about genes! Lifestyle factors are still very important in determining whether you actually get Alzheimer's.
Two Alzheimer's risk genes linked to brain atrophy
A study involving 50 older adults (50+) with no cognitive difficulties and 90 who had been diagnosed with MCI has examined the top nine genetic variants associated with Alzheimer's risk, excluding the APOe4 gene, to find which of them was associated with atrophy in the cortex and hippocampus.
Only ABCA7 and MA4A6A were associated with brain atrophy.
New gene linked to amyloid beta plaque buildup
A study involving nearly 500 individuals has found that a variant of the IL1RAP gene was associated with higher rates of amyloid plaque buildup in the brains of Alzheimer's patients and older adults at risk for the disease, and its effect on amyloid buildup was stronger than that of APOE4.
IL1RAP codes for the key immune signaling factor Interleukin-1 Receptor Accessory Protein, which plays a central role in the activity of microglia, the immune system cells that clear up waste products such as plaques and tangles.
Additionally, the IL1RAP variant was associated with:
- a lower level of microglial activity
- greater atrophy of the temporal cortex
- faster cognitive decline
- greater likelihood of progression from MCI to Alzheimer's.
(2013). Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.
Nature Genetics. 45(12), 1452 - 1458.
(2017). Linkage, whole genome sequence, and biological data implicate variants in RAB10 in Alzheimer’s disease resilience.
Genome Medicine. 9(1), 100.
(2017). Genetic variants specific to aging-related verbal memory: Insights from GWASs in a population-based cohort.
PLOS ONE. 12(8), e0182448.
(2017). AD FAMILY HISTORY MODULATES EFFECTS OF TOMM40 ‘523’ POLY-T ON MTL ATROPHY AND HYPOMETABOLISM IN PRECLINICAL AND AD COHORTS.
Alzheimer's & Dementia: The Journal of the Alzheimer's Association. 13(7), P54 - P55.
(2017). Genetic assessment of age-associated Alzheimer disease risk: Development and validation of a polygenic hazard score.
PLOS Medicine. 14(3), e1002258.
(2016). Common variants in ABCA7 and MS4A6A are associated with cortical and hippocampal atrophy.
Neurobiology of Aging. 39, 82 - 89.
(2015). GWAS of longitudinal amyloid accumulation on 18F-florbetapir PET in Alzheimer’s disease implicates microglial activation gene IL1RAP.
Brain. 138(10), 3076 - 3088.