Alzheimer Markers Detected in Healthy Individuals with Genetic AD Risk
The effects of aggregate genetic AD risk are detectable before symptoms appear, even early in life.
Heritability estimates for sporadic Alzheimer disease (AD) are over 60%. Along with the APOE (apolipoprotein E) gene, meta-analyses of genome-wide association studies (GWAS) have linked 21 common genetic variants with the disease. Their effect sizes are small, however, and recent findings suggest that “numerous additional loci distributed throughout the genome explain a much larger portion of the variance than the select few that surpass GWAS-level significance thresholds,” wrote the authors of a new study published in Neurology.
Additionally, while β-amyloid accumulation is likely a key event in AD pathogenesis, growing evidence further implicates nonamyloid mechanisms–including those involved in immune and cytoskeletal function–in common AD genetic risk loci. This suggests that “genetic variants influence AD markers early in the lifespan, before amyloid accumulation has begun,” they stated, which could later prove to be useful in the early identification of at-risk individuals before the onset of symptoms.
Researchers at Harvard Medical School and Yale University used data from 2 large observational cohort studies to explore links between AD markers and aggregate genetic risk in the preclinical stages of dementia. They used statistics from the International Genomics of Alzheimer's Project genome-wide association study to calculate polygenic risk scores (PGRS) of older participants who were clinically normal, those who had mild cognitive impairment (MCI), and those who had AD dementia. In addition, they computed PGRS of younger, healthy participants aged 18-35. In the older group, they then examined associations between PGRS and AD markers including cognitive decline, clinical progression, hippocampus volume, and β-amyloid. In the younger group, they assessed associations between PGRS and hippocampus volume.
Their findings show that the older adults without dementia and elevated PGRS had several AD markers, including worse memory and smaller hippocampus volume at baseline. They also had increased risk of clinical progression within 3 years of follow-up. Though florbetapir PET scans also revealed AD-like levels of β-amyloid burden in this group, the association was not statistically significant as measured by CSF β-amyloid. Elevated PGRS were associated with smaller hippocampus volume in the younger group of participants as well, providing evidence that the effects of aggregate genetic AD risk are detectable before symptoms appear, even early in life.
These patterns were evident only when PGRS included many loci that are below the GWAS-level significance, suggesting that “aggregation across a large number of loci is likely a more sensitive method to establish underlying genetic risk to AD dementia,” according to the authors. “Understanding the early influence of genetic risk will provide important insights into mechanisms of AD development throughout the lifespan as well as improve detection of at-risk individuals before clinical symptoms and widespread neuronal damage has ensued,” they concluded.
Mormino EC, Sperling RA, Holmes AJ, et al. Polygenic risk of Alzheimer disease is associated with early- and late-life processes. Neurology. 2016; pii: 10.1212/WNL.0000000000002922.