The low (and still falling) cost of modern omics technologies ensure that databases of genetic information are expanding at a fast pace. Researchers who study aging have amassed a wealth of information on the biochemistry of people at various ages, but considerable focus has been placed on the genetics of extremely old individuals. The hope has always been to identify particular genes or protein interactions or other aspects of cellular biochemistry that are meaningfully protective, and thus could serve as a starting point for the development of therapies that will slow aging.
Unfortunately what has emerged from this research is (a) the likelihood that previous estimates of the contribution of genetic variants to life expectancy were too high, (b) that very few gene variants show even modest correlations with life span in multiple study populations, and © that the landscape of the genetics of longevity is likely one in which thousands of gene variants provide individually tiny, conditional effects that vary from individual to individual. This is not to say that surprises do not exist, see the sizable effect of the very rare PAI-1 loss of function mutation for example, but these surprises are not relevant to the overwhelming majority of people.
Today's open access paper fits squarely into this new view of the genetics of longevity, while focusing specifically on risk of Alzheimer's disease and its association with genetic variants other than the well-known APOE gene. Like all such studies, many associations are found when analyzing prevalence of gene variants in very old people. But few were found elsewhere, and few will be replicated in other studies. Further, correlations between the presence of variants and Alzheimer's disease risk appear modest at best. So: small effect sizes, nothing that could be the basis for therapies, and more reinforcement of the view of genetics noted above.
Increased genetic protection against Alzheimer's disease in centenarians
While the effect of the apolipoprotein E (APOE) gene on Alzheimer's disease (AD) is well-characterized, the search for additional reliable genetic factors for AD has been ongoing. A recent genome-wide association study (GWAS) analysis identified a total of 83 genetic variants associated with AD using 111,326 clinically diagnosed/"proxy" AD cases and 677,663 controls of White/European ancestry. In this list of genetic variants, 44 were novel loci at the time of publication. Given that individual single-nucleotide polymorphisms (SNPs) typically have a limited impact on disease risk, polygenic risk scores that aggregate the effect of multiple genetic loci have been developed for various human diseases and phenotypes.
We constructed a polygenic protective score specific to Alzheimer's disease (AD PPS) based on the current literature among the participants enrolled in five studies of healthy aging and extreme longevity in the USA, Europe, and Asia. This AD PPS did not include variants on apolipoprotein E (APOE) gene. Comparisons of AD PPS in different data sets of healthy agers and centenarians showed that centenarians have stronger genetic protection against AD compared to individuals without familial longevity. The current study also shows evidence that this genetic protection increases with increasingly older ages in centenarians (centenarians who died before reaching age 105 years, semi-supercentenarians who reached age 105 to 109 years, and supercentenarians who reached age 110 years and older). However, the genetic protection was of modest size: the average increase in AD PPS was approximately one additional protective allele per 5 years of gained lifetime. Additionally, we show that the higher AD PPS was associated with better cognitive function and decreased mortality.
Taken together, this analysis suggests that individuals who achieve the most extreme ages, on average, have the greatest protection against AD. This finding is robust to different genetic backgrounds with important implications for universal applicability of therapeutics that target this AD PPS.
View the full article at FightAging
