Longevity genes and somatic alterations in Alzheimer’s disease

The objectives of using ADSP data are twofold. First, we aim to investigate the relationship between pro-aging/longevity-associated variants and Alzheimer’s disease (AD). ADSP provides an independent cohort that will allow us to replicate and validate the potential effects of variants identified in our Einstein longevity cohort. Second, we aim to study the relationship between somatic alterations, including clonal somatic mutation burden, loss of chromosome Y (LOY), and clonal hematopoiesis of indeterminate potential (CHIP), and AD. This objective is highly relevant to our ongoing projects investigating the connection between somatic mutations and AD/healthy aging.
For the first objective, we will use ADSP whole-genome sequencing (WGS) data to investigate coding and non-coding variants identified in our Einstein longevity cohort. We will use available ADSP phenotypes, including AD case/control status, age at AD diagnosis, and related clinical information, to assess the potential biological roles of these variants in AD pathology, while considering APOE haplotype as an important genetic background.
For the second objective, we will investigate the effects of different types of somatic alterations, as well as their potential interplay, on AD. We will use Mutect2 to identify clonal somatic mutations from CRAM files, which will also allow us to identify CHIP carriers. In addition, we will estimate LOY using VCF data with BaySeq-Y, a method we developed to estimate the fraction of cells without chromosome Y based on VCF files.
At this time, I do not have any planned collaborations with researchers outside Einstein.

Based on our previous studies of longevity-associated variants in the Einstein longevity cohort, as well as methods we have developed to measure somatic mutations, such as BaySeq-Y for estimating loss of chromosome Y (LOY), we are well positioned to address two key questions using the ADSP cohort. First, we will investigate whether longevity-associated variants identified in our cohort confer resilience to Alzheimer’s disease (AD). Second, we will examine the relationship between different types of somatic mutations and AD, and assess whether the resilience effects implicated by some pro-longevity variants may be mediated, at least in part, through reduced somatic mutation burden.
This research will establish a connection across complementary cohorts, allowing us to validate findings from our Einstein longevity cohort in ADSP and to generate novel insights into the genetic and somatic mechanisms underlying resilience to AD and healthy aging.