Further, the measured phenotypes are highly heritable cross-sectionally and longitudinally; however considerable familial phenotypic heterogeneity is present. To better understand this heterogeneity and the why and how these families are protected we will: conduct a third in-home visit with existing participants; recruit and enroll the grandchildren of the proband generation for their initial visit; combine linkage and association analyses to identify rare and lineage specific variants for cross-sectional and longitudinal HAPs and EL and their interaction with lifestyle exposures; perform comprehensive OMICs on LLFS pedigrees to discover biologic mechanisms leading to the heterogeneous familial patterns of HAPs and EL in LLFS pedigrees, and discover additional causal variants. Finally, we will combine all the data using systems biology and data integration to more comprehensively explain the biology of healthy aging.

The purpose of the LLFS is to study families in the United States and Denmark that are ALL enriched for exceptional longevity (EL). EL is a complex trait that is likely influenced by multiple genes with small effects interacting with lifetime exposures. The knowledge gained from studying these families will be in why and how they are protected and thus living exceptionally healthy long lives.

This project is supported by the National Institutes of Health’s National Institute on Aging, grant U19AG063893.

Alzheimer’s Disease Related Research Findings from LLFS

Xicota, Barral, and colleagues (https://pubmed.ncbi.nlm.nih.gov/38380866/) performed a genome wide search using the short read whole genome sequence (WGS) data from the LLFS dataset (n=3475) to understand the genetic contributions to delayed onset of late onset AD (LOAD) and confirmed the association in 6 external datasets (n=14,260). We identified several tightly linked SNPs in the MTUS2 gene (rs73154407, p = 7.6 × 10⁻⁹) that were significantly associated with LOAD, and the association of MTUS2 variants with LOAD was confirmed in 5 independent datasets. Subsequently, this study showed that the allelic association was stronger in those with high levels of Aβ42/40 ratio than in those with lower levels of Aβ42/40 ratio. This finding sheds light on AD biology in that MTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.

Genes associated with physiological dysregulation may play a role in AD onset. Arbeev and colleagues (https://pubmed.ncbi.nlm.nih.gov/32235003/) found that genes associated with the age-related increase in physiological dysregulation (PD) frequently represented pathways implicated in axon guidance and synaptic function, which in turn were linked to AD and related traits (e.g., amyloid, tau, neurodegeneration). As a follow-up, Arbeev et al (https://pubmed.ncbi.nlm.nih.gov/37719713/)  then investigated the hypothesis that genes involved in PD and axon guidance/synapse function may jointly influence onset of AD. We found significant interactions between SNPs in the UNC5C and CNTN6, and PLXNA4 and EPHB2 genes that influenced AD onset in both datasets. Our findings suggest the joint contribution of genes involved in PD and axon guidance/synapse function (essential for the maintenance of complex neural networks) to AD development.