Rare genetic coding variants associated with age-related episodic memory decline implicate distinct memory pathologies in the hippocampus

Abstract

ABSTRACTBackgroundApproximately 40% of people aged 65 or older experience memory loss, particularly in episodic memory. Identifying the genetic basis of episodic memory decline is crucial for uncovering its underlying causes.MethodsWe investigated common and rare genetic variants associated with episodic memory decline in 742 (632 for rare variants) Ashkenazi Jewish individuals (mean age 75) from the LonGenity study. All-atom MD simulations were performed to uncover mechanistic insights underlying rare variants associated with episodic memory decline.ResultsIn addition to the common polygenic risk of Alzheimer’s Disease (AD), we identified and replicated rare variant association inITSN1andCRHR2. Structural analyses revealed distinct memory pathologies mediated by interfacial rare coding variants such as impaired receptor activation of corticotropin releasing hormone and dysregulated L-serine synthesis.DiscussionOur study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.