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

ABSTRACT

Background: Approximately 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. Methods: We 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. Results: In addition to the common polygenic risk of Alzheimer's Disease (AD), we identified and replicated rare variant association in ITSN1 and CRHR2 . 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. Discussion: Our study uncovers novel risk loci for episodic memory decline. The identified underlying mechanisms point toward heterogeneous memory pathologies mediated by rare coding variants.