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Genetic variants associated with age-related episodic memory decline implicate distinct memory pathologies.

Amanat Ali1, Sofiya Milman1,2, Erica F Weiss3

  • 1Department of Medicine, Albert Einstein College of Medicine, Bronx, New York, USA.

Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|November 19, 2024
PubMed
Summary

This study identifies new genetic factors, including rare variants in ITSN1 and CRHR2, contributing to age-related episodic memory decline. These findings reveal diverse molecular mechanisms underlying memory impairment in older adults.

Keywords:
Alzheimer's diseaseepisodic memory declineprotein modelingrare variants

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Area of Science:

  • Genetics
  • Neuroscience
  • Molecular Biology

Background:

  • Episodic memory decline affects approximately 40% of individuals aged 65 and older.
  • Understanding the genetic underpinnings of memory loss is vital for identifying causes and potential interventions.

Purpose of the Study:

  • To investigate genetic variants, both common and rare, associated with episodic memory decline.
  • To explore the molecular mechanisms of memory pathologies linked to identified rare variants.

Main Methods:

  • Analysis of common and rare genetic variants in 742 Ashkenazi Jewish individuals (mean age 75) from the LonGenity study.
  • Utilized all-atom molecular dynamics simulations to elucidate mechanistic insights of rare variants.

Main Results:

  • Identified and replicated rare variant associations in ITSN1 and CRHR2, beyond common Alzheimer's disease polygenic risk.
  • Revealed distinct memory pathologies, including impaired corticotropin releasing hormone receptor activation and dysregulated L-serine synthesis, mediated by rare coding variants.

Conclusions:

  • Uncovered novel genetic risk loci (ITSN1, CRHR2) for episodic memory decline.
  • Demonstrated that rare coding variants contribute to heterogeneous memory pathologies via specific molecular mechanisms.