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

Abstract

Background: Approximately 40% of people aged ≥ 65 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 molecular dynamics 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, we identified and replicated rare variant associations 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 heterogenous memory pathologies mediated by rare coding variants.

Highlights: We demonstrated the contribution of the common polygenic risk of Alzheimer's disease to episodic memory decline. We discovered and replicated two risk genes associated with episodic memory decline implicated by rare variants, were discovered and replicated. We demonstrated molecular mechanisms and potential novel memory pathologies underlying interfacial rare coding variants. Molecular dynamics simulations were performed to understand the downstream effects of risk rare coding variants.

Keywords: Alzheimer's disease; episodic memory decline; protein modeling; rare variants.

FIGURE 1

Distribution of memory measures. A, Memory trajectories of 923 subjects and 10 subjects with the worst residual memory slope (red) derived from the linear mixed model. B–D, The correlation between the residual memory slope and baseline age (B), education years (C), and sex (D).

FIGURE 2

Common genetic variants associated with episodic memory decline. A, Manhattan plot demonstrating GWAS results for episodic memory decline. The red and blue lines represent thresholds for genome‐wide significance (p < 5 × 10⁻⁸) and suggestive significance (p  <  1 × 10⁻⁵), respectively. B–D, Detailed view of the GWAS SNPs demonstrating associations ± 400 kb from lead SNPs (labeled). The x axis represents the variant position on the chromosome and nearby gene positions. The right y axis indicates the GWAS p value, and the left y axis indicates the rate of recombination. Each plot point indicates a SNP in the dataset color‐coded by (r2) value using the EUR population from the 1000G LD panel. LD plots were generated using the Locus Zoom plot (locuszoom.org). E–G, Cell type–specific regulatory architecture of the following GWAS‐significant SNPs: rs548640610 (E), rs541421523 (F), and rs35990795 (G). A 1000 bp window flanking the SNPs is shown along with the genome tracks illustrating the aggregate accessibility of scChip‐seq and scATAC‐seq clusters at the locus. A blue line in E–G indicates the location of GWAS‐significant SNPs. EUR, European; GWAS, genome‐wide association study; LD, linkage disequilibrium; SNP, single nucleotide polymorphism.

FIGURE 3

Rare variant association analyses. A, The Manhattan plot for 7010 prioritized rare coding variants across the exome. See Table S2 in supporting information for variant annotations. B, The Manhattan plot for the gene‐level rare variant association analysis.

FIGURE 4

3D crystal structure of CRHR2 bound to G proteins. Different subunits are colored differently and labeled. Amino acids are represented with sticks. The red‐boxed region in (A) is magnified in the successive images (B and C). A, 3D structure of CRHR2 complex; (B) wild type Arg148; (C) mutant Trp148; (D) the percentage of simulation time during which intermolecular contact was retained between CRHR2:Arg148/Trp148 and Gα protein. 3D, three dimensional; CRHR2, corticotropin releasing hormone receptor 2.

FIGURE 5

3D structure of PSPH‐bound phosphoserine. Amino acids are represented with sticks. The red‐boxed region in (A) is magnified in the successive images (B and C). (A) Crystal structure of PSPH complex; (B) wild type Thr152; (C) mutant Ile152; (D) average percentage of simulation time a wild type PSPH residue maintains contact with phosphoserine ligand (L); (E) average percentage of simulation time a mutant PSPH residue maintains contact with phosphoserine. Charged and polar amino acids are shown in orange and blue color, respectively. 3D, three dimensional; PSPH, phosphoserine phosphatase.