Frequency of Variants in Mendelian Alzheimer’s Disease Genes Within the Alzheimer’s Disease Sequencing Project

Authors

• Dongyu Wang
• Alexandra Scalici
• Yanbing Wang
• Honghuang Lin
• Achilleas Pitsillides
• Nancy Heard-Costa
• Carlos Cruchaga
• Ellen Ziegemeier
• Joshua C Bis
• Myriam Fornage
• Eric Boerwinkle
• Philip L De Jager
• Ellen Wijsman
• Josée Dupuis
• Alan E Renton
• Sudha Seshadri
• Alison M Goate
• Alzheimer's Disease Neuroimaging Initiative (ADNI), The Alzheimer's Disease Sequencing Project
• Anita L DeStefano
• Gina M Peloso

Language

English

Publication Date

4-1-2025

Journal

Journal of Alzheimer's Disease

DOI

10.1177/13872877251320375

PMID

40084664

PMCID

PMC13174641

PubMedCentral® Posted Date

5-15-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

Background:

Prior studies examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer’s Disease Sequencing Project (ADSP).

Objective:

To characterize previously-reported clinically-relevant variants and DM variants in PSEN2, PSEN1, APP within the participants from the ADSP.

Methods:

We identified rare variants (MAF< 1%) in PSEN2, PSEN1, and APP in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (Ntotal = 31,490). We additionally curated variants from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.

Results:

We detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in PSEN2, 25 in PSEN1, and 2 in APP. The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with noncarriers (p-value=7.8×10−57). Additionally, we identified 197 rare variants (MAF < 1%) within ADSP participants not reported in known clinical databases.

Conclusion:

A small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.

Keywords

Humans, Alzheimer Disease, Presenilin-2, Presenilin-1, Amyloid beta-Protein Precursor, Genetic Variation, Male, Exome Sequencing, Female, Gene Frequency, Whole Genome Sequencing, Genetic Predisposition to Disease, Aged, Alzheimer’s Disease, Genetic Profile, Genetic Data Bases, Whole Genome Sequencing, Whole Exome Sequencing

Published Open-Access

yes

Recommended Citation

Wang, Dongyu; Scalici, Alexandra; Wang, Yanbing; et al., "Frequency of Variants in Mendelian Alzheimer’s Disease Genes Within the Alzheimer’s Disease Sequencing Project" (2025). Faculty, Staff and Student Publications. 1384.
https://digitalcommons.library.tmc.edu/uthsph_docs/1384