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Basic Science and Pathogenesis
Alexandra N Regelson1,2, Derek B Archer1,2, Alaina Durant1,3
1Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN, USA.
Alzheimer'S & Dementia : the Journal of the Alzheimer'S Association
|December 24, 2025
Summary
Researchers identified nine genes linked to cognitive decline, including novel rare variants in SIGIRR, PLA2G4A, and HPN associated with executive function decline in aging and Alzheimer's Disease (AD).
Area of Science:
- Genetics
- Neuroscience
- Aging Research
Background:
- Alzheimer's Disease (AD) exhibits significant heritability, yet much of it remains unexplained, potentially due to disease heterogeneity.
- Sensitive longitudinal cognitive measures can serve as endophenotypes to uncover genetic drivers of cognitive decline.
Purpose of the Study:
- To identify novel genetic drivers of cognitive decline in aging and Alzheimer's Disease (AD) using rare variant analysis.
- To leverage sensitive longitudinal cognitive measures as endophenotypes in a large-scale genetic study.
Main Methods:
- Utilized whole genome sequencing data from 8,481 participants across 8 cognitive aging cohorts.
- Performed rare variant analyses on harmonized memory, executive function, and language domains using SKAT-O testing.
- Included variants with minor allele frequency < 0.01 and high/moderate impact, adjusting for covariates and using FDR for multiple comparisons.
Main Results:
- Identified 9 genes associated with cognitive domains: APOE and PSEN1 with baseline memory, PEDS1-UBE2V1 with baseline language.
- Discovered 6 genes (HPN, HPN-AS1, GAB1, CXCL3, SIGIRR, PLA2G4A) associated with executive function decline.
- Found significant associations between high-impact variants in SIGIRR, PLA2G4A, and HPN and executive function decline.
Conclusions:
- Highlighted novel rare variants associated with cognitive function and decline in aging and AD.
- GAB1 identified as a potential therapeutic target for AD, with observed effects in AD patients and mouse models.
- PLA2G4A shows altered expression patterns in AD and healthy aging, suggesting a role in disease progression.
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