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Basic Science and Pathogenesis.

Neetesh Pandey1, Sandra Barral2, Richard Mayeux3

  • 1Columbia University, New York, NY, USA.

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|December 25, 2025
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Summary
This summary is machine-generated.

Rare variants in the PCAT5 gene are associated with cognitive performance in diverse populations, suggesting a role in Alzheimer's disease and related dementias (ADRD). This finding holds significance for understanding ADRD pathology beyond APOE.

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Area of Science:

  • Genetics
  • Neuroscience
  • Gerontology

Background:

  • Traditional Alzheimer's disease and related dementia (ADRD) studies use binary outcomes, potentially limiting power to detect genetic associations.
  • Objective measures of cognitive function (endophenotypes) may enhance the discovery of novel genetic loci for ADRD.
  • The Mexican Health and Aging Study (MHAS) provides a valuable dataset for exploring genetic influences on cognitive aging.

Purpose of the Study:

  • To investigate the association between rare genetic variants and cognitive performance across multiple domains.
  • To replicate findings in multi-ethnic cohorts to ensure generalizability.
  • To identify novel genetic loci associated with cognitive decline and ADRD risk.

Main Methods:

  • Genome-wide gene-based tests using whole-genome sequencing data from 1,930 Mexican individuals (MHAS).
  • Replication analyses in two independent cohorts: Washington Heights Inwood Aging Project (WHICAP) and Multi-Ethnic Study of Atherosclerosis (MESA).
  • Filtering of variants by allele frequency (<1%) and imputation quality (>=80%), with adjustments for age, sex, education, and APOE status.

Main Results:

  • A genome-wide significant association was found for the PCAT5 locus in MHAS, which was replicated in both WHICAP and MESA cohorts.
  • The association with PCAT5 remained significant after adjusting for APOE status in all cohorts.
  • Stratified analysis in MESA revealed a nominally significant association in African Americans, suggesting a cross-ethnic role.

Conclusions:

  • Strong evidence supports the association of rare variants in PCAT5 with cognitive performance across diverse populations.
  • PCAT5 may contribute to ADRD pathology independently of APOE, highlighting its potential as a therapeutic target.
  • Further biological research is warranted to elucidate the mechanisms underlying PCAT5's role in neurodegeneration.