Association between WWOX/MAF variants and dementia-related neuropathologic endophenotypes

Area of Science:

• Neurogenetics
• Neuropathology
• Alzheimer's Disease Research

Background:

• The WWOX and MAF gene locus is a known risk factor for Alzheimer's disease (AD).
• Previous research suggested a WWOX variant as a risk allele for hippocampal sclerosis (HS).
• The role of this locus in non-plaque and non-tau Alzheimer's disease neuropathological changes (ADNC) requires further investigation.

Purpose of the Study:

• To investigate the association between the WWOX/MAF genetic locus and specific neuropathological changes (NC) in the brain.
• To determine if genetic variants in this locus are preferentially linked to non-ADNC, such as limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC).

Main Methods:

• Meta-analysis of genome-wide association study (GWAS) data and autopsy measures from multiple large cohorts.
• Analysis included data from the National Alzheimer's Coordinating Center, Religious Orders Study, and Rush Memory and Aging Project.
• Statistical adjustments were made to assess associations independent of ADNC.

Main Results:

• No significant associations were found between WWOX/MAF variants and ADNC.
• Several WWOX/MAF variants showed significant associations with LATE-NC, HS, and brain arteriolosclerosis.
• These associations remained significant after adjusting for ADNC, indicating independence from AD pathology.

Conclusions:

• WWOX genetic variants are pathologically associated with LATE-NC and HS.
• The WWOX/MAF locus is implicated in neurodegenerative processes beyond typical ADNC.
• These findings highlight the importance of considering genetic contributions to diverse neuropathological conditions.