rs117042529 (FZD10): Alzheimer's Cognitive Resilience

Key takeaways

• rs117042529 is located within the FZD10 and PIWIL1 locus, where FZD10 encodes a Wnt pathway receptor and PIWIL1 is involved in RNA silencing.
• A sex-stratified genome-wide association study of cognitive resilience to Alzheimer's disease analyzed this locus across more than 5,000 participants.
• GTEx brain tissue data (953 donors) links the alternate allele to substantially higher expression of FZD10-AS1, a long non-coding RNA near FZD10, in the cerebellum and cortex.
• The genetic architecture of cognitive resilience to Alzheimer's disease differs by biological sex, with heritability estimated at 15 to 44% within each sex.
• Evidence for this specific variant is preliminary; no confirmed association statistics for rs117042529 appear in the available study excerpt.

What the research says A sex-stratified genome-wide association study (GWAS) of cognitive resilience to Alzheimer's disease neuropathology harmonized cognitive and neuropathological data across multiple aging cohorts, analyzing males (n = 2,093) and females (n = 2,931) separately and a combined sex-interaction cohort (n = 5,024), finding that resilience phenotypes are 15 to 44% heritable within each sex. The FZD10 (Frizzled Class Receptor 10) and PIWIL1 (PIWI Like RNA-Mediated Gene Silencing 1) locus containing rs117042529 was part of this genome-wide analysis, though specific association statistics for this variant are not available from the provided study excerpt. Separately, expression quantitative trait locus (eQTL) analysis from GTEx v11 (953 donors) shows that the alternate allele at rs117042529 is associated with increased expression of FZD10-AS1, a long non-coding RNA antisense to FZD10, in both brain cerebellum and brain cortex GTEx Portal.

Reported associations

• Cognitive resilience to Alzheimer's disease neuropathology: This locus was included in a sex-stratified GWAS examining why some individuals remain cognitively intact despite significant amyloid plaque burden (amyloid plaques are protein deposits that are a primary hallmark of Alzheimer's disease) at autopsy, using harmonized cognitive and neuropathological data across multiple aging cohorts (combined n > 5,000).
• Brain FZD10-AS1 expression (eQTL): The alternate allele is associated with increased expression of FZD10-AS1 in brain cerebellum (slope +0.77 log2-normalized units, p = 5.1 x 10^-6) and brain cortex (slope +0.77, p = 5.8 x 10^-6) GTEx Portal.

Evidence quality The cognitive resilience GWAS used harmonized samples totaling more than 5,000 participants (sex-stratified: males n = 2,093, females n = 2,931; combined sex-interaction: n = 5,024), a moderate size for GWAS of complex phenotypes. The primary highlighted finding from that study was a female-specific locus on chromosome 10 (rs827389, beta in females = 0.08, p in females = 5.76 x 10^-9), not the FZD10-PIWIL1 region; specific p-values and effect sizes for rs117042529 are not available from the provided study text, which precludes direct appraisal of that association's strength. The GTEx eQTL signal (953 donors, false discovery rate below 5%) is an independent functional finding, showing a slope of approximately +0.77 log2-normalized units in two distinct brain regions, suggesting the alternate allele has a tissue-specific regulatory effect on FZD10-AS1 expression. Both lines of evidence should be treated as preliminary for this specific variant until independent replication is available.

Tissue-specific expression effects

• FZD10-AS1: The alternate allele at rs117042529 is associated with increased expression in brain cerebellum and brain cortex, with similar magnitude in both regions (slope approximately +0.77 log2-normalized units, false discovery rate below 5%) GTEx Portal.

Lifestyle considerations No lifestyle considerations on file for this variant.