rs11668758 (CLPTM1): Memory, Alzheimer's, and Brain APOC2

Key takeaways

• rs11668758 sits near the CLPTM1 gene and was examined in a 27,000-person cross-ancestry GWAS of late-life memory performance and decline linked to Alzheimer's disease research
• GTEx tissue data shows this variant increases APOC2 (Apolipoprotein C-II, a protein involved in fat metabolism) expression across three basal ganglia brain regions, cerebellum, and heart, while reducing it in lung and spleen
• This variant also increases CLPTM1 expression specifically in testis tissue, with a highly significant signal from 953 donors
• Memory performance and decline are highly heritable traits that share genetic architecture with Alzheimer's disease and neuropsychiatric conditions
• No drug-response or lifestyle guidance is currently available for this variant

What the research says A cross-ancestry genome-wide association study (GWAS - a technique that scans hundreds of thousands of genetic positions across the genome to find variants correlated with a trait) examined late-life memory performance (n=27,633) and memory decline (n=22,365; 129,201 longitudinal observations) across four aging cohorts: ACT, ADNI, NACC, and ROS/MAP/MARS. Memory performance was found to be highly heritable across both non-Hispanic White and non-Hispanic Black ancestry groups, with genetic overlap identified across Alzheimer's disease, neuropsychiatric, and autoimmune traits. In parallel, GTEx v11 eQTL data (953 donors, FDR-corrected at FDR<0.05) establishes rs11668758 as an expression quantitative trait locus (eQTL - a genetic variant that influences how much a gene is expressed in specific tissues) for both CLPTM1 in testis and APOC2 in multiple brain and peripheral tissues GTEx Portal.

Reported associations

• APOC2 brain and peripheral tissue expression (eQTL): GTEx data (953 donors, FDR<0.05) links rs11668758 to increased APOC2 expression in three basal ganglia brain structures: putamen (p=3.5e-21), caudate nucleus (p=5.2e-23), and nucleus accumbens (p=5.8e-21), as well as in cerebellum (p=7.7e-8) and heart atrial appendage (p=1.2e-8). Reduced APOC2 expression was observed in spleen (p=7.2e-11) and lung (p=6.2e-15) GTEx Portal
• CLPTM1 testis expression (eQTL): GTEx data (953 donors, FDR<0.05) associates rs11668758 with increased expression of the CLPTM1 gene (Cleft Lip and Palate Transmembrane Protein 1) in testis tissue (p=6.5e-43) GTEx Portal
• Late-life memory performance and decline (research context): The study from which this variant derives its primary research context investigated memory performance (n=27,633) and memory decline (n=22,365) as endophenotypes (measurable biological traits used as indicators of underlying genetic risk) for Alzheimer's disease across four harmonized aging cohorts. Novel loci were identified for memory decline on chromosome 4 and for memory performance on chromosomes 2, 7, and 15, and the study found high heritability estimates for memory traits across ancestries.

Evidence quality The tissue-expression evidence from GTEx (953 donors, cis-window, FDR<0.05) is statistically robust, particularly the CLPTM1 testis signal (p=6.5e-43) and the APOC2 basal ganglia signals (p values of 3.5e-21 to 5.8e-21). These eQTL findings describe changes in gene expression levels, not disease outcomes, and should be interpreted as mechanistic data rather than clinical evidence. The memory-performance GWAS provides important disease context for this locus, drawing on a large cross-ancestry sample using harmonized cognitive measures from four aging cohorts, but the available text excerpt does not explicitly name rs11668758 among the top variant-level findings reported, and the study metadata does not include a PMID, which limits direct replication assessment. No conflicting findings were identified in the provided data, though evidence for a direct disease association for this specific variant remains preliminary.

Tissue-specific expression effects

• CLPTM1: rs11668758 is associated with increased expression of CLPTM1 in testis tissue (p=6.5e-43, based on 953 GTEx donors) GTEx Portal
• APOC2: This variant is associated with increased expression of APOC2 (Apolipoprotein C-II, involved in triglyceride metabolism) in three basal ganglia brain regions (putamen, caudate nucleus, and nucleus accumbens), in cerebellum, and in heart atrial appendage, while reducing APOC2 expression in spleen and lung GTEx Portal

Lifestyle considerations No lifestyle considerations on file for this variant.