P4‐377: A TOMM40 SNP IN APOE E4 NON‐CARRIERS INCREASES RISK FOR MULTIPLE TYPES OF DEMENTIA

Recently, our group reported that the APOE ε4 allele is a strong risk factor across the Lewy Body Disease (LBD) spectrum and occurs at an increased frequency in pure dementia with Lewy Bodies (DLB) relative to Parkinson's disease dementia (PDD). Despite an association between neurodegenerative disease and APOE ε4many APOE ε4 non-carriers develop Alzheimer's disease (AD). AD GWAS have found a strong association between AD quantitative traits, such as age-at-onset, and SNPs within the APOE region that include both APOE ε4 and SNPs within the TOMM40 gene. Subjects were classified into 5 categories: dementia with high-level Alzheimer disease (AD) neuropathologic changes (NCs) but without Lewy body disease (LBD) NCs (AD; n=253), dementia with high-level AD NCs and LBD NCs (LBD-AD; n=234), dementia with LBD NCs and no or low levels of AD NCs (pure DLB (pDLB); n=92), Parkinson disease dementia (PDD) with and without neuropathologic data (PDD; n=139), and controls with no or low levels of AD NCs and no LBD NCs (controls; n=278). All subjects were tested for associations between APOE locus SNPs and disease. As expected, preliminary results show that the proportion of APOE ε4 and certain TOMM40 alleles is significantly higher in the AD, LBD-AD, pDLB, and PD groups compared with the control group. Among the APOE ε4 non-carriers (3/3 only) the TOMM40 rs2075650 G allele is associated with disease for LBD-AD (OR, 3.32; CI, 1.63-6.79; p= 0.0006), AD (OR, 3.16; CI, 1.60-6.24; p= 0.0013) and PDD (OR, 2.81; CI, 1.43-5.53; p= 0.0015) compared to controls. The pDLB group APOE ε4 non-carriers, that also carry the TOMM40 rs2075650 G allele, have an earlier age-at-onset compared to G allele non-carriers (p-value, 0.017). Among the APOE ε4 non-carriers the TOMM40 rs59007384 T allele is significantly associated with PDD (OR, 5.06; CI, 2.48 to 10.31; p<0.0001). An association with dementia or age-at-onset and TOMM40 SNPs in APOE ε4 non-carriers suggests that multiple sites within the APOE gene region may contribute to dementia risk.