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P2‐076: Alzheimer’s Disease Genetic Risk Variants Beyond Apoe ε4 Predict Mortality in The Adult Changes in Thought (ACT) Study
Author(s) -
Mez Jesse,
Marden Jessica R.,
Mukherjee Shubhabrata,
Brewster Paul,
Hamilton Jamie L.,
Gilsanz Paola,
Zahodne Laura B.,
Gross Alden L.,
Gibbons Laura E.,
Crane Paul K.,
Larson Eric B.,
Glymour M. Maria
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.1281
Subject(s) - apolipoprotein e , incidence (geometry) , disease , medicine , population , proportional hazards model , allele , demography , gerontology , cognitive decline , single nucleotide polymorphism , longevity , dementia , genetics , biology , genotype , gene , physics , environmental health , sociology , optics
Background:There is tremendous interest in finding novel genetic risk factors for AD among individuals lacking the apolipoprotein E ε4 allele (non-APOE4’s). Translocase of the Outer Mitochondrial Membrane-kD40 (TOMM40), which affects mitochondrial function, is a gene with strong linkage disequilibrium to APOE. A TOMM40 variable poly-T length polymorphism at rs10524523 within intron 6 may increase risk for late-onset AD (LOAD). Specifically, the “very long” (VL) poly-T length predicts faster memory decline and earlier age of LOAD onset, compared to the “short” (S) poly-T length. However, other studies find no effect of VL genotype or a beneficial effect. AD family history (FH) also influences mitochondrial function and may modulate TOMM40 effects. Outcomes of interest included longitudinal memory decline, medial temporal lobe (MTL) neuropathology, and a metabolic AD risk factor, insulin resistance (IR). Methods: Linear mixed modeling assessed FH and TOMM40 main effects and interactions, among non-APOE4’s, in 914 late middle-aged participants enrolled in the Wisconsin Registry for Alzheimer’s Prevention (WRAP), and 381 elders enrolled in the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Memory factors were derived from neuropsychological testing. FreeSurfer was used to derive MTL cortical thickness (CT). Arterial spin labeling (ASL) in WRAP and fluorodeoxyglucose Positron Emission Tomography (FDG-PET) in ADNI were used to gauge glucose metabolism. IR was derived from fasting glucose and insulin. Results: TOMM40 VL’s who were FHand FH+ respectively showed protective and detrimental effects. Figures 1 and 2 indicate that FHVL’s showed significantly less memory decline relative to S/S’s over 7-9 years in WRAP and 3 years in ADNI, whereas FH+ VL’s showed more decline. FHVL’s showed less MTL CT atrophy over 3 years than S/S’s in ADNI (Figure 3), whereas FH+ VL’s showed more atrophy. FHVL’s had less MTL hypometabolism, such as in WRAP (Figure 4). Finally, FHand FH+ VL’s respectively showed 20% lower and higher IR in both cohorts. IR mediated FH*TOMM40 effects on brain pathology. Conclusions:Findings in both late middleaged and elder cohorts suggest that FH strongly changes the effect of TOMM40 on cognitive, neuroimaging, and metabolic outcomes. Accounting for FH may resolve discrepancies in the TOMM40 literature.