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“Genetic Haplotypes and Family History of Alzheimer's Disease Modify Homocysteine and Influence Neurovascular Pathology”
Author(s) -
Webb Joe L,
Willette Auriel A
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.lb374
Subject(s) - homocysteine , neuropathology , medicine , neurovascular bundle , genotype , apolipoprotein e , alzheimer's disease , vascular dementia , pathology , endocrinology , vascular disease , biomarker , dementia , disease , biology , genetics , gene
Objective To delineate novel relationships between Alzheimer disease (AD) factors, such as Translocase of the Outer Mitochondrial Membrane ‐ kD 40 (TOMM40) genotype, AD family history (FH), the vascular risk factor homocysteine, and vascular neuropathology. Methods We performed linear mixed model regression on longitudinal imaging and biomarker data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. Among 210 healthy adults with 1 or 2 Apolipoprotein ɛ4 (APOE4) alleles (mean age 73.8), we stratified by TOMM40 genotypes S/L (n=84), L/L (n=49), L/VL (n=68). Main effects and interactions between TOMM40 and FH were conducted on neurovascular outcomes, including white matter hyperintensities (WMH), infarctions, as well as total intracranial volume. Vascular risk factors were similarly tested, including homocysteine and total cholesterol. Models were adjusted for age, gender, body mass index and hyperglycemia status. Results FH * TOMM40 interactions showed that L/L and L/VL genotypes respectively exercised “beneficial” effects for FH negative (FH−) and “detrimental” effects for FH positive (FH+) participants. In FH+, for example, risk alleles were associated with higher serum homocysteine (P=0.024), total cholesterol (P=0.005), infarction occurrence (P=0.045), and greater WMH burden (P = 0.032). Total intracranial volume was also smaller (P<0.001). Homocysteine levels mediated FH * TOMM40 associations with neurovascular measures. Conclusions These results suggest that FH modulates TOMM40's effects on vascular markers and neurovascular pathology of AD in APOE4 participants. These interactions between FH and TOMM40 influence on neuropathology may be mediated via homocysteine suggesting that TOMM40 genotype could serve as a novel predictor for AD and that homocysteine may be one potential mechanism. Support or Funding Information This study was supported in part by the National Institutes of Health award number K99AG047282, an Iowa State University Stewart Research Award and an Iowa State University University Honor's Program Research Award. Role of Funding: The funding sources had no role in the design or conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the abstract.