Premium
P3‐103: ATP5H, ZCCHC14, AND PRKCH AS GENETIC RISK FACTORS FOR ALZHEIMER DISEASE AND VASCULAR DEMENTIA
Author(s) -
Young Sympascho,
Fok Alice C.,
Robin Hsiung Ging-Yuek
Publication year - 2018
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.2018.06.1460
Subject(s) - dementia , apolipoprotein e , vascular dementia , medicine , disease , odds ratio , genotype , allele , alzheimer's disease , diabetes mellitus , logistic regression , oncology , vascular disease , endocrinology , genetics , biology , gene
Background: Extensive research ties mitochondria to Alzheimer’s disease (AD), but how mitochondria contribute to AD risk or progression remains unsettled. If other pathologies primarily perturb mitochondria in AD, downstream mitochondrial changes could represent inconsequential biomarkers of or perhaps mediate the effects of the responsible upstream pathologies. Alternatively, mitochondria may independently contribute to AD. Methods: We generated complete mtDNA sequences from 150 AD and 297 control subjects from the KU ADC clinical cohort. For a replication cohort we considered publically available ADNI mtDNA haplogroup data (191 AD, 279 control). Results:In the KUADC cohort, the haplogroup J frequency was significantly increased in those with AD (16.0% vs 7.4%; p1⁄40.008), with an odds ratio (OR) of 2.38, lower confidence interval (LCI) of 1.29, and upper confidence interval (UCI) of 4.39. Four J-defining variants appeared to mediate this association (C295T, T489C, C16069T, G13708A). We also observed that the haplogroup K frequency was lower in those with AD (4.7% vs 11.1%; p1⁄40.023), with an OR of 0.39, LCI of 0.17, and UCI of 0.90. A haplogroup K pre-variant, the synonymous T9698C transition, additionally associated with lower AD risk (p1⁄40.039). The ADNI cohort similarly showed a significant increase in haplogroup J in AD participants (12.6% vs 6.5%; p1⁄40.031), with an OR of 2.084, LCI of 1.10, and UCI of 3.93. ADNI AD and control haplogroup K frequencies were comparable. Conclusions:Detailed haplogroup analysis based on mtDNA deep sequencing indicates inherited mtDNA haplogroup variants associate with AD, which argues mitochondria independently contribute to AD. Further analysis to determine if other factors mediate observed mtDNA-AD associations is indicated.