Alzheimer's & dementia : the journal of the Alzheimer's Association
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Observational research shows that higher body mass index (BMI) increases Alzheimer's disease (AD) risk, but it is unclear whether this association is causal. We applied genetic variants that predict BMI in Mendelian randomization analyses, an approach that is not biased by reverse causation or confounding, to evaluate whether higher BMI increases AD risk. ⋯ Mendelian randomization effect estimates per BMI point (95% confidence intervals) were as follows: ADGC, odds ratio (OR) = 0.95 (0.90-1.01); HRS, OR = 1.00 (0.75-1.32); GERAD1, OR = 0.96 (0.87-1.07). One subscore (cellular processes not otherwise specified) unexpectedly predicted lower AD risk.
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A rare variant in TREM2 (p. R47H, rs75932628) was recently reported to increase the risk of Alzheimer's disease (AD) and, subsequently, other neurodegenerative diseases, i.e. frontotemporal lobar degeneration (FTLD), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (PD). Here we comprehensively assessed TREM2 rs75932628 for association with these diseases in a total of 19,940 previously untyped subjects of European descent. ⋯ Our data show that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (odds ratio or OR = 2.71, P = 4.67 × 10(-25)). No consistent evidence for association was found between this marker and the risk of FTLD (OR = 2.24, P = .0113 across 2673 cases/9283 controls), PD (OR = 1.36, P = .0767 across 8311 cases/79,938 controls) and ALS (OR = 1.41, P = .198 across 5544 cases/7072 controls). Furthermore, carriers of the rs75932628 risk allele showed significantly increased levels of CSF-total-tau (P = .0110) but not Aβ42 suggesting that TREM2's role in AD may involve tau dysfunction.