The role of TREM2 R47H as a risk factor for Alzheimer's disease, frontotemporal lobar degeneration, amyotrophic lateral sclerosis, and Parkinson's disease

Abstract

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. These data were combined with those from 28 published data sets by meta-analysis. Furthermore, we tested whether rs75932628 shows association with amyloid beta (Aβ42) and total-tau protein levels in the cerebrospinal fluid (CSF) of 828 individuals with AD or mild cognitive impairment. 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.

Keywords: Alzheimer disease; Amyotrophic lateral sclerosis; Frontotemporal lobar degeneration; GWAS; Genetic association; Imputation; Meta-analysis; Neurodegenerative disease; Parkinson disease; R47H; Rare variant; TREM2; rs75932628.

Fig. 1

Meta-analyses of data sets assessing the association between TREM2 rs75932628 and Alzheimer's disease (AD; A), frontotemporal lobar degeneration (FTLD; B), amyotrophic lateral sclerosis (ALS; C), and Parkinson's disease (PD; D). The x-axis depicts the odds ratio (OR). Study-specific ORs (black diamond) and 95% confidence intervals (CI, lines) were calculated using an additive model. The summary OR and 95% CI (gray diamonds) were calculated based on fixed-effect meta-analysis. I² is an estimate of the amount of heterogeneity that is beyond chance. Note that effect estimates for data sets “Benitez, 2013, Spain” (A), “Borroni, 2013, Italy”, “Ruiz, 2013, Spain” (B), “Benitez, 2013, Spain”, “Benitez, 2013, USA”, and “Rayaprolu, 2013, Poland” (D) have been calculated after continuity correction to account for zero cell counts. For further details on all data sets and publications included in the respective meta-analyses see Supplementary Table 1.

Fig. 2

Box plot of the distribution of total tau protein levels in the cerebro-spinal fluid (CSF) dependent on the TREM2 rs75932628 genotype in 828 German patients with Alzheimer's disease and mild cognitive impairment. Horizontal lines represent median values, boxes represent interquartile ranges, and whiskers extend to 1.5× the interquartile range; values outside this range are depicted as circles. Total tau protein levels (measured in pg/ml) have been log-transformed to the basis 10. Carriers of the TREM2 rs75932628 risk allele (T) showed an increase in total tau protein levels in the CSF.