TREM2 Burden associates solely with Alzheimer’s Disease, and decreases the Chance to become a Centenarian

Abstract

AbstractBackgroundRare TREM2 variants are major risk factors for Alzheimer’s disease (AD), but TREM2 variants may also confer a higher risk for other neurodegenerative diseases and a lower probability for cognitively healthy aging. We studied the TREM2 burden associated with different types of dementia and cognitively healthy centenarians (CHCs).MethodWe included participants of the 100‐Plus Study, Amsterdam Dementia Cohort, Longitudinal Aging Study Amsterdam and various Dutch memory clinics. TREM2 variants (R47H, R62H, Q33X, R62C, T96K) were genotyped with a high density array or imputed using standard methods (TOPMED reference panel). To avoid family bias and ethnic differences, related individuals and those of non‐European ancestry were excluded. Frequencies of individual variants and the burden of TREM2 variants were compared in AD dementia, dementia with Lewy Bodies (DLB), frontotemporal dementia (FTD), cognitively normal controls and CHCs (correcting for 5 principal components).ResultWe identified 242 carriers of TREM2 mutations and 6,683 controls without a TREM2 mutation with a mean age of 69 years (SD ±14 years), 50% female (Table 1). TREM2 variants were significantly associated with AD dementia (OR 1.4, 95%CI 1.1‐1.8, p = 0.01) (Table 2). R47H conferred the highest risk for AD (OR 2.8, 95%CI 1.4‐5.6, p = 0.004), compared to 1.3‐fold increased risk of R62H (95%CI 0.9‐1.7, p = 0.11). The carrier frequency was not increased in DLB (OR 1.4, 95%CI 0.7‐2.6, p = 0.34) and was not increased in FTD compared to controls (OR 0.59, 95%CI 0.3‐1.3, p = 0.18). Of interest, the allele frequency of TREM2 variants in centenarians is half of the expected frequency (OR = 0.46, 95%CI 0.1‐1.1, p = 0.10), and only concerns R62H.ConclusionWe replicate the association of TREM2 with increased risk of AD. In contrast to previous reports no association was observed with DLB or FTD. Cognitively healthy centenarians show a negative trend for TREM2 allele frequency suggesting that carrying a TREM2 variant decreases chances of survival to extreme age.