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Introduction
Alzheimer's disease (AD), the most prevalent form of dementia in the elderly, is characterized by the progressive loss of cognitive function. It is pathologically characterized by the extracellular accumulation of amyloid β proteins and intracellular formation of neurofibrillary tangles (1). Accumulating evidence has suggested an important role of the genetic component, which is estimated to be 60-80%, in the pathogenesis of AD (2). Numerous susceptible loci containing common variants [minor allele frequency (MAF) >5%] have been identified in recent decades (3). However, only the Ɛ4 allele of apolipoprotein E (APOE) is confirmed to be the most important variant conferring a 3- to 4-fold risk to AD (4). Furthermore, since most of the loci reside in the intronic or intergenic regions, the biological mechanisms remain difficult to interpret. With the advent of next-generation sequencing, more and more rare coding variants (MAF<1%) with a moderate effect on the risk of AD, including those in phospholipase Cγ2 (PLCG2), ABI family member 3 (ABI3) and triggering receptor expressed on myeloid cells 2 (TREM2), have been identified (5).
TREM2 is located on chromosome 6p21.1 and encodes a transmembrane protein on microglial cells. The protein is involved in the innate immunity within the central nervous system (CNS) by stimulating phagocytosis and inhibiting cytokine production (6). The association between TREM2 and AD was first suggested by findings indicating that homozygous loss-of-function variants of TREM2 caused autosomal recessive Nasu-Hakola disease, which is characterized by polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and early-onset dementia (7). Subsequent genome-wide and exome-wide sequencing revealed that rare coding variants of TREM2 may confer a risk of AD (4,8). A rare missense variant, p.Arg47His (R47H, rs75932628), has been identified as a risk factor of AD in Caucasians (4,8), but not in African-American or Asian populations (9,10). Additional rare variants, including p.Arg62His (R62H, rs143332484), p.Asp87Asn (D87N, rs142232675) and p.His157Tyr (H157Y, rs2234255), have also been detected in AD subjects and indicated to increase the susceptibility to AD (11,12). Furthermore, certain TREM2 mutations, such as p.Gln33stop, p.Tyr38Cys and Thr66Met, have been identified only in patients with AD but not in normal controls, and appear to be causative (13), However, due to the low frequency of these variants, studies with a small sample size may not have adequate power to identify the...