rs75932628

rs75932628(T), a SNP in the TREM2 gene on chromosome 6 resulting in an R47H substitution, was found to confer a significantly higher risk of late-onset Alzheimer's disease based on two articles published together in 2013 in the New Engl. J. of Med. In one study, the odds ratio for rs75932628(T) was 2.9 (CI: 2.09 to 4.09, P=3.42×10−10). The mutation had a frequency of 0.46% in controls 85 years of age or older. The authors also observed the association in additional sample sets (odds ratio, 2.90; 95% CI, 2.16 to 3.91; P=2.1×10−12 in combined discovery and replication samples), and found that carriers of rs75932628-T between the ages of 80 and 100 years without Alzheimer's disease had poorer cognitive function than noncarriers (P=0.003). In the other study, analysis of the rs75932628(T) in a series that included 1887 patients with Alzheimer's disease showed a strong, highly significant association (odds ratio, 5.05, CI: 2.77 to 9.16; P=9.0×10−9). Four other TREM2 gene variants (D87N, T66M, Y38C, and Q33X) were also associated with higher risk for a frontotemporal dementia–like syndrome when homozygous. Notably, a 2018 study has raised the possibility that in TREM2 R47H mutation carriers, an APOE4 allele may be required for Alzheimer's to develop. Other studies confirming (or in some cases, refuting) an association between R47H and Alzheimer's include: Data shows that rs75932628 is highly significantly associated with the risk of AD across 24,086 AD cases and 148,993 controls of European descent (OR 2.71, p = 4.67 × 10e-25). Based on a study of ~1,000 Alzheimer patients, the R47H mutation does appear to be a risk factor for AD (OR = 2.19, CI:1.04-4.51, p = .03). Individuals with p.R47H associated AD (n = 12) had significantly earlier symptom onset than individuals with no TREM2 variants (n = 551) (55.2 years vs. 61.7 years (p = .02). Based on a Caucasian population comprising ~1,600 late-onset Alzheimer cases, carriers of the R47H variant are at increased risk (OR 7.40, p = 3.66e-06). A study of 474 AD patients from the northwest region of the UK showed a significant association of the R47H mutation with AD (OR 11.08, CI: 2.55-48.09, and Yates' corrected p value = 0.000146). Meta-analysis of 2 family-based and 5 case-control cohorts yielded an overall summary estimate (using case-control data only) for an odds ratio of 1.67 (CI: 0.95-2.92) for the association between the TREM2 R47H and increased AD risk; so while this study replicates the association, it finds a weaker effect than have other studies. A study of ~3,000 AD patients from Spain did see the R47H association with AD (OR 4.12, CI: 1.21-14.00, p = 0.014). A meta-analysis comprising 32,598 subjects from 4 previous studies demonstrated the large effect of the p.R47H variant in AD risk (OR 4.11, CI: 2.99-5.68, p = 5.27×10e-18). No association was seen between R47H and AD in a study of ~2,000 Japanese patients with late-onset AD. Additional studies include: