Ramanan VK, Wang X, Przybelski SA, Raghavan S, Heckman MG, Batzler A, Kosel ML, Hohman TJ, Knopman DS, Graff-Radford J, Lowe VJ, Mielke MM, Jack CR, Petersen RC, Ross OA, Vemuri P. Variants in PPP2R2B and IGF2BP3 are associated with higher tau deposition. Brain Communications. PMID: 33426524 [PubMed] PMCID: PMC7780444
Tau deposition is a key biological feature of Alzheimer's disease that is closely related to cognitive impairment. However, it remains poorly understood why certain individuals may be more susceptible to tau deposition while others are more resistant. The recent availability of assessment of tau burden through positron emission tomography provides an opportunity to test the hypothesis that common genetic variants may influence tau deposition. We performed a genome-wide association study of tau-positron emission tomography on a sample of 754 individuals over age 50 (mean age 72.4 years, 54.6% men, 87.6% cognitively unimpaired) from the population-based Mayo Clinic Study of Aging. Linear regression was performed to test nucleotide polymorphism associations with AV-1451 (F-flortaucipir) tau-positron emission tomography burden in an Alzheimer's-signature composite region of interest, using an additive genetic model and covarying for age, sex and genetic principal components. Genome-wide significant associations with higher tau were identified for rs76752255 (=9.91 × 10, = 0.20) in the tau phosphorylation regulatory gene (protein phosphatase 2 regulatory subunit B) and for rs117402302 (=4.00 × 10, = 0.19) near (insulin-like growth factor 2 mRNA-binding protein 3). The association remained genome-wide significant after additionally covarying for global amyloid burden and cerebrovascular disease risk, while the association was partially attenuated after accounting for amyloid load. In addition to these discoveries, three single nucleotide polymorphisms within (microtubule-associated protein tau) displayed nominal associations with tau-positron emission tomography burden, and the association of the (apolipoprotein E) ɛ4 allele with tau-positron emission tomography was marginally nonsignificant (=0.06, = 0.07). No associations with tau-positron emission tomography burden were identified for other single nucleotide polymorphisms associated with Alzheimer's disease clinical diagnosis in prior large case-control studies. Our findings nominate and as novel potential influences on tau pathology which warrant further functional characterization. Our data are also supportive of previous literature on the associations of genetic variation with tau, and more broadly supports the inference that tau accumulation may have a genetic architecture distinct from known Alzheimer's susceptibility genes, which may have implications for improved risk stratification and therapeutic targeting.