Alzheimer's genetic risk is reduced in primary age‐related tauopathy: a potential model of resistance?

Abstract

Abstract Objective Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles ( NFT s) and a significant proportion of individuals additionally develop amyloid plaques (A β ) consistent with Alzheimer's disease ( AD ). In an effort to identify the independent genetic risk factors for NFT s and A β , we investigated genotypic frequencies of AD susceptibility loci between autopsy‐confirmed AD and primary age‐related tauopathy ( PART ), a neuropathological condition defined by characteristic neurofibrillary tau tangles ( NFT s) with minimal or absent A β . Methods General linear models assessed the odds of AD ( N = 1190) relative to PART ( N = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank ( PENN ; AD N = 312; PART N = 65) and National Alzheimer's Coordinating Center ( NACC ; AD N = 878; PART N = 311). We also evaluated the odds of Braak stage NFT burden. Results Three genotypes significantly associated with reduced AD risk relative to PART in the PENN ( N = 377) and NACC ( N = 1189) cohorts including APOE ε 4, APOE ε 2, and rs6656401 in the CR 1 gene. The genotypes rs6733839 in the BIN 1 gene and rs28834970 in the PTK 2B gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis ( N = 1566), APOE ε 4 dosage was highly associated with higher Braak stage of NFT burden in Probable PART and AD , but not Definite PART . Interpretation The presence of genotypic differences between PART and AD suggest that PART can provide a genetic model of NFT risk and potential A β resistance to inform disease‐modifying therapies.