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

Objective: Nearly all adults >50 years of age have evidence for neurofibrillary tau tangles (NFTs) and a significant proportion of individuals additionally develop amyloid plaques (A) consistent with Alzheimer's disease (AD). In an effort to identify the independent genetic risk factors for NFTs and A, 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 (NFTs) with minimal or absent A.

Methods: General linear models assessed the odds of AD ( = 1190) relative to PART ( = 376) neuropathologically confirmed cases from two independent series: the Penn Brain Bank (PENN; AD = 312; PART = 65) and National Alzheimer's Coordinating Center (NACC; AD = 878; PART = 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 ( = 377) and NACC ( = 1189) cohorts including 4, 2, and rs6656401 in the gene. The genotypes rs6733839 in the gene and rs28834970 in the gene approached significance in the PENN cohort and were significantly associated with reduced AD risk in the NACC cohort. In a combined cohort analysis ( = 1566), 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 resistance to inform disease-modifying therapies.