Farrell K, Han N, Iida M, Walker J, Richardson T, Bhangale T, White C, Crary J. Identification of common variants influencing risk of primary age-related tauopathy. Poster presented at the 2019 American Association of Neuropathologists, Inc. 95th Annual Meeting; June 2019. Atlanta, GA. [abstract] J Neuropathol Exp Neurol. 2019 Jun; 78(6):571-2. doi: 10.1093/jnen/nlz034.

Primary age-related tauopathy (PART) is a designation introduced to describe Alzheimer-type tauopathy that develops in the absence of significant amyloid beta (Ab) pathology. Subjects with PART may have normal cognition, amnestic mild cognitive impairment, or an amnestic dementia. There is a critical need to better understand PART given its high prevalence, relationship to Alzheimer disease (AD), and potential to lead to mechanistic insights involving the pathogenesis of tauopathies. We obtained fresh frozen and formalin-fixed paraffin-embedded sections from 20 brain repositories in the United States and abroad, from subjects aged 50-108 years old with minimal or no amyloid pathology. Hippocampal and cortical sections were assessed using immunohistochemistry for abnormal hyperphosphorylated tau (p-tau) and Ab. NFT burden was measured using semi-quantitative and computer-assisted morphometrics. Single nucleotide polymorphism (SNP) chips were used to genotype the subjects. Genetic association tests were first analyzed on the entire cohort (n¼893) and then subsequent analysis focused on subjects with no neuritic plaques (CERAD¼0). Using Braak stage as a semi-quantitative trait, our results on the entire cohort showed suggestive signals on chromosomes 19 and 22, however they did not reach genome wide significance (p  510-8). Similarly, results using quantitative p-tau burden as our trait had suggestive signals, but none crossed the genome wide significant threshold. However, when the cohort was controlled for subjects without any neuritic plaques (n¼713), a genome wide significant hit was found on chromosome 4 using Braak stage as a quantitative trait. Additionally, using quantitative p-tau burden as our trait, other genome wide signals were observed. Our results support to the hypothesis that PART is an Ab-independent process with a unique neuropathological and genetic signature.

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