Abstract Details

Title Convergent Evidence for a Longevity Genetic Locus Associated with Tau Load in PART

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S34 - Aging and Dementia: Risk Factors, Biomarkers, and Neuropathology (2:06 PM-2:17 PM)

Poster/Presentation
Number 007

Background GWAS have identified longevity-associated SNPs, but these loci have not been evaluated relative to age-related pathological accumulation including NFTs and amyloid-beta (Aβ). PART is characterized neuropathologically by NFTs in the absence of Aβ pathology. Previous work demonstrated that PART has reduced frequency of AD-susceptibility alleles relative to AD, suggesting genetic evidence for Aβ “resistance.” We hypothesized that longevity-associated genetic loci may further confer increased resistance in PART.

Objective Evaluate whether single nucleotide polymorphisms (SNPs) previously associated with longevity are protective against neurofibrillary tangle tau (NFT) pathology in primary age-related tauopathy (PART) or Alzheimer’s disease (AD).

Design/Methods We evaluated 765 aging individuals from the Religious Orders Study or Memory and Aging Project (ROSMAP) characterized post-mortem as PART (Braak=I-IV, CERAD=0) or AD (Braak=III-VI, CERAD=2-3). We extracted 29 SNPs previously associated with longevity (age ≥ 90 or event-free survival) from the Affymetrix panel. We performed linear regression to relate SNP x Group interactions, adjusting for sex and age. In a validation study with 155 ADNI cases we related significant SNPs to floretaucipir in the superior temporal cortex (STC; consistent with Braak V-VI) in cases defined as amyloid-negative or amyloid-positive (florbetapir>1.11) using a similar regression model.

Results The ROSMAP cohort revealed a significant interaction for proxy SNP rs8102566 (ATCAY; d’ 0.95) x Group associated with dose-dependent reduced Braak NFT severity in PART relative to AD (β=-0.36, p=0.008). In ADNI we observed a similar association for rs10412199 (ATCAY) x Group interaction associated with reduced dose-dependent STC floretaucipir uptake (β=-0.12, p=0.022) in amyloid-negative cases.

Conclusions We observed convergent neuropathological and PET evidence for a locus in ATCAY, previously implicated in neuronal development, associating with reduced NFT severity in PART, but not AD. These findings enrich evidence that NFTs in PART may be guided by distinct mechanisms from AD NFTs and that common genetic variation may contribute to “resistance” in PART.

Authors/Disclosures
Kyra O'Brien, MD (University of Pennsylvania) PRESENTER	Dr. O'Brien has nothing to disclose.
David A. Wolk, MD, FAAN (University of Pennsylvania)	Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Functional Neuromodulation. Dr. Wolk has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for GSK. The institution of Dr. Wolk has received research support from Biogen. Dr. Wolk has received publishing royalties from a publication relating to health care. Dr. Wolk has received personal compensation in the range of $5,000-$9,999 for serving as a CME speaker with Eli Lilly.
	No disclosure on file
	No disclosure on file
	No disclosure on file
Philip De Jager, MD, PhD (Columbia University Irving Medical Center)	Dr. De Jager has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. De Jager has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Puretech. Dr. De Jager has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for roche. Dr. De Jager has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for biogen. The institution of Dr. De Jager has received research support from roche. The institution of Dr. De Jager has received research support from Biogen. The institution of Dr. De Jager has received research support from puretech.
Julie A. Schneider, MD, MS (Rush Alzheimer'S Disease Center)	Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eli Lilly. Dr. Schneider has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for alnylam. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for apellis. Dr. Schneider has received personal compensation in the range of $5,000-$9,999 for serving as an Expert Witness for National Hockey League. The institution of Dr. Schneider has received research support from NIH. Dr. Schneider has received personal compensation in the range of $500-$4,999 for serving as a scientific advisor with Fondation Alzheimer, France.
David A. Bennett, MD (Rush University Medical Center)	Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Origent. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AbbVie. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a Study section, DMC, NACA Council with NIH. Dr. Bennett has received personal compensation in the range of $10,000-$49,999 for serving as a invited lectures with AMCs. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a invited paper with National Academy of Sciences. Dr. Bennett has received personal compensation in the range of $5,000-$9,999 for serving as a lecture with National Academy of Neuropsychology.
Corey McMillan, PhD (University of Pennsylvania)	Dr. McMillan has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Elsevier. The institution of Dr. McMillan has received research support from Biogen. The institution of Dr. McMillan has received research support from NIH.

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