Abstract Details

Title Tau and neurodegeneration mismatch is a signature of polypathology in AD continuum

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) P1 - Poster Session 1 (5:30 PM-6:30 PM)

Poster/Presentation
Number 9-011

Objective To validate interpretation of the relationship between tau pathology and neurodegeneration within the ATN research framework

Background The ATN framework provides biological classification of individuals along the Alzheimer’s Disease (AD) pathological continuum by determining the presence/absence of cerebral beta-amyloid plaques (A), tau-based pathology (T), and neurodegeneration (N). The presence of A and T are required for definition of AD and N is thought driven by presence of T. In this context, individuals who are A+T+N+ are thought to have AD while those who are A+, but with T and N mismatch (i.e. T-N+), are argued to have AD and concomitant suspected non-Alzheimer’s pathologic (SNAP) change. These predictions have not been validated

Design/Methods

87 individuals from the PENN Brain Bank with autopsy, antemortem MRI, and CSF were classified based on ATN status. Standard cutoffs were used to define A+ (CSF abeta<192), T+ (CSF p-tau>23), and N+ (either t-tau>93 or age- and ICV-adjusted hippocampal volume with 90% sensitivity to AD in ADNI).

Results Consistent with the ATN framework, all of the A+T+N+ group (n=20) had AD as high (n=8; 40%) or intermediate (n=12; 60%) level AD neuropathological change. The mismatched A+T-N+ group (n=15) was mixed with two high (13%), nine intermediate (60%), and two low (13%) level AD pathology; two (13%) had no AD pathology. Amongst those with at least low probability AD, the A+T-N+ group had an increased composite rating of non-AD pathology based on staging of alpha-synuclein, TDP-43, and atherosclerosis (0-9 scale; median: 4, range: 5 versus median: 3, range 6, p<0.05). There was a trend for A+T-N+ group to be older (mean=76.3±6.4 vs. mean=70.0±13.7, p=0.09) and have smaller hippocampi (mean=4886.9±1103.2 vs. mean=5161.6±1150.6, p>.1).

Conclusions These findings are consistent with the notion that in the setting of cerebral beta-amyloid plaques, neurodegeneration in absence of tau (A+T-N+) is an indicator of mixed AD pathology

Authors/Disclosures
David A. Wolk, MD, FAAN (University of Pennsylvania) PRESENTER	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.
John Q. Trojanowski, MD, PhD (University of PA School of Med)	Dr. Trojanowski has nothing to disclose.
David Irwin, MD (University of Pennsylvania)	The institution of Dr. Irwin has received research support from NIH. The institution of Dr. Irwin has received research support from Prevail. The institution of Dr. Irwin has received research support from Passage Bio. The institution of Dr. Irwin has received research support from Alector. The institution of Dr. Irwin has received research support from Transposon. The institution of Dr. Irwin has received research support from Denali. The institution of Dr. Irwin has received research support from Cervo Med.
Murray Grossman, MD, FAAN (University of Pennsylvania)	Dr. Grossman has received personal compensation in the range of $5,000-$9,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Neurology. The institution of Dr. Grossman has received research support from NIH.
Leslie M. Shaw, PhD (Perelman School of Med, U of PA)	Dr. Shaw has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Biogen. Dr. Shaw 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. Shaw has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. The institution of Dr. Shaw has received research support from NIA. The institution of Dr. Shaw has received research support from MJ Fox foundation for Parkinsons Research.
Jeffrey S. Phillips, PhD (Penn FTD Center, Department of Neurology)	No disclosure on file
	No disclosure on file
	No disclosure on file
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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