Abstract Details

Title Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer’s Disease Neuropathology

Topic Aging, Dementia, and Behavioral Neurology

Presentation(s) S15 - Innovative Diagnostics in Dementia (1:48 PM-2:00 PM)

Poster/Presentation
Number 005

Background Cerebrospinal fluid (CSF) biomarkers of Aβ_1-42 and p-tau₁₈₁ are the gold standard for detection of Alzheimer’s disease (AD) during life. Yet, CSF biomarker validation studies have largely used clinical endpoints and/or Aβ-PET imaging as the reference. Few CSF-to-autopsy studies exist, and existing ones have been restricted to late-stage AD. In vivo detection of early AD neuropathology is crucial as it is an opportune time for prevention and therapeutic intervention.

Objective This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathological changes among brain donors who had normal cognition at time of lumbar puncture (LP).

Design/Methods The study included brain donors from the National Alzheimer’s Coordinating Center (NACC) who had CSF biomarker data and normal cognition. Due to lack of standardization of CSF analysis in NACC, antemortem CSF concentrations of Aβ_1-42, p-tau₁₈₁, and t-tau were measured using three assay methods: ELISA (n=9), Luminex (n=21), and Lumipulse (n=49). Neuropathological diagnosis of AD was based on a Braak≥3 and CERAD≥2. Logistic regression tested associations between each CSF biomarker and AD status, controlling for age, sex, APOE ε4, LP and death interval, and CSF assay method. Area under the curve (AUC) evaluated accuracy for discriminating AD+/AD- brain donors.

Results Of the 79 brain donors (n=40, 50.6% male; n=77, 97.5% white), 26 (32.9%) had autopsy-confirmed AD. Average age at LP was 80.3 (SD=6.1) years. Log-CSF p-tau₁₈₁/Aβ_1-42 was the optimal predictor of AD+ (OR=15.86, 95% CI=4.34-57.94, p<.001), and had a high discrimination accuracy (AUC=.903). CSF p-tau₁₈₁ was the second-best predictor of AD status (AUC=.832, OR=1.04, 95% CI=1.02-1.06, p<.001), followed by CSF Aβ_1-42 (AUC=.758, OR=0.995, 95% CI=0.992-0.999, p=0.005), and CSF t-tau that had the lowest discrimination accuracy (AUC=.746, OR=1.003, 95% CI=1.001-1.005, p=0.009).

Conclusions

This study validates the usefulness of CSF Aβ_1-42 and p-tau₁₈₁ for the early detection of AD pathophysiological processes, especially the ratio p-tau₁₈₁/Aβ_1-42.

Authors/Disclosures
Michelle J. Safransky PRESENTER	Miss Safransky has nothing to disclose.
Kaj Blennow	Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for ALZPath. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for AriBio. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Beckman-Coulter. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BioArctic. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Lilly. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Moleac Pte. Ltd. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Neurimmune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Ono Pharma. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Prothena. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Quanterix. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Siemens Healthineers. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for ALZPath. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AriBio. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Beckman-Coulter. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for BioArctic. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Lilly. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Moleac Pte. Ltd. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Neurimmune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Ono Pharma. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Prothena. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Quanterix. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Siemens Healthineers. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Julius Clinical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AC Immune. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Celdara Medical. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Eisai. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche Diagnostics. Kaj Blennow has received personal compensation in the range of $500-$4,999 for serving as a Co-founder with Brain Biomarker Solutions.
Henrik Zetterberg (Sahlgrenska University Hospital/Molndal)	Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Abbvie, Acumen, Alector, Alzinova, ALZpath, Amylyx, Annexon, Apellis, Artery Therapeutics, AZTherapies, Cognito Therapeutics, CogRx, Denali, Eisai, LabCorp, Merry Life, Nervgen, Novo Nordisk, Optoceutics, Passage Bio, Pinteon Therapeutics, Prothena, Quanterix, Red Abbey Labs, reMYND, Roche, Samumed, Siemens Healthineers, Triplet Therapeutics, and Wave. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Alzecure, BioArctic, Biogen, Cellectricon, Fujirebio, Lilly, Novo Nordisk, Roche, and WebMD. Henrik Zetterberg has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Wiley and Elsevier. Henrik Zetterberg has stock in Brain Biomarker Solutions.
Yorghos Tripodis	Yorghos Tripodis 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 American Medical Association.
	No disclosure on file
Jason Weller, MD (University of Florida Health)	Dr. Weller has nothing to disclose.
Breton Asken	Breton Asken has nothing to disclose.
Gil D. Rabinovici, MD, FAAN (UCSF Memory & Aging Center)	Dr. Rabinovici has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Eli Lilly. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alector. Dr. Rabinovici has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Merck. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novo Norodisk. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Consultant for C2N. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Johnson & Joihnson. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving on a Speakers Bureau for Peerview. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Medscape. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA Neurology. Dr. Rabinovici has received personal compensation in the range of $10,000-$49,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for JAMA. The institution of Dr. Rabinovici has received research support from NIH. The institution of Dr. Rabinovici has received research support from American College of Radiology. The institution of Dr. Rabinovici has received research support from Alzheimer's Association. The institution of Dr. Rabinovici has received research support from Rainwater Charitable Foundation. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Topic Chair, Course Director and teacher with AAN. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Grant reviewer with NIH. Dr. Rabinovici has received personal compensation in the range of $500-$4,999 for serving as a Invited speaker with ANA.
	No disclosure on file
Ann C. McKee, MD (VA Boston)	Dr. McKee has nothing to disclose.
Thor D. Stein, MD, PhD (VA Boston Healthcare System)	Dr. Stein has nothing to disclose.
Michael Alosco, PhD (Boston University)	The institution of Michael Alosco, PhD has received research support from NIH. The institution of Michael Alosco, PhD has received research support from Life Molecular Imaging Inc.

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