Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer’s Disease Neuropathology
Michelle Safransky1, Kaj Blennow2, Henrik Zetterberg3, Yorghos Tripodis1, Brett Martin1, Jason Weller4, Breton Asken5, Gil Rabinovici6, Wendy Qiu7, Ann McKee8, Thor Stein9, Michael Alosco1
1Boston University, 2University of Goteborg, Sahlgrenska University Hospital, 3Sahlgrenska University Hospital/Molndal, 4Boston VA Healthcare System, 5University of Florida, 6UCSF Memory & Aging Center, 7Boston University School of Medicine, 8VA Boston, 9VA Boston Healthcare System
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).
Background:
Cerebrospinal fluid (CSF) biomarkers of Aβ1-42 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.
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 Aβ1-42, 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/Aβ1-42 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 Aβ1-42 (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 Aβ1-42 and p-tau181 for the early detection of AD pathophysiological processes, especially the ratio p-tau181/Aβ1-42.