Identifying early changes in imaging, plasma, and digital cognitive biomarkers that correspond to Alzheimer's disease pathology in the presence of autopsy-confirmed co-pathologies.

INTRODUCTION: Alzheimer's disease (AD) biomarkers are assessed on their ability to detect AD pathophysiology in vivo, with confirmation of AD neuropathology only at autopsy. METHODS: Positron emission tomography (PET), plasma, and cognitive AD biomarkers were compared to AD neuropathology in Harvard Aging Brain Study participants (10 cognitively unimpaired; 6 mild cognitive impairment). Different PET methods were evaluated, for example, standardized uptake volume ratio (SUVR), distribution volume ratio (DVR), spatial extent (EXT), and partial-volume correction (PVC). RESULTS: Amyloid beta (Aβ)-PET ((11)C-Pittsburgh compound B [PiB]), tau-PET ((18)F-flortaucipir [FTP]), and plasma tau phosphorylated at threonine 217 (p-tau217) correlate with Aβ plaques (A-score), Braak tau neurofibrillary tangle (NFT) stage (B-score), and neuritic plaques (C-score), whereas plasma glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and cognitive measures did not; although digital Clock Drawing Test (dCDT) latency features did, in an exploratory comparison. Correlations were stronger for Aβ-PET DVR and Aβ-PET EXT (than SUVR with/without PVC) and tau-PET SUVR (composite reference and PVC). DISCUSSION: These findings support the innovative use of imaging, plasma, and digital cognitive tools for detecting AD pathophysiology in a largely cognitively unimpaired population. HIGHLIGHTS: Amyloid beta-positron emission tomography (Aβ-PET), tau-PET imaging, and plasma tau phosphorylated at threonine 217 (p-tau217) correlate with ABC scores Correlations were larger for Aβ-PET distribution volume ratio (DVR) and tau-PET standardized uptake volume ratio (SUVR; composite reference, partial volume correction [PVC]) Digital Clock Drawing Test latency features correlate with A- and Cscores Standard cognitive measures mostly did not correlate with ABC scores Plasma glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) biomarkers did not correlate with ABC scores.