CSF apolipoprotein B levels predict future visuospatial cognitive decline and synaptic pathology in cognitively unimpaired healthy elderly with a parental history of Alzheimer’s disease

Abstract

AbstractBackgroundWe examine the role of brain apolipoprotein B (apoB) as a putative CSF indicator of early tau pathology in pre‐symptomatic Alzheimer’s disease (AD).MethodAmong 129 cognitively unimpaired elderly at increased risk of AD (PREVENT‐AD cohort), we assessed blood and cerebrospinal fluid apoB, apoC3 and apoE protein levels with those of amyloid β42, total tau and phosphorylated tau. We compared results with amyloid‐b (NAV4694) and tau (flortaucipir) positron emission tomography uptake and cognitive assessment alterations over 6‐8 years. Tangle and plaque pathologies were contrasted with cortical APOB, APOC3 and APOE mRNA levels in 240 autopsied subjects enrolled in the Religious Orders Study and Memory and Aging Project (ROSMAP) studies with diagnoses of cognitively unimpaired, mild cognitive impairment, or AD.ResultAmong cognitively unimpaired participants, we observed significant correlations between baseline CSF, but not blood, apoB levels and both CSF t‐tau (R2 = 0.23, P < 0.0001) and P‐tau (R2 = 0.28, P < 0.0001). Similar associations were observed when using PET flortaucipir‐binding in entorhinal, parahippocampal and fusiform regions. No association was detected between CSF apoB and CSF Aβ42 levels or cerebral Ab deposition. Baseline CSF apoB levels were associated with visuospatial cognitive decline over the course of 6‐8 years (R2 = 0.13, P < 0.02) and alterations in several synaptic proteins in the CSF. Contribution from peripheral apoB was found to be negligible. In ROSMAP, APOB gene expression failed to correlate with either tangle pathology or amyloid plaque deposition.ConclusionCSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at‐risk individuals predisposed to develop visuospatial cognitive decline over time.