The neuropathologic basis for translational biomarker development in the macaque model of late-onset Alzheimer's disease.

Abstract

BackgroundAccurate placement of the macaque within the Alzheimer's disease (AD) research framework is essential to discover early-stage predictive biomarkers.ObjectiveTo assess utility of the aging macaque in advancing translational biomarker development for preclinical AD, we evaluated relative signal strength of comparable neuropathologic phenomena in macaques and patients.MethodsWe compared pathology in patient and macaque formalin-fixed paraffin embedded (FFPE) tissues using identical criteria. We quantified expression of amyloid-β (Aβ), pTau, and inflammatory and senescence markers across species. Distribution of AD-relevant markers were compared in FFPE and perfused frozen macaque brain to assess expression of labile proteins that could inform in-life fluid biomarkers.ResultsAβ pathology in macaques closely approximated patient pathology. Complex plaque composition in macaques implied significant disruption of synaptic connectivity. In FFPE tissue, pretangle pTau immunoreactivity placed the macaque in Braak Stage 1b. In perfused frozen tissue, soluble pTau distribution approximated Braak Stage III-IV. In macaque, Aβ, pTau, and acetylcholinesterase labeling co-localized to AD-vulnerable circuits. Significant association of glial fibrillary acidic protein with Aβ occurred in humans only. The senescence marker p16 correlated positively with pTau expression and negatively with Aβ in patients only. Macaques lacked neuropathologic co-morbidities.ConclusionsAD-relevant neuropathologic signals in the macaque support biomarker discovery in the areas of Aβ plaque evolution and associated synaptic disruption as well as early-stage tau phosphorylation. Relative protection from accumulation of senescence markers, fibrillar tau and neuropathologic co-morbidities in macaque implicate species difference in rates of biological brain aging. We provide over 4000 digital slides for further study.