HETEROGENEITY IN TAU, AMYLOID AND CO-MORBID PATHOLOGIES IN ALZHEIMER'S DISEASE

Abstract

Distribution of fibrillar Tau inclusions, amyloid plaque load and Lewy body burden are known, independent, contributors to cognitive impairment in the elderly. Patients with neurodegenerative disorders like Alzheimer's (AD) contain significant heterogeneity in molecular, pathological, and clinical presentation. We sought to quantitatively characterize common co-morbid pathologies in AD and understand their relationship to each other and disease status. Sections from 275 clinically and post-mortem confirmed AD cases were stained and IHC quantified for Tau, Amyloid, TDP-43 and Lewy-type pathology, across several brain regions: frontal, temporal, parietal and occipital cortices, hippocampus and entorhinal cortex, as well as amygdala for TDP-43. Association of each pathology and total pathology burden with MMSE score, total white matter rarefaction score, CERAD neuritic plaque density and CAA total score, were examined. Across the AD cohort there was significant heterogeneity in the total level of Tau pathology at each disease stage, but particularly in early stages of disease. We also present the largest study of the role of TDP-43 positive lesions in AD to date. Including age and sex as covariates, subjects with cognitive impairment, but low levels of Tau pathology tended to have higher levels of co-morbid pathologies, such as Lewy-type pathology. Cognitive impairment in elderly subjects and AD patients is often multifactorial. Understanding how heterogeneity in and between pathologies interact and relate to cognitive impairment and progression can enable stratified approaches to development of single agent and combination therapeutics.