Mesial temporal tau pathology impacts basal forebrain degeneration in early Alzheimer's disease.

INTRODUCTION: The cholinergic basal forebrain system, particularly the nucleus basalis of Meynert (Ch4), is selectively vulnerable to amyloid beta (Aβ) and tau in Alzheimer's disease (AD). Their interplay may be a critical driver of AD progression, but remains poorly understood. METHODS: Data from 779 older individuals in the Australian Imaging, Biomarker, and Lifestyle study were analyzed, all of whom underwent 18F-NAV4694 Aβ and 18F-MK6240 tau positron emission tomography and magnetic resonance imaging. RESULTS: The co-occurrence of Aβ and mesial-temporal (MTL) tau pathologies was associated with reduced Ch4 volumes in cognitively unimpaired individuals. MTL tau burden was associated with Ch4 volumes exclusively in cognitively unimpaired individuals with established Aβ pathology, which was not observed for the hippocampus. This association persists in individuals with mild cognitive impairment, but was not apparent in AD dementia. DISCUSSION: Findings underscore early Ch4 degeneration associated with Aβ and tau pathologies, supporting potential cognitive benefits of cholinergic therapies in early disease stages. HIGHLIGHTS: Early-stage tau pathology in the mesial-temporal (MTL) region was assessed using 18F-MK6240 positron emission tomography. Co-occurring amyloid beta and MTL tau was linked to reduced nucleus basalis of Meynert (Ch4) volume in cognitively unimpaired individuals. Ch4 volume was associated with MTL tau burden exclusively in preclinical Alzheimer's disease (AD). No comparable association was observed between MTL tau and hippocampal volume. The MTL tau-Ch4 association persisted into the prodromal stage of AD.