Relationship of cholinergic basal forebrain atrophy with the time course of Alzheimer's disease pathology and cognitive decline in adults with Down syndrome: a longitudinal cohort study.

INTRODUCTION: Adults with Down syndrome (DS) display increased Alzheimer's disease (AD) risk. The cholinergic system declines early in the AD continuum and relates to cognitive and functional decline. We aimed to identify the timeline of cholinergic decline in relation to hippocampal atrophy within the AT(N) framework in DS. METHODS: Three-hundred fifty-eight adults with DS were assessed for longitudinal changes in cholinergic basal forebrain and hippocampal volume, amyloid positron emission tomography (PET), tau PET, and cognitive performance. RESULTS: Amyloid PET increased at 36.5 years old, while tau accumulation, cholinergic basal forebrain (ChBF), and hippocampal volumetric changes occurred in the participants' 40s. Cognitive decline on the modified cued recall test initiated at 41.7 years old. ChBF and hippocampal volumes negatively associated with AD pathology and positively associated with cognitive performance, with ChBF effects moderated by hippocampal volume. DISCUSSION: The timeline presented will inform the design of clinical trials targeting the cholinergic system or utilizing volumetric measures as biomarkers of efficacy or cognition. HIGHLIGHTS: The first longitudinal assessment of cholinergic basal forebrain and hippocampal volume in DSAD. The AT(N) framework utilized sporadic AD is consistent in DSAD. Cholinergic basal forebrain volume is an alternate measure of neurodegeneration in the AT(N) framework. Cholinergic effects on total recall on the mCRT are moderated by the hippocampus.