Effect of tau burden and Lewy pathology on neuropsychiatric symptoms in Aβ-positive individuals.

INTRODUCTION: Neuropsychiatric symptoms (NPS) are common across the Alzheimer's disease (AD) spectrum. We aimed to evaluate the effects of amyloid beta (Aβ), tau, and Lewy body (LB) pathologies on NPS in Aβ-positive individuals. METHODS: In 336 Aβ-positive participants from the Alzheimer's Disease Neuroimaging Initiative cohort, spanning from cognitively unimpaired to those with early dementia, NPS were assessed. Aβ and tau positron emission tomography were conducted. In a subgroup of 238 participants, dichotomized LB pathology was assessed by detecting α-synuclein seeding activity. The effects of Aβ, tau, and LB pathologies on NPS were evaluated using logistic regression analyses. RESULTS: Greater tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. In subgroup analyses, LB pathology was associated with delusion, anxiety, apathy, and sleep disturbance, independent of Aβ and tau burden. DISCUSSION: Tau and LB pathologies are major determinants of NPS in Aβ-positive individuals, each contributing distinct symptom profiles. HIGHLIGHTS: Tau burden was associated with delusion, agitation/aggression, irritability/lability, aberrant motor behavior, and appetite/eating disorder. Tau in frontal, temporal, and limbic cortices was associated with delusion. In amyloid beta (Aβ)-positive individuals, co-occurring Lewy body (LB) pathology is associated delusion, anxiety, apathy, and sleep disturbance, independent of tau. Tau and LB pathologies are associated with the distinct profiles of neuropsychiatric symptoms in Aβ-positive individuals.