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In Alzheimer's disease (AD), neuropsychiatric symptoms (NPS) correlate with tau deposition in the brain. Here, we investigated the association of PET-based Braak stages with NPS and assessed whether they predict annual changes in NPS. We evaluated 231 individuals in the aging and AD continuum. Participants were assigned a Braak stage at baseline and followed for 1.97 (s.d. 0.62) years. NPS were investigated using the Mild Behavioral Impairment Checklist (MBI-C) and the Neuropsychiatric Inventory Questionnaire severity (NPI-Q-S) and distress (NPI-Q-D) scales. Multiple linear regressions (MLR) assessed the association of Braak stages with baseline NPS and the annual change in NPS scores. At baseline, stages I-II, III-IV, and V-VI were associated with higher MBI-C, NPI-Q-S, and NPI-Q-D scores. Stages V-VI were associated with a significant annual increase in MBI-C scores. These findings suggest that tau accumulation may manifest clinically with an increase in NPS, which seems to be an early event in AD pathophysiology. Moreover, PET-based Braak staging appears to be a good predictor of NPS severity progression., Competing Interests: Declaration of Interest E.R.Z. serves on the scientific advisory board of Next Innovative Therapeutics. Z.I. has served as an advisor/consultant to CADTH, Eisai, Eli Lilly, Lundbeck/Otsuka, Novo Nordisk, and Roche. S.G. has served as a scientific advisor to Cerveau Therapeutics. Outside the work presented in this paper, P.R.N. provides consultancy services for Roche, Cerveau Radiopharmaceuticals, Lilly, Eisai, Pfizer, and Novo Nordisk. P.R.N. also serves as a clinical trials investigator for Biogen and Novo Nordisk. The other authors declare that they have no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. Methods: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ( ζ / δ ) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. Results: 14-3-3 ζ / δ was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 ζ / δ correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. Conclusions: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation. [ABSTRACT FROM AUTHOR]