ALZHEIMER’S DISEASE PROTEOMIC PROGRESSION IN THE OLFACTORY BULB IS MODIFIED BY PARKINSON’S DISEASE CO-PATHOLOGY

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide. However, AD exhibits interindividual variability in clinical presentation, progression rates and neuropathological features. A major source of this heterogeneity is frequent proteinopathy co-occurrence, with α-synuclein (α-syn) pathology present in 40-60% of AD cases. Concomitant Parkinson’s disease (PD) pathology has emerged as a key modifier of AD progression, accelerating cognitive decline and worsening clinical outcomes. The olfactory bulb (OB), an early and preferentially vulnerable region in both disorders, provides a window to study their molecular interplay. This study aimed to determine how PD pathology stages modify the proteomic landscape associated with AD progression in the OB. Post-mortem human OB samples from 103 individuals of both sexes were analyzed in 12 groups: 3 with AD (Braak tau I-II, III-IV, V-VI) and 9 with AD+PD co-pathology (combining Braak tau I-VI and Braak α-syn 1–6). Proteomic profiling was performed using liquid chromatography–tandem mass spectrometry (LC–MS/MS) in subjects across Braak tau stages I–VI, stratified according to concurrent PD pathology (Braak α-syn 1–6). In total, 30,297 peptides from 5,495 proteins were identified. Differential protein expression was analyzed across AD progression within each PD stage group to identify PD-specific effects on AD-related proteomic alterations. Bioinformatic analyses support a stage-dependent modulatory effect of PD pathology on AD proteomic progression. We acknowledge donors and the Netherlands and Spanish Biobank Networks. Funding: UCLM/ERDF (2025-GRIN-38350), JCCM/ERDF (SBPLY/24/180225/000065), and MICINN (PID2019-108659RB). AAG was supported by a UCLM/FSE+ predoctoral contract.