Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease

Concurrent Alzheimer's disease pathology is increasingly recognized as a poor prognostic factor in Parkinson's disease (PD), yet reliable clinical indicators for early identification of AD copathology remain poorly established.

To investigate baseline motor and nonmotor symptom profiles associated with amyloid-β (Aβ) copathology in newly diagnosed PD.

Among patients with PD who underwent Aβ imaging, we retrospectively identified 152 patients who completed the Cross-Cultural Smell Identification Test (CC-SIT), autonomic function tests, neuropsychological assessment, and Neuropsychiatric Inventory Questionnaire (NPI-Q) at drug-naive state. Predictors of Aβ positivity were identified using stepwise multivariable logistic regression and validated with Random Forest classifiers employing Boruta feature selection.

Compared with Aβ-negative counterparts (n = 93), Aβ-positive (Aβ + PD, n = 59) patients demonstrated greater olfactory dysfunction (CC-SIT, P = 0.002), dysautonomia (Composite Autonomic Severity Scale [CASS], P < 0.001), and mood disturbance (NPI-Q-mood, P < 0.001) and higher prevalence of probable rapid eye movement sleep behavior disorder (P = 0.009) and neurogenic orthostatic hypotension (P = 0.006). Aβ + PD patients showed greater motor disability (Unified Parkinson's Disease Rating Scale Part III [UPDRS-III], P < 0.001) despite comparable striatal dopamine transporter uptake. Logistic regression identified lower CC-SIT scores (odds ratio [OR] = 0.821, 95% confidence interval [CI_95%]: 0.703-0.959), higher CASS scores (OR = 1.380, CI_95%: 1.144-1.666), higher NPI-Q-mood scores (OR = 1.057, CI_95%: 1.005-1.111), higher UPDRS-III (OR = 1.080, CI_95%: 1.030-1.132), and APOE ε4 carrier status (OR = 3.643, CI_95%: 1.479-8.969) as independent predictors of Aβ positivity, which were also confirmed as important variables by Boruta feature selection.

Our findings suggest that greater motor and nonmotor symptom burden at diagnosis, characterized by olfactory/autonomic dysfunction, mood disturbance, and motor deficits disproportionate to dopaminergic denervation, was associated with Aβ positivity in PD. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.