Study Identifies Greater Symptom Burden at Parkinson Diagnosis in Patients With Amyloid Copathology

A recent retrospective study reported that patients newly diagnosed with Parkinson disease (PD) who harbored concurrent amyloid-β (Aβ) pathology showed a distinct clinical signature at baseline, including greater olfactory impairment, more severe dysautonomia, heightened mood disturbance, and motor disability exceeding what would be expected from dopaminergic denervation alone.

These findings, recently published in Movement Disorders, suggest that specific nonmotor and motor profiles at diagnosis may help flag patients at elevated risk for Alzheimer disease (AD) copathology, a factor increasingly recognized as a driver of poorer PD trajectories.¹

Study Overview

Led by Han Kyu Na, MD, a neurologist and medical researcher at Yonsei University College of Medicine in South Korea, the study retrospectively identified 152 patients with drug-naive PD who had undergone amyloid imaging with ¹⁸F-florbetaben PET between July 2016 and February 2025, along with dopamine transporter (DAT) imaging, olfactory testing (Cross-Cultural Smell Identification Test [CC-SIT]), autonomic function testing, neuropsychological assessment, and the Neuropsychiatric Inventory Questionnaire (NPI-Q). Patients were classified as Aβ-positive (n = 59, 38.8%) or Aβ-negative (n = 93, 61.2%) based on visual assessment of delayed-phase PET scans. Predictors of Aβ positivity were assessed using multivariable logistic regression and validated with Random Forest classifiers incorporating Boruta feature selection.

Key Findings

Compared with Aβ-negative patients, the Aβ-positive group had lower CC-SIT scores (4.15 vs 6.01, indicating worse smell identification; P = .002), higher Composite Autonomic Severity Scale scores (4.81 vs 3.18; P <.001), and greater NPI-Q mood subscores (P <.001). Probable REM sleep behavior disorder (67.8% vs 46.2%; P = .009) and neurogenic orthostatic hypotension (47.5% vs 25.8%; P = .006) were also more common in the Aβ-positive group. Notably, cognitive test performance did not differ significantly between groups at baseline.

Motor disability, measured by UPDRS Part III, was significantly greater in Aβ-positive patients (29.59 vs 22.18; P <.001) despite comparable striatal dopamine transporter uptake between groups. Using a residual-based "motor reserve" model, in which motor scores predicted from dopaminergic denervation in the Aβ-negative group served as a reference, the investigators found that Aβ-positive patients had significantly worse-than-predicted motor function (P <.001), suggesting Aβ copathology may impair motor circuits independent of nigrostriatal degeneration.

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A stepwise logistic regression model identified five independent predictors of Aβ positivity: lower CC-SIT score (odds ratio [OR], 0.821), higher autonomic severity score (OR, 1.380), greater mood disturbance (OR, 1.057), APOE ε4 carrier status (OR, 3.643), and higher UPDRS-III score (OR, 1.080), with strong discriminative performance (area under the curve, 0.813). These variables were corroborated by a Random Forest model using Boruta-confirmed features (area under the curve, 0.807). Over a median follow-up of roughly 4 to 5 years, Aβ-positive patients also had more than triple the hazard of converting to PD dementia compared with Aβ-negative patients (hazard ratio, 3.505; P <.001).

Clinical Context

AD pathology is among the most common copathologies identified at PD autopsy and has been linked to a distinct, more cognitively impaired PD phenotype with faster functional decline.² Diagnostic criteria for PD dementia have historically relied on longitudinal cognitive and functional assessment rather than biomarker-based prediction at diagnosis, underscoring the clinical need for earlier risk indicators.³

Prior biomarker work in the Parkinson Progression Markers Initiative cohort similarly found that cerebrospinal fluid Aβ levels tracked with motor severity and less favorable motor phenotypes without corresponding baseline cognitive differences, a pattern consistent with the present findings.⁴ Until now, no validated clinical markers existed to flag AD copathology risk early in the PD disease course, with most prior data drawn from advanced-stage cohorts.

Interpretation

The authors proposed that shared vulnerability of olfactory, limbic, and autonomic networks to both Aβ and α-synuclein pathology may underlie the observed symptom clustering, and that Aβ may impair motor circuits through extra-nigrostriatal mechanisms rather than accelerating dopaminergic cell loss itself. They emphasized that individual features carry limited specificity on their own, since each is common across the broader PD population, and that constellations of features, rather than isolated symptoms, may better flag distinct, biologically meaningful subtypes.

Limitations

Because amyloid imaging was not performed systematically at diagnosis, more than a third of patients were scanned specifically for clinical concern about rapid cognitive decline, the prevalence of Aβ positivity and between-group differences may be inflated relative to the general PD population. The study was also cross-sectional with inconsistent intervals between DAT and Aβ imaging, precluding causal inference, and was conducted at a single center with a modest sample size lacking external validation; tau pathology was not assessed. The authors noted that validation in independent, prospective cohorts may be needed to confirm whether these Aβ-associated clinical profiles generalize to the broader PD population, and suggested that incorporating tau biomarkers could further refine early risk stratification for AD copathology in PD.

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REFERENCES
1. Na HK, Sun Y, Park CW, et al. Greater Motor and Nonmotor Burden at Diagnosis Is Associated With Amyloid Copathology in Parkinson's Disease. Mov Disord. Published online July 28, 2026. doi:10.1002/mds.70446
2. Aarsland D, Batzu L, Halliday GM, et al. Parkinson disease-associated cognitive impairment. Nat Rev Dis Primers. 2021;7(1):47. Published 2021 Jul 1. doi:10.1038/s41572-021-00280-3
3. Dubois B, Burn D, Goetz C, et al. Diagnostic procedures for Parkinson's disease dementia: recommendations from the movement disorder society task force. Mov Disord. 2007;22(16):2314-2324. doi:10.1002/mds.21844
4. Kang JH, Irwin DJ, Chen-Plotkin AS, et al. Association of cerebrospinal fluid β-amyloid 1-42, T-tau, P-tau181, and α-synuclein levels with clinical features of drug-naive patients with early Parkinson disease. JAMA Neurol. 2013;70(10):1277-1287. doi:10.1001/jamaneurol.2013.3861