Objective To determine whether beta-amyloidopathy correlates with apathy rating scores independently of mood changes and other neurodegenerative processes in Parkinson disease (PD). Methods In this cross-sectional study, patients with PD (n = 64, 48 male and 16 female, mean age 69.2 +/- 6.7 years, Hoehn & Yahr stage 2.7 +/- 0.5, Montreal Cognitive Assessment score 25.3 +/- 3.0) underwent [C-11]Pittsburgh compound B beta-amyloid, [C-11]dihydrotetrabenazine vesicular monoamine transporter type 2 (VMAT2), and [C-11]methyl 4 piperidinyl propionate acetylcholinesterase brain PET imaging and clinical assessments, including the Marin Apathy Evaluation Scale, Clinician Version. Patients were recruited on the basis of having at least 1 risk factor for PD dementia, but they were excluded if they had dementia. Results Mean apathy rating score was 25.4 +/- 6.4, reflecting predominantly subclinical apathy. Apathy rating scale scores correlated with amyloid binding, cognitive, depressive, and anxiety scores but not significantly with age, duration of disease, striatal VMAT2, or cholinergic binding. Multiple regression analysis model (p < 0.0001) showed significant regressor effects for global beta-amyloid burden (p = 0.0038) with significant covariate effects for global cognitive z scores (p = 0.028) and for anxiety (p = 0.038) but not with depressive scores. Voxel-based analysis showed robust correlation between apathy rating scale scores and beta-amyloid binding in bilateral nuclei accumbens, inferior frontal, and cingulate cortices (family-wise error rate-corrected p < 0.005). Conclusion Apathy is independently associated with beta-amyloidopathy in patients with PD at risk of dementia. Regional brain findings are most robust for beta-amyloidopathy in the nuclei accumbens, inferior frontal, and cingulate regions. Findings may provide an explanation for the often treatment-refractory nature of apathy in advancing PD despite optimized dopaminergic and antidepressant pharmacotherapy. ClinicalTrials.gov identifier: NCT01565473.