Clinical, Biological, and Functional Connectivity Profile of Patients With De Novo Parkinson Disease Who Are APOE ε4 Carriers

BACKGROUND AND OBJECTIVES: Growing evidence suggests that the APOE ε4 allele, a genetic risk factor for Alzheimer disease (AD), influences the clinical-pathologic features of Parkinson disease (PD). APOE ε4 promotes brain amyloid accumulation, indicating a PD subtype more susceptible to late copathology. However, the early correlates of APOE ε4 carriers in PD are not known. In this study, we used a multimodal approach to define the clinical, neurochemical, and neurophysiologic profiles of APOE ε4 carriers in PD at onset. METHODS: We conducted a single-center, cross-sectional study at Tor Vergata Hospital (Rome, Italy), enrolling newly diagnosed, drug-naïve PD participants and age-matched/sex-matched healthy controls (HCs). Patients with PD were stratified by APOE genotype into ε4 and non-ε4 carriers and evaluated through a comprehensive clinical assessment and the measurement of CSF amyloid peptides and tau protein levels. Group differences in high-density EEG-based functional connectivity (FC) were analyzed using network-based statistics to identify APOE ε4-modulated patterns. Clinical and biomarker associations with network metrics were tested using analysis of covariance and correlation analyses. RESULTS: The study included 66 PD participants (mean age 63.2 [10.1] years, 35% female, 52 ε4 noncarriers, 14 ε4 carriers) and 55 HCs (mean age 62.0 [15.2] years, 42% female). PD ε4, compared with PD non-ε4, demonstrated higher motor impairment, especially in bradykinesia (16.4 [7.6] vs 11.0 [5.6], p = 0.02) and gait disturbances (3.46 [2.23] vs 1.94 [1.46], p = 0.003) Movement Disorder Society-sponsored Unified Parkinson's Disease Rating Scale part III scores, and reduced CSF amyloid-β42 (Aβ42)/amyloid-β40 (Aβ40) ratio (0.09 [0.03] vs 0.13 [0.03], p < 0.001). Network analyses identified ε4-related FC alterations: decreased α-band connectivity (F = 3.9, p = 0.034) and increased β-band connectivity (F = 9.8, p < 0.001). In ε4 carriers, α-FC correlated inversely with gait disturbances (r = -0.62, p = 0.02) and positively with Montreal Cognitive Assessment (r = 0.57, p = 0.03) and CSF Aβ42/Aβ40 (r = 0.54, p = 0.04). β-FC correlated with bradykinesia in both groups, with stronger associations in ε4 carriers (r = 0.54, p = 0.04) than in non-ε4 (r = 0.28, p = 0.04). DISCUSSION: APOE ε4 defines a PD subtype characterized by greater motor impairment, reduced CSF Aβ42/Aβ40, and distinct FC abnormalities since the onset. An early amyloid-mediated network disruption thus emerges as the potential biological signature of ε4 carriers. Although limited by single-center and cross-sectional design, this study supports APOE ε4 as a stratification marker for early diagnostic and therapeutic strategies in PD.