Clinical, Biological, and Functional Connectivity Profile of Patients With De Novo Parkinson Disease Who Are <i>APOE</i> ε4 Carriers.

Abstract

Growing evidence suggests that the <i>APOE</i> ε4 allele, a genetic risk factor for Alzheimer disease (AD), influences the clinical-pathologic features of Parkinson disease (PD). <i>APOE</i> ε4 promotes brain amyloid accumulation, indicating a PD subtype more susceptible to late copathology. However, the early correlates of <i>APOE</i> ε4 carriers in PD are not known. In this study, we used a multimodal approach to define the clinical, neurochemical, and neurophysiologic profiles of <i>APOE</i> ε4 carriers in PD at onset. 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 <i>APOE</i> 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 <i>APOE</i> ε4-modulated patterns. Clinical and biomarker associations with network metrics were tested using analysis of covariance and correlation analyses. 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], <i>p</i> = 0.02) and gait disturbances (3.46 [2.23] vs 1.94 [1.46], <i>p</i> = 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], <i>p</i> < 0.001). Network analyses identified ε4-related FC alterations: decreased α-band connectivity (<i>F</i> = 3.9, <i>p</i> = 0.034) and increased β-band connectivity (<i>F</i> = 9.8, <i>p</i> < 0.001). In ε4 carriers, α-FC correlated inversely with gait disturbances (<i>r</i> = -0.62, <i>p</i> = 0.02) and positively with Montreal Cognitive Assessment (<i>r</i> = 0.57, <i>p</i> = 0.03) and CSF Aβ42/Aβ40 (<i>r</i> = 0.54, <i>p</i> = 0.04). β-FC correlated with bradykinesia in both groups, with stronger associations in ε4 carriers (<i>r</i> = 0.54, <i>p</i> = 0.04) than in non-ε4 (<i>r</i> = 0.28, <i>p</i> = 0.04). <i>APOE</i> 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 <i>APOE</i> ε4 as a stratification marker for early diagnostic and therapeutic strategies in PD.