APOE4-dependent cholinergic/dopaminergic contributions to clinical symptoms across Alzheimer’s disease spectrum: A retrospective observational study

Clinical heterogeneity in Alzheimer’s disease (AD) may reflect differential involvement of neurotransmitter systems, but whether the associations of cholinergic and dopaminergic imaging biomarkers with cognitive and neuropsychiatric symptoms differ according to apolipoprotein E ε4 ( APOE4 ) status remains unclear. We studied 387 patients across the amyloid-confirmed AD spectrum. Patients were stratified by APOE4 status into 205 carriers and 182 non-carriers. Basal forebrain volume (BFV), striatal dopamine transporter uptake (DAT), and regional brain perfusion were examined in relation to cognitive performance and neuropsychiatric inventory scores. APOE4 carriers showed lower BFV than non-carriers, whereas APOE4 non-carriers showed lower DAT. In APOE4 carriers, lower BFV was associated with memory dysfunction and AD-typical temporoparietal hypoperfusion; the BFV-memory association was attenuated after inclusion of posterior cingulate perfusion. Lower BFV was also associated with several neuropsychiatric symptoms, including hallucinations, delusions, anxiety, apathy, aberrant motor behavior, and appetite changes, with direct associations remaining for hallucinations, delusions, and apathy after accounting for regional perfusion. In APOE4 non-carriers, lower DAT was associated with poorer performance across widespread cognitive domains and with hallucinations, delusions, and anxiety. These DAT associations largely persisted even after adjustment for regional perfusion. APOE4 status was associated with differences in the clinical and brain perfusion correlates of cholinergic and dopaminergic degeneration in AD. APOE4 carriers showed a BFV-dominant pattern linked to AD-typical perfusion changes and memory dysfunction, whereas non-carriers showed a DAT-dominant pattern with largely perfusion-independent associations with cognitive and neuropsychiatric manifestations.