Free-water imaging of the nucleus basalis of Meynert in apolipoprotein E4 carriers

Introduction The apolipoprotein E ( APOE ) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD) and cardiovascular disease. This study aimed to investigate the interactive effects of APOE ε4 genotype and cardiovascular risk on the microstructure of the nucleus basalis of Meynert (NBM), a key cholinergic region affected early in AD, using advanced diffusion magnetic resonance imaging. Methods This cross-sectional study included 167 cognitively unimpaired older adults from the Arizona APOE Cohort. Participants were stratified by genotype: APOE ε4 non-carriers ( N = 83), heterozygous carriers ( N = 51), and homozygous carriers ( N = 33). Cardiovascular risk was quantified using a composite score calculated by assigning points based on the presence of risk factors (myocardial infarction/peripheral vascular disease, hypertension, diabetes, hypercholesterolemia) and categorized levels of continuous variables (systolic and diastolic blood pressure, body mass index) with higher scores indicating greater risk. Participants underwent comprehensive neuropsychological assessments, structural MRI, diffusion MRI, and Pittsburgh Compound-B (PiB) Positron Emission Tomography imaging. Results A significant interaction was found between APOE genotype and cardiovascular risk on NBM FW levels ( p = 0.02). In APOE ε3/ε3 and ε3/ε4 carriers, greater cardiovascular risk was associated with increased NBM FW. Conversely, APOE ε4/ε4 carriers exhibited similar FW values regardless of their cardiovascular risk category. Furthermore, elevated NBM FW accounted for approximately 25% of the variance in systolic blood pressure, homocysteine, and cholesterol-to-HDL ratio ( p ’s 0.01). Cardiovascular risk had a more pronounced effect on corrected fractional anisotropy (FA) than on FW measures ( p ’s 0.05). Conclusions The findings suggest that the APOE ε4/ε4 accelerates early microstructural alterations within the basal forebrain cholinergic system potentially through mechanisms involving altered lipid homeostasis, compromised neurovascular integrity, and sustained neuroinflammatory responses. These effects appear to indicate a genotype-specific vulnerability. Free-water imaging of the NBM emerges as a sensitive, non-invasive biomarker capable of detecting these APOE -modulated microstructural changes before overt atrophy or cognitive decline. Understanding the multifactorial pathways through which APOE ε4 and cardiovascular factors confer risk may enable increased understanding in genetically susceptible individuals prior to widespread neurodegeneration.