Free-water imaging in Nucleus Basalis of Meynert of Apolipoprotein E4 carriers

Edward Ofori^1*B. Blair Braden¹Kewei Chen¹Yi Su²Richard J Caselli³Eric M Reiman^2,4

• ¹Arizona State University, Tempe, United States
• ²Banner Health, Phoenix, Arizona, United States
• ³Mayo Clinic Arizona, Scottsdale, Arizona, United States
• ⁴Banner Neurodegenerative Disease Research Center, Biodesign Institute, Arizona State University, Tempe, Arizona, United States

The apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and cardiovascular diseases, yet their interaction effect on early neurodegenerative processes remains incompletely understood. In this advanced diffusion magnetic resonance imagingMRI (dMRI) imaging study, we investigated the effects of APOE ε4 genotype and cardiovascular risk on free-water imaging metrics in the nucleus basalis of Meynert (NBM), a cholinergic nucleus impacted early during the accumulation of AD pathology.Leveraging the deeply phenotyped Arizona APOE Cohort, our cross-sectional analysis included 167 cognitively unimpaired older adults who were stratified into three groups: APOE ε4 noncarriers (N=83), heterozygous ε4 carriers (N=51), and homozygous ε4 carriers (N=33).Participants' cardiovascular risk was quantified using a composite score calculated by assigning points based on the presence of riskof 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 and ~50% were in the low cardiovascular risk across all groups. Participants underwent comprehensive neuropsychological assessments, anatomical and diffusion magnetic resonance imaging to derive free-water corrected maps. Our central finding was an interaction effect of cardiovascular risk and genotype, resulting in similar FW values for APOE ε4/4 carriers across cardiovascular risk category whereas increased free-water with greater cardiovascular risk in APOE ε3/3 and APOE ε3/4 carriers (P=0.02). Further increased NBM freewater levels accounted for ~ 25% of the variance in systolic blood pressure, homocysteine and cholesterol to HDL levels (P's<0.01). Cardiovascular risk effects were more impactful on corrected FA measures than free-water measures. Collectively, these findings provide novel evidence that APOE ε4/4 may potentiate early cholinergic system-related physiological changes via effects on lipid metabolism, neurovascular integrity, and/or inflammatory pathways. This investigation highlights the utility of free-water imaging as a sensitive marker for capturing APOE-modulated neurobiological changes in regions critically affected in the earliest stages of AD. Understanding the multifactorial pathways through which APOE ε4 and cardiovascular factors confer risk may enable timely therapeutic interventions in genetically susceptible individuals prior to widespread neurodegeneration.