Influence of APOE genotype on α4β2 nicotinic acetylcholine receptor binding in mild Alzheimer‘s dementia as assessed by (-)-[18F]Flubatine PET

Aim/Introduction: The question of whether the presence of the APOE ε4 allele impacts α4β2 nicotinic acetylcholine receptor (α4β2-nAChR) availability in Alzheimer’s dementia (AD) was so far mainly studied post-mortem, and is subject of a controversial debate. We aimed to answering this question in vivo using the recently developed α4β2-nAChR-specific radioligand (-)-[18F] Flubatine and PET.
Materials and Methods: Non-smoking, drug-naïve AD-APOE ε4+ (n=7; 76±6ys; 6 females; MMSE 24±3) and AD-APOE ε4- (n=9; 75±7ys; 7 females; MMSE 24±2, n. sign. vs. AD-APOE ε4+) were investigated using (-)-[18F]Flubatine (370 MBq, ECAT Exact HR+, 0-90min p.i.) and compared with non-smoking healthy controls (HC; n=13; 72±4ys; 7 females). For quantification of the α4β2-nAChR availability, kinetic modeling (1TCM, Logan) was performed and the distribution volume (VT) was calculated. VOI analyses of a-priori selected brain regions and exploratory SPM analyses were carried out (ANCOVA, significance at P<0.05 and T>3.0; P<0.003).
Results: Compared with HC, in AD-APOE ε4+, there was significantly lower VT within the basal forebrain, hippocampus, amygdala, and fronto-temporal cortices. Compared with HC, in ADAPOE ε4-, voxel-based analysis revealed significantly lower VT in minor clusters within the fronto-temporo-parietal and posterior cingulate cortices. In AD-APOE ε4+, directly compared with AD-APOE ε4-, there was significantly lower VT within the basal forebrain, hippocampus, amygdala, fronto-temporal, and cingulate cortices. Conclusion: Using the recently developed (-)-[18F]Flubatine and PET, we demonstrated for the first time in-vivo the influence of APOE ε4 on α4β2-nAChR availability in mild AD. In contrast to earlier studies, we show that the APOE ε4 genotype modulates the α4β2-nAChR pathophysiology in AD. If replicated in larger cohorts, our findings encourage adjusting cholinergic drug therapy to the APOE genotype in patients with AD. References: None.