Basal Forebrain Volume is Associated With Cortical Amyloid Burden in Cognitively Unimpaired Older Adults at Varying Genetic Risk for Alzheimer's Disease

BACKGROUND: In mild cognitive impairment and dementia due to Alzheimer's disease (AD), postmortem and in vivo neuroimaging studies have demonstrated significant neuronal loss in the basal forebrain cholinergic system (BFCS), which provides the primary cholinergic input to the cerebral cortex. Within the BFCS, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a posteriorly located cluster of magnocellular neurons. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in preclinical AD. This study investigates the relationship between BFCS sub-regional volume and Aβ burden in cognitively unimpaired middle-aged individuals. METHODS: Cognitively unimpaired participants aged 50-67 with a first-degree family history for AD were genetically screened to three groups matched for age and sex: APOE genotype ε4ε4, ε3ε4, and ε3ε3 (n = 15 each). Aβ burden was calculated using distribution volumes ratios (DVR) using [¹¹C]PiB-PET, with a whole cerebellum reference region. BFCS and MTL subregional volumes (i.e., entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using 3T-MRI. RESULTS: nbM, but not other BFCS regions, was found to be inversely associated with global Aβ burden (Pearson r(43) = -0.40, p = 0.004). When stratified by Aβ-positivity, the observed inverse association was limited to Aβ+ participants (Pearson r(9) = -0.7, p = 0.008). MTL volumes were not consistently associated with global Aβ burden. CONCLUSIONS: We observed nbM, but not MTL volume, to show robust inverse association with cortical amyloid burden in cognitively unimpaired, Aβ+, middle-aged adults. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.