Abstract
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 this region, atrophy is most prominent in the nucleus basalis of Meynert (nbM), a group of posteriorly clustered magnocellular neurons in the BFCS. However, less is known surrounding the relationship between amyloid deposition, BFCS atrophy, and medial temporal lobe (MTL) volume loss in the preclinical stages of AD. The current study investigates the relationship between sub-structural BFCS volume and cortical Aβ burden in cognitively unimpaired middle-aged individuals at varying genetic risk for AD. METHODS: Cognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: APOE genotype ε4ε4 (n=15), ε3ε4 (n=15), and ε3ε3 (n=15), matched for age and sex. Participants underwent imaging with [(11)C]PiB PET and structural 3T MRI. Distribution volumes ratios (DVR) with a whole cerebellum reference region were calculated for [(11)C]PiB PET analyses. BFCS sub-structural volumes were obtained from the SPM8 Anatomy Toolbox (Cholinergic nuclei [Ch] 1-3, Ch4). MTL subregional volumes (entorhinal cortex, hippocampus, amygdala, parahippocampal gyrus) were extracted using Freesurfer. RESULTS: BFCS amyloid burden was highest among APOE ε4 homozygotes (Ch1-3, F(2, 42)=3.26, P=0.048; Ch4, F(2, 42)=3.82, P= 0.03). Ch4 (nbM), but not Ch1-3 volume, was found to be inversely associated with global Aβ burden (Pearson r=-0.40, P=0.007). MTL subregional volumes were not associated with global Aβ burden in the pooled sample. Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (P=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson r = -0.70, P=0.02) in Aβ+ participants. CONCLUSIONS: We observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, Aβ+, middle-aged adults at varying genetic risk for AD. These findings provide further in vivo evidence suggesting that nbM atrophy is an early structural correlate of AD pathogenesis, potentially preceding MTL atrophy.