APOE and Alzheimer disease: The basal forebrain cholinergic system is one of the earliest brain regions vulnerable to degeneration during AD.233 The correlations between enhanced BACE1 activity, Aβ accumulation with atrophy of basal forebrain and loss of functional connectivity have been found in neuropathological and neuroimaging studies.234–237 Furthermore, such an inverse correlation seems to be intensified with the ε4 allele of the apolipoprotein E (APOE) gene, which is one of the strongest risk factors for LOAD.238