Basal forebrain volume is associated with cortical amyloid burden in cognitively unimpaired older adults at varying genetic risk for Alzheimer's disease.

BACKGROUND

The primary cholinergic input to the cerebral cortex arises from the nucleus basalis of Meynert (nbM), a group of magnocellular neurons clustered within the posterior basal forebrain cholinergic system (BFCS). Postmortem and neuroimaging studies have demonstrated significant neuronal loss and BFCS atrophy, most prominently in the nbM, in both mild cognitive impairment and dementia due to Alzheimer's disease (AD). However, less is known surrounding the relationship between accumulating Alzheimer's pathology, BFCS atrophy, and cognition during early preclinical stages of AD.

METHODS

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. Cognitively unimpaired participants aged 50-65 with a first-degree family history for AD were genetically screened to select three groups: genotype ε4ε4 (n=15), ε3ε4 (n=15), and ε3ε3 (n=15), matched for age and sex. Participants underwent imaging with [C]PiB PET and structural 3T MRI. Distribution volumes ratios () with a whole cerebellum reference region were calculated for [C]PiB PET analyses. BFCS sub-structural volumes were obtained from regions of interest generated from the SPM8 Anatomy Toolbox (Ch1-3, Ch4).

RESULTS

BFCS amyloid burden was highest among ε homozygotes (Ch1-3, F(2, 42)=3.26, =0.048; Ch4, F(2, 42)=3.82, = 0.03). Ch4(nbM), but not Ch1-3 volume, was found to be inversely associated with global Aβ burden (Pearson =-0.40, =0.007). Exploratory analyses in groups stratified by amyloid positivity demonstrated reduced Ch4 volume (=0.032) and significant inverse associations between Ch4 volume and amyloid burden (Pearson = -0.70, =0.02) in Aβ+ participants. Medial temporal lobe (MTL) volumes were neither significantly different between Aβ+ vs. Aβ- participants nor were they associated with global amyloid burden in either Aβ+ participants, Aβ- participants, or the pooled sample.

CONCLUSIONS

We observed nbM (Ch4), but not MTL volume, to be significantly inversely associated with cortical amyloid burden in cognitively unimpaired, Aβ+, older adults at varying genetic risk for AD. These findings provide further evidence suggesting BFCS (specifically nbM) atrophy may precede medial temporal atrophy in the preclinical stage of AD and that nbM atrophy is an early structural correlate of AD pathogenesis.