Regional transcriptional vulnerability to basal forebrain functional dysconnectivity in mild cognitive impairment patients

Nucleus basalis of Meynert (NbM), one of the earliest targets of Alzheimer's disease (AD), may act as a seed for pathological spreading to its connected regions. However, the underlying basis of regional vulnerability to NbM dysconnectivity remains unclear. NbM functional dysconnectivity was assessed using resting-state fMRI data of health controls and mild cognitive impairment (MCI) patients from the Alzheimer's disease Neuroimaging Initiative (ADNI2/GO phase). Transcriptional correlates of NbM dysconnectivity was explored by leveraging public intrinsic and differential post-mortem brain-wide gene expression datasets from Allen Human Brain Atlas (AHBA) and Mount Sinai Brain Bank (MSBB). By constructing an individual-level tissue-specific gene set risk score (TGRS), we evaluated the contribution of NbM dysconnectivity-correlated gene sets to change rate of cerebral spinal fluid (CSF) biomarkers during preclinical stage of AD, as well as to MCI onset age. An independent cohort of health controls and MCI patients from ADNI3 was used to validate our main findings. Between-group comparison revealed significant connectivity reduction between the right NbM and right middle temporal gyrus in MCI. This regional vulnerability to NbM dysconnectivity correlated with intrinsic expression of genes enriched in protein and immune functions, as well as with differential expression of genes enriched in cholinergic receptors, immune, vascular and energy metabolism functions. TGRS of these NbM dysconnectivity-correlated gene sets are associated with longitudinal amyloid-beta change at preclinical stages of AD, and contributed to MCI onset age independent of traditional AD risks. Our findings revealed the transcriptional vulnerability to NbM dysconnectivity and their crucial role in explaining preclinical amyloid-beta change and MCI onset age, which offer new insights into the early AD pathology and encourage more investigation and clinical trials targeting NbM.