Tau-vulnerable medial temporal lobe connectivity drives a functional-to-synaptic cascade in Alzheimer's disease

Distinct tau-vulnerable and relatively spared subregions exist within the medial temporal lobe (MTL). However, it remains unclear that how functional connectivity (FC), anchored to tau-vulnerable MTL subregions, is related to tau pathology, synaptic dysfunction, and cognitive decline across the Alzheimer's disease (AD) continuum. We here probe into this with resting-state fMRI data from a discovery cohort (ADNI; N = 386; cognitively normal [CN], mild cognitive impairment [MCI], and AD; 144 with 2-year follow-up) and an independent validation cohort at local hospital (N = 100; CN, subjective cognitive decline [SCD], and MCI; 25 receiving high-frequency repetitive transcranial magnetic stimulation [HF-rTMS]). We first separated the MTL into subregions with high and low neurofibrillary tangle (NFT) burden based on histological atlases, and calculated the seed-based whole-brain FC for each subregion. Second, group differences were assessed using ANCOVA, and associations with amyloid-β (Aβ)/tau pathology, synaptic biomarkers, and cognitive performance were examined. Third, serial mediation, cross-lagged, and longitudinal regression analyses were performed to investigate the proposed pathological sequence, with additional evidence from HF-rTMS intervention and autopsy-confirmed Braak staging. Our results showed that, with the development of AD, FC reductions were focused on the high-NFT MTL network, particularly involving the inferior temporal gyrus and precuneus. Baseline tau burden in high-NFT MTL regions was able to predict subsequent FC alterations. Interestingly, FC between the high-NFT MTL and global brain showed region-specific associations with synaptic biomarkers, including negative associations in the cerebellum and positive associations in the precentral gyrus. We also observed a divergent association between the FC and cognition or pathology at different AD stages, shifting from positive in the early stages to negative in advanced AD. Serial mediation analyses supported a pathway linking tau burden to cognitive impairment through altered high-NFT MTL connectivity in the precuneus and occipital regions and subsequent synaptic dysfunction. Cross-lagged and longitudinal analyses further confirmed the proposed temporal sequence. Furthermore, HF-rTMS-related cognitive improvements were partially associated with enhanced synaptic plasticity through changes in precuneus-high-NFT MTL connectivity. Collectively, these findings support a spatiotemporal framework linking the dysfunction of tau-vulnerable MTL network to synaptic impairment and cognitive decline, highlighting high-NFT MTL-based FC as a potential imaging marker tracking AD progression.