Tau deposition patterns within the medial temporal lobe follow the connectivity of the entorhinal and perirhinal cortex – a combined post-mortem and 7T fMRI study

In aging, tau pathology can develop in the medial temporal lobe (MTL), but generally only progresses to the cortex in the context of amyloidosis, driving neurodegeneration and Alzheimer’s disease (AD) dementia. Functional connectivity shapes this cortical tau expansion, supporting trans-neuronal tau spreading. However, it is unclear whether MTL tau accumulation itself follows within-MTL connections – particularly those of the transentorhinal (Brodmann area 35 [A35]) and entorhinal cortex (ErC), the earliest cortical sites of tau accumulation in AD and variably affected in aging. To address this, we assessed three-dimensional neurofibrillary tangle (NFT) burden across 14 MTL subregions using post-mortem quantitative histopathology in 25 individuals ( n  = 4 amyloid-β negative; n  = 21 amyloid-β positive) on the AD continuum. These data were combined with high-resolution 7T resting-state functional MRI-based functional connectivity among the same 14 subregions obtained from 30 young healthy controls. We examined covariance in NFT burden across MTL subregions and tested associations with functional connectivity strength. We then applied seed-based connectivity analyses to identify which MTL subregion’s connectivity profile best predicted MTL NFT patterns. NFT levels were highest and comparable across A35 (0.62 ± 0.40), posterior cornu ammonis 1 (CA1; 0.61 ± 0.46), anterolateral ErC (alErC; 0.60 ± 0.39), and anterior CA1 (0.57 ± 0.43). We found a significant positive association between MTL connectivity and covariance in MTL NFTs ( β  = 0.49, p  < 0.001), with closely connected MTL regions showing similar NFT levels. When assessing seed-based connectivity as a predictor of NFT patterns, alErC ( ρ  = 0.66, p  < 0.001), A36 ( ρ  = 0.64, p  < 0.001), and posteromedial ErC (pmErC; ρ  = 0.59, p  < 0.001) connectivity showed the strongest, comparable correspondence with MTL NFT deposition. This pattern was consistent within low (Braak 0–II) and high (Braak III–VI) NFT burden groups. These results suggest that within-MTL tau propagation is shaped by intrinsic network organization, highlighting entorhinal and perirhinal connectivity profiles as potential drivers of MTL tau progression and as candidate targets for therapeutic interventions.