To evaluate the effect of mesial temporal lobe (MTL) disconnection on the distribution of Alzheimer’s disease (AD) pathology using rare post-mortem tissue from World War II veterans who survived 50 years after unilateral penetrating brain injuries.

AD pathology is defined by amyloid-beta (aβ) plaques and neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau (p-tau). NFTs appear to spread from the MTL to the association cortices (AC), matching clinical progression of AD. In vitro and animal studies support the tau propagation hypothesis, suggesting that p-tau moves through the brain along neurons and across synapses. This pathway represents an important target in the search for disease-modifying AD treatments, but there is currently limited evidence in humans.

The extent of AD pathology was assessed in the MTL and AC of lesional and non-lesional hemispheres from 15 veterans. Systematic quantitative neuropathological methods were applied to measure aβ plaque area coverage (%Aβ) and the proportion of neurons affected by NFTs (%NFT). Traumatic disconnection of the MTL and AC was defined using 3D digital lesion reconstructions generated from post-mortem reports and anatomical photographs. Clustered statistics were used to perform within-case comparisons.

The overall extent of AD pathology was equal between hemispheres (%Aβ: lesional=1.23%, non-lesional=1.72%, χ²=1.358, p=0.244; %NFT: lesional=7.89%, non-lesional=9.25%, χ²=0.476, p=0.490). %Aβ was equal in the MTL and AC (MTL=1.60%, AC=1.11%, χ²=2.009, p=0.156) while %NFT was lower in the AC than MTL (MTL=10.5%, AC=3.46%, χ²=11.360, p<0.001). %NFT was more markedly reduced in the AC of the lesional hemisphere (MTL=10.19%, AC=1.70%, p<0.001) than the non-lesional hemisphere (MTL=10.79%, AC: 5.09%, p=0.039). Traumatic disconnection of the MTL reduced %NFT in the AC compared with the contralateral hemisphere, adjusting for %NFT in the ipsilateral MTL (disconnected=0.86%, connected=3.16%, p=0.015).

Traumatic disconnection of the MTL reduced AD-related p-tau pathology in the AC. This provides novel evidence supporting the tau propagation hypothesis in humans.