Prion Disease Induces Alzheimer Disease-Like Neuropathologic Changes.


Tousseyn, Thomas MD, PhD; Bajsarowicz, Krystyna MS; Sánchez, Henry MD; Gheyara, Ania MD, PhD; Oehler, Abby BS; Geschwind, Michael MD, PhD; DeArmond, Bernadette MD, MPH; DeArmond, Stephen J. MD, PhD


We examined the brains of 266 patients with prion disease (PrionD) and found that 46 patients (17%) had Alzheimer disease (AD)-like changes. To explore potential mechanistic links between PrionD and AD, we exposed human brain aggregates (BrnAggs) to a brain homogenate from a patient with sporadic Creutzfeldt-Jakob disease and found that neurons in human BrnAggs produced many [beta]-amyloid (A[beta]; A[beta]42) inclusions, whereas uninfected control-exposed human BrnAggs did not. Western blot analysis of 20 pooled Creutzfeldt-Jakob disease-infected BrnAggs verified A[beta]42 levels higher than those in controls. We next examined the CA1 region of the hippocampus from 14 patients with PrionD and found that 5 patients had low levels of scrapie-associated prion protein (PrPSc), many A[beta]42 intraneuronal inclusions, low apolipoprotein E-4 (APOE-4), and no significant nerve cell loss. Seven patients had high levels of PrPSc, low A[beta]42, high APOE-4, and 40% nerve cell loss, suggesting that APOE-4 and PrPSc together cause neuron loss in PrionD. There were also increased levels of hyperphosphorylated tau protein (H[tau]) and H[tau]-positive neuropil threads and neuron bodies in both PrionD and AD groups. The brains of 6 age-matched control patients without dementia did not contain A[beta]42 deposits; however, there were rare H[tau]-positive threads in 5 controls, and 2 controls had few H[tau]-positive nerve cell bodies. We conclude that PrionD may trigger biochemical changes similar to those triggered by AD and suggest that PrionD is a disease involving PrPSc, A[beta]42, APOE-4, and abnormal tau.