Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy

More than two hundred individuals developed Creutzfeldt-Jakob disease (CJD) worldwide as a result of treatment, typically in childhood, with human cadaveric pituitary-derived growth hormone contaminated with prions(1,2). Although such treatment ceased in 1985, iatrogenic CJD (iCJD) continues to emerge because of the prolonged incubation periods seen in human prion infections. Unexpectedly, in an autopsy study of eight individuals with iCJD, aged 36-51 years, in four we found moderate to severe grey matter and vascular amyloid-beta (A beta) pathology. The A beta deposition in the grey matter was typical of that seen in Alzheimer's disease and A beta in the blood vessel walls was characteristic of cerebral amyloid angiopathy(3) and did not co-localize with prion protein deposition. None of these patients had pathogenic mutations, APOE epsilon 4 or other high-risk alleles(4) associated with early-onset Alzheimer's disease. Examination of a series of 116 patients with other prion diseases from a prospective observational cohort study(5) showed minimal or no A beta pathology in cases of similar age range, or a decade older, without APOE epsilon 4 risk alleles. We also analysed pituitary glands from individuals with A beta pathology and found marked A beta deposition in multiple cases. Experimental seeding of A beta pathology has been previously demonstrated in primates and transgenic mice by central nervous system or peripheral inoculation with Alzheimer's disease brain homogenate(6-11). The marked deposition of parenchymal and vascular A beta in these relatively young patients with iCJD, in contrast with other prion disease patients and population controls, is consistent with iatrogenic transmission of A beta pathology in addition to CJD and suggests that healthy exposed individuals may also be at risk of iatrogenic Alzheimer's disease and cerebral amyloid angiopathy. These findings should also prompt investigation of whether other known iatrogenic routes of prion transmission may also be relevant to A beta and other proteopathic seeds associated with neurodegenerative and other human diseases.