Guam ALS-PDC is a distinct double-prion disorder featuring both tau and A? prions

The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is an endemic neurodegenerative disease that features widespread tau tangles, occasional alpha-synuclein Lewy bodies, and sparse beta-amyloid (A beta) plaques distributed in the central nervous system. Extensive studies of genetic or environmental factors have failed to identify a cause of ALS-PDC. Building on prior work describing the detec-tion of tau and A beta prions in Alzheimer's disease (AD) and Down syndrome brains, we investigated ALS-PDC brain samples for the presence of prions. We obtained postmortem frozen brain tissue from 26 donors from Guam with ALS-PDC or no neurological impairment and 71 non-Guamanian donors with AD or no neurolog-ical impairment. We employed cellular bioassays to detect the prion conformers of tau, alpha-synuclein, and A beta proteins in brain extracts. In ALS-PDC brain samples, we detected high titers of tau and A beta prions, but we did not detect alpha-synuclein prions in either cohort. The specific activity of tau and A beta prions was increased in Guam ALS-PDC compared with sporadic AD. Applying partial least squares regression to all biochemical and prion infectivity measurements, we demonstrated that the ALS-PDC cohort has a unique molecular signature distinguishable from AD. Our findings argue that Guam ALS-PDC is a distinct double-prion disorder featuring both tau and A beta prions.

Automated summary

The amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC) of Guam is a neurodegenerative disease characterized by tau tangles, alpha-synuclein Lewy bodies, and sparse beta-amyloid plaques. The presence of tau and beta-amyloid prions was detected in ALS-PDC brain samples, but not alpha-synuclein prions. The unique molecular signature of ALS-PDC distinguishes it from Alzheimer's disease.