Spatiotemporal characterization of Alzheimer disease pathology in living human brain tissue

Alzheimer disease begins in the brain many years before symptoms, but early changes are usually studied after death or indirectly through fluid and imaging biomarkers. Here we show that small brain biopsies collected during ventriculoperitoneal shunt surgery can be used to study Alzheimer disease pathology and protein turnover during life. We analysed biopsies from 18 individuals with suspected normal pressure hydrocephalus, alongside matched ventricular and lumbar cerebrospinal fluid and post-mortem control brain tissue. Amyloid plaques were present in 9 of 18 biopsies, while mature tau tangles were rare. Matrix-assisted laser desorption/ionization mass spectrometry imaging mapped amyloid plaque chemistry within tissue. Phosphorylated tau 217 was enriched around plaques, supporting a local relationship between amyloid and tau pathology. Stable isotope labelling, which tracks newly made proteins, detected rapid tau labelling within approximately 3 hours and estimated brain tau half-life at about 34 days. Amyloid plaques showed little detectable turnover.