Abstract Body

Recent advances in the development of novel Alzheimer’s disease (AD) measures of amyloid, tau, and neurodegeneration have enabled a better understanding of the links between amyloid-beta (Aβ), tau species and neurodegeneration in AD and related dementias. The discoveries of novel tau species in CSF and blood, including specific phospho-tau (p-tau) and truncated species containing the microtubule binding region of tau (MTBR-tau) which aggregates in tau tangles, have greatly expanded our understanding of tau biology and tau target development. The longitudinal Aβ, tau, and neurofilament light chain (NfL) changes previously measured in CSF are now being measured accurately in blood, enabling interpretation and understanding of AD progression in much larger and more robust populations.

The longitudinal results indicate that a pathophysiological cascade of events begin with altered Aβ42/Aβ40 ratios, followed by increases in amyloid plaques as measured by amyloid PET, associated with increased phosphorylation of specific CSF tau species (e.g., p-tau217, p-tau181), before increases in p-tau205, NfL, total tau concentrations, hypometabolism, and atrophy. Finally, some species of MTBR-tau increase before or with tau aggregation by tau PET and onset of clinical symptoms and correlate with longitudinal tau aggregation and clinical progression.

These findings indicate that CSF and blood plasma biomarkers of Aβ, p-tau, MTBR-tau and NfL measures can accurately identify stages of preclinical and clinical AD and inform about the sequential progression of AD.