Leveraging Alzheimer’s disease subtypes toward novel biological insight and precision medicine

Alzheimer’s disease (AD) is characterized by the build up of pathological proteins amyloid-ꞵ and tau. These proteins can be imaged in the living human brain using positron emission tomography (PET).

A recent large-scale survey of PET images in AD patients found that tau can accumulate in four different patterns across the population, suggesting the presence of “subtypes” of AD. These subtypes may help explain the great variability seen in response to current AD treatments. However, very little is known about what causes these subtypes.

This proposal seeks to characterize the clinical and biological characteristics of AD tau subtypes, with a special focus on information relevant to clinical trials and developing novel treatments.

We leverage an existing large, single-site dataset of 1,538 individuals along the AD spectrum with longitudinal tau-PET, fluid, neuroimaging and cognitive markers, as well as sequencing of thousands of proteins extracted from cerebrospinal (CSF) fluid and blood. First, we will track differences in how clinical AD biomarkers change in AD subtypes over 2 and 4-year intervals.

Second, we will determine differences in the underlying biology of AD subtypes by comparing their CSF proteomes, searching for novel biomarkers and potential treatment targets.

Finally, we will build a secure platform allowing other labs and clinics worldwide to identify AD subtypes using their own data. Together, these goals will advance our common understanding of AD subtypes.