Davide Micheletti
Project Summary: Alzheimer's disease (AD) is the most common cause of dementia, affecting millions of
people worldwide. Although approved therapies can slow disease progression, they are most
effective when initiated before widespread tau accumulation and irreversible neurodegeneration.
Because AD begins years before symptoms develop, identifying individuals most likely to develop
rapid tau accumulation remains a major challenge. During this preclinical stage, amyloid may
already be elevated while tau pathology, which is more closely linked to cognitive decline, remains
subtle, spatially heterogeneous, and difficult to quantify.
Tau PET allows researchers to visualize and quantify tau pathology in living people, but current
analyses focus primarily on measuring the amount and spatial distribution of existing tau pathology.
Dynamic tau PET also measures how the tracer is delivered through brain tissue before binding to
tau proteins, providing information related to regional cerebral perfusion. Although this information
is typically overlooked, it may reveal biological features of the brain that influence which regions are
most vulnerable to future tau accumulation.
This project will use advanced mathematical modeling of dynamic tau PET scans from cognitively
unimpaired older adults from the Harvard Aging Brain Study to identify perfusion-related brain
phenotypes and networks, determine how they relate to the spatial distribution of early tau
pathology, and test whether they improve prediction of where and how quickly tau accumulates
beyond established AD biomarkers (e.g., amyloid PET and plasma biomarkers). By integrating
molecular imaging with measures of brain perfusion, this work aims to improve our understanding
of the earliest stages of AD and establish a new framework for identifying individuals and brain
regions most vulnerable to tau accumulation. Ultimately, these findings could improve participant
selection for prevention trials and motivate future studies using dynamic tau PET or combining tau
PET with MRI-based measures of cerebral perfusion, cerebrovascular function, vascular risk, blood
biomarkers, and cognition.