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.