Mathematical Models of Tau-PET Measures and Cognitive Decline in Alzheimer's Disease Across the Lifespan

PROJECT SUMMARY/ ABSTRACT
Many specifics of the pathological process of Alzheimer’s disease (AD) remain unknown, such as the precise,
functional relationship between tau accumulation and cognitive decline as a function of age, as well as other
biomarkers that may modify these relationships. Conventional statistical approaches cannot easily answer
questions about the relationship between tau and cognition, due to their dynamic relationship, unknown time
lags, and complex measurement error structures. Mathematical modeling techniques—commonly used in
infectious disease epidemiology and computational biology—are specialized for the study of complex
relationships between biological variables, while incorporating prior knowledge about the relevant physiologic
system. The proposed project leverages my quantitative expertise from dissertation research on infectious
disease, using data from across the age span of AD onset to elucidate the relationship between tau-PET
measures and cognition.
As more tau-targeting drugs move through the pipeline, it is important to determine the optimal timing and
duration of treatment for trial design and for post-approval clinical guidelines. The ideal timing for tau-targeting
therapies may depend on factors such as age, amyloid, or vascular burden. Existing and emerging blood-
based biomarkers may offer important information about how tau spreads in the brain and the timing of
subsequent atrophy and cognitive decline longitudinally. A growing number of studies now perform tau-PET,
and including repeated neuroimaging, making it possible for an improved understanding of the dynamics of tau
and cognition in relation to other biomarkers.
We propose a biologically motivated, mathematical modeling approach to understand how neuroimaging and
other biomarkers can be used to better understand Alzheimer’s disease biology. We plan to fit mechanistic
models to data from three cohorts across the age span of AD diagnosis: Alzheimer’s Disease Neuroimaging
Initiative (ADNI), Longitudinal Early-onset Alzheimer's Disease Study (LEADS), and The 90+ Study. The long-
term objective of this research is to improve our understanding of the age-specific pathophysiology of AD,
determining the precise relationship between tau and cognition, with the ultimate goal of guiding therapeutic
development and trials for AD treatment.
The proposed training activities include hands-on research experience, as well as didactics, advanced
coursework, and directed readings and mentorship with the primary mentor Professor M. Maria Glymour and
co-mentor Professor Gil Rabinovici, MD. Scientific advisors Professors María Corrada (MPI: The 90+ Study;
University of California, Irvine), clinical neuropsychologist and Professor Adam Staffaroni, and Professor Roy
Anderson (Imperial College London) will also contribute their expertise.

Grant Number: 5R00AG073454-06
NIH Institute/Center: NIH
Principal Investigator: Sarah Ackley