Elucidating the Relationship Between Tau Accumulation, White Matter Degeneration, and Cognition in preclinical Alzheimer Disease.

Alzheimer disease (AD) is characterized by a prolonged preclinical phase of approximately 20 years, during which widespread brain disruptions occur1. Although neurodegeneration in AD has traditionally been associated with grey matter, emerging evidence confirms that concurrent white matter (WM) deterioration occurs2–4. Broadly, while amyloid deposition correlates with increases in neuroinflammation and WM hyperintensities, tau affects WM microstructure, the result of axonal injury that occurs through its prion- like spread along WM pathways5,6. Tau tangle accumulation measured by positron emission tomography and WM microstructural damage precede clinical symptom onset, emphasizing their pivotal role in AD manifestation. However, the relationship between tau and WM degeneration remains underexplored. Autosomal dominant AD (ADAD), a rare genetic form, has a known genetic origin and relatively uniform phenotypic expression that can be leveraged to investigate preclinical pathophysiology7. Those with ADAD exhibit early symptoms with fewer age-related comorbidities , and the high penetrance of ADAD mutations alongside the highly heritable nature of their age at symptom onset, enables precise disease staging relative to expected year of symptom onset (EYO), even in those who are asymptomatic. The Dominantly Inherited Alzheimer Network (DIAN) has been coordinating a global study of this relatively rare form of AD, allowing us to observe the changes that occur in the preclinical period of AD without the confounding influence of age- related comorbidities. Given the shared pathophysiology between ADAD and sporadic late-onset AD (LOAD)8, observations derived from ADAD cohorts are profoundly influential. These insights can shape hypotheses about the early processes in LOAD, before the manifestation of outward symptoms. This K01 aims to use multimodal data from DIAN to identify progression patterns of tau accumulation in ADAD (Aim 1) and understand the spatiotemporal relationship between tau and WM degeneration (Aim 2), as well as their impact on cognition. This proposal will also explore how exposure to antibody treatments interact with these relationships (Aim 3). The overarching hypothesis is that tau accumulation and spread drives symptom onset through damage to WM pathways. I hypothesize that tau spatial progression will manifest in distinct patterns9,10, tau will correlate with spatial patterns of WM degeneration2,5,11, and these together will impact cognition. This research fills a knowledge gap regarding how tau pathology triggers symptom onset and will apply lessons learned from observational data to novel tau antibody clinical trial data. The comprehensive mentoring and training objectives will build on my expertise in ADAD to include a foundational understanding of tau protein biology (goal 1), risk and resilience (goal 2), clinical translational research (goal 3), and professional development (goal 4). Protected time will ensure the candidate meets all objectives, and completion of this K01 will provide preliminary data for future R01s exploring individualized trajectories and outcomes. Project Number: 1K01AG095307-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: Nicole McKay | Institution: WASHINGTON UNIVERSITY, SAINT LOUIS, MO | Award Amount: $129,876 | Activity Code: K01 | Study Section: Special Emphasis Panel[ZRG1 AN-N (80)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11371959