Novel diffusion MRI signature for early detection of alzheimer's disease

The National Institute on Aging awarded the University of California, San Diego $150,512 on August 2, 2026, under the Aging Research program (CFDA 93.866) to develop and validate a novel diffusion MRI neuroimaging biomarker for early detection of Alzheimer's disease.

The project focuses on microstructural changes in gray matter mean diffusivity (GMD) that may precede macrostructural atrophy visible on conventional MRI. Current AD detection relies primarily on macrostructural metrics such as cortical thickness and volume, which capture changes after substantial tissue loss has occurred. The work will develop a validated diffusion MRI signature by analyzing biphasic changes in GMD and cortical thickness in early disease states, clarifying the nature and timing of these trajectories. The investigators propose integrating this diffusion-based imaging measure alongside established AD biomarkers (amyloid-beta and tau) to improve specificity and sensitivity for identifying individuals at imminent risk for cognitive decline, independent of traditional pathology markers alone.

Performance occurs in La Jolla, California, with a period extending from August 2, 2026, through August 1, 2027. The award is classified as a Project Grant, an assistance type supporting time-limited biomedical research directed toward understanding aging processes and age-related diseases.

Abstract

Alzheimer's disease (ad) is the 5TH leading cause of death in adults over the age of 65, with an estimated 6.9 million americans aged 65 and older living with ad dementia today. Early identification of ad is critical to slowing disease progression and would greatly reduce significant public health costs associated with this disease. Neuroimaging signatures derived from magnetic resonance imaging (MRI) serve as useful tools to identify ad-related changes, and have demonstrated associations with ad symptom severity, biomarkers, and progression to ad dementia. Most prior research has been limited to ad signatures that rely on macrostructural neuroimaging metrics (e.g., cortical thickness, volume), though our prior work and converging evidence suggests that diffusion MRI metrics in gray matter, such as gray matter mean diffusivity (GMD), may capture very early, microstructural changes that predate macrostructural atrophy. Currently, no diffusion signature has been developed and validated in a sample of ad cases and controls. Moreover, some evidence- including our own-suggests dynamic, biphasic changes in GMD and cortical thickness in very early disease states, though the nature and timing of these changes are poorly understood. Clarification of early trajectories in diffusion and macrostructural ad signatures is needed to improve the specificity and sensitivity of these imaging biomarkers for identifying very early ad-related changes. Given that current measures of ad pathology (AΒ, TAU) alone are not deterministic of progression to dementia, integrating neuroimaging measures that reflect subtle atrophy, such as a diffusion MRI signature, alongside ad biomarkers may more accurately identify individuals at imminent risk for cognitive decline. This project will develop a novel, validated ad-related neuroimaging biomarker of microstructural changes that can improve early identification and disease monitoring, and serve as a potential outcome measure in intervention trials. Further, the candidate will examine relationships between this novel diffusion signature and underlying biological mechanisms, as well as delineate trajectories in diffusion and structural ad signatures across the ad continuum. The training opportunities afforded by the nrsa F32 funding mechanism will facilitate the applicant's long-term goal of becoming an independent investigator in the field of aging and ad, with specific training goals related to development of skills in MRI processing and analysis techniques, integration of ad biomarkers and multimodal imaging data, advanced longitudinal modeling, and interdisciplinary collaboration. These training goals will be supported by a mentorship team with expertise in ad and neuroimaging research at the university of california SAN diego departments of neurosciences and psychiatry.