Plasticity reserve in alzheimer's disease: longitudinal insights from preclinical and prodromal stages

The National Institute on Aging awarded the University of Arizona $396,241 on September 1, 2026, under the Aging Research program (CFDA 93.866) to conduct a longitudinal, multi-modal study tracking neuroplasticity changes in preclinical and prodromal Alzheimer's disease stages using transcranial magnetic stimulation (TMS) integrated with blood and MRI biomarkers.

The study employs TMS to assess non-invasive, repeatable neurophysiological measures of neuroplasticity and correlates these findings with amyloid-tau-neurodegeneration (ATN) biomarkers, including plasma amyloid beta, tau, and hippocampal neurodegeneration, to identify reliable predictors of cognitive decline. The research compares the predictive effectiveness of a TMS-centric model, a blood and MRI biomarker model, and an integrative model combining both approaches. The work addresses a gap in longitudinal disease monitoring by offering an alternative to postmortem and animal studies, with TMS providing greater accessibility than techniques like positron emission tomography imaging for tracking early disease progression and identifying individuals at risk of symptom emergence.

The University of Arizona, operating as the Arizona Board of Regents, performs the work in Tucson, Arizona. The period of performance runs from September 1, 2026, through August 31, 2027. In alignment with open science principles, all anonymized research data will be shared via OpenNeuro and the University of Arizona Research Data Repository.

Abstract

The ATN framework marks a turning point in alzheimer's disease (ad) research, focusing on key biomarkers like amyloid, TAU, and neurodegeneration, which enhances diagnostic methods and deepens our understanding of the disease. Nonetheless, accurately identifying those on the cusp of cognitive decline, crucial for optimizing clinical trials, remains a difficult task. Existing research, encompassing both postmortem and animal studies, shows that diminished neuroplasticity can be detected prior to the emergence of symptoms in early ad. While these findings provide important insights into neuroplasticity deficits in ad, the limitations of these methodologies in longitudinal disease monitoring necessitate the exploration of alternative research approaches. Transcranial magnetic stimulation (TMS) steps in as a viable alternative, offering non-invasive and repeatable neurophysiological evaluations that can be more accessible than techniques like pet imaging. Our study employs a longitudinal, multi-modal approach, integrating TMS with the aim of tracking neuroplasticity changes and how these relate to ATN biomarkers, such as plasma amyloid beta and TAU, alongside hippocampal neurodegeneration. We are poised to assess the effectiveness of a TMS-centric model, compare IT against a model based on blood and MRI biomarkers, and consider an integrative model that combines both. Our goal is to establish the most reliable TMS and ATN biomarkers to predict cognitive decline, identifying clear predictor thresholds. In line with open science principles, all anonymized data from our research will be shared via openneuro and the university of arizona research data repository. The significance of this study stems from its potential to conduct non-invasive, in vivo assessments of ad-affected brain functionalities, substantially enhancing understanding of the disease's underlying processes and progression patterns. The utilization of TMS as a predictive tool embodies the innovative spirit of this research, complementing and potentially expanding the predictive capacities of the established ATN framework. This study is designed to fortify longitudinal disease monitoring and inspire new therapeutic strategies. The collaborative ethos of this project, supported by efforts to share data, underscores its potential to influence and propel the ongoing battle against ad within the research community.