BACKGROUND:
Frontotemporal dementia (FTD) and related disorders are a heterogeneous group of neurodegenerative syndromes driven by distinct molecular pathologies (e.g., TDP-43, tau) that overlap clinically with Alzheimer’s disease (AD). Gaps remain in translating basic science discoveries about pathogenesis into accessible, early-detection tools, particularly for underrepresented populations. We present a translational, equity-focused research program that links mechanistic biology with scalable diagnostic approaches and community-based implementation to improve timely diagnosis and reduce disparities.
METHODS:
We conducted a multi-arm study combining (1) basic-science analyses of postmortem and induced pluripotent stem cell (iPSC)-derived neuronal models to map molecular cascades distinguishing TDP-43 vs tau pathology; (2) a prospective clinical cohort (n = 420) recruited with deliberate oversampling of historically underserved groups, undergoing multimodal assessment—plasma proteomics (neurofilament light, phosphorylated tau species, candidate TDP-43 peptides), structural and functional MRI, and brief smartphone-based cognitive and speech tasks; and (3) machine-learning integration to derive a multimodal early-detection algorithm. We evaluated diagnostic accuracy for FTD vs AD, profiled early pathophysiologic signatures, and assessed barriers to equitable access through mixed-methods community interviews.
RESULTS:
Mechanistic studies identified convergent pathways of synaptic dysfunction and proteostasis imbalance that differentiate TDP-43 and tau phenotypes and nominate plasma peptide targets. In the clinical cohort, a combined biomarker + digital cognitive model demonstrated high discrimination between FTD and AD and detected disease-stage changes prior to overt clinical impairment. Importantly, algorithm performance remained robust after stratifying by race, education, and socioeconomic status when community-informed calibration and local normative adjustments were applied. Qualitative findings revealed modifiable access barriers (service awareness, cost, mistrust) and community preferences for decentralized screening.
CONCLUSION:
Integrating basic pathogenesis research with multimodal biomarkers and community-centered implementation yields a feasible pathway for earlier, more equitable detection of FTD and related disorders and clarifies molecular targets for future therapeutic development.