Biology subjects

Upadhyaya, Y.

Publications and source records attributed to Upadhyaya, Y..

2 recordsLinked to original sources

bioRxiv2026

Divergent amyloid trajectories distinguish normal aging from Alzheimer's disease progression

Aging is the greatest risk factor for Alzheimer's disease (AD), yet how and when AD-related pathological progression diverges from aging remains poorly understood. This distinction is particularly difficult at early stages, when clinically and biomarker-defined populations contain individuals following fundamentally different trajectories. Here, we model AD progression as a deviation from aging using longitudinal amyloid PET and a self-supervised trajectory-learning framework. In ADNI, the learned trajectory revealed a shared early path that bifurcated into an aging branch and an AD-related branch. The two branches showed distinct profiles in amyloid burden, cognitive decline, risk of progression to AD dementia, and genetic risk. Unseen participants from the independent NACC cohort were projected onto the trajectory without retraining, further reproducing key branch-specific biological and genetic patterns. Together, the bifurcating trajectory provides a biologically grounded framework for resolving early-stage heterogeneity and enabling risk stratification beyond binary amyloid status.

neuroscience↗

bioRxiv2026

Cross-Regional Trajectory Analysis Reveals Distinct Temporal Progression of Shared Proteomic Programs in Alzheimer's Disease

Alzheimer's pathology progresses through anatomically distinct brain regions, yet how molecular programs are temporally organized across vulnerable regions remains poorly understood. Here, we reconstructed continuous proteomic trajectories from matched dorsolateral prefrontal cortex (DLPFC) and superior temporal gyrus (STG) proteomes to investigate cross-regional molecular progression in AD. The inferred trajectories closely recapitulated established neuropathological staging while remaining independent of age, sex, and race. Across regions, a mitochondrial bioenergetic protein subset declined substantially earlier in the STG than in the DLPFC, revealing a previously unrecognized regional temporal offset in metabolic dysfunction. In parallel, a broadly shared proteomic program progressed in both regions but more rapidly in the STG, indicating that shared molecular responses differ in their temporal progression despite overall coordination. Together, these findings demonstrate that regional vulnerability in AD is reflected not only by the molecular programs involved but also by their temporal organization during disease progression.

neuroscience↗