Directly converted human neuronal spheroids preserve donor age and model Alzheimer disease
The three-dimensional cell platform maintains biological aging markers while spontaneously developing hallmark pathologies of sporadic Alzheimer disease.
bioRxiv · 1 Oct · Alsolami S, Wang M, Sarraf Sabedot T et al.
In a new preprint, researchers developed directly induced neuronal spheroids using primary fibroblasts from young, unimpaired aged, and sporadic Alzheimer disease human donors, as well as non-human primates. The team converted fibroblasts directly into three-dimensional neuronal spheroids without pluripotency. Single-nucleus RNA sequencing confirmed that approximately 96% of cells acquired a neuronal identity. The resulting electrophysiologically active neurons preserved donor-specific epigenetic age and supported astrocytes and microglia. Spheroids from Alzheimer donors spontaneously displayed neuronal degeneration, amyloid-beta accumulation, progressive Tau pathology, and metabolic dysfunction. Multi-omics profiling separated physiological aging from Alzheimer disease. Drug tests showed oxaliplatin shifted cells toward oxidative metabolism, and trametinib modulated inflammatory and age-associated programs.
Why it matters
Reprogramming cells through pluripotency typically erases biological age, obscuring how aging drives late-onset neurodegenerative disorders. By preserving donor epigenetic age, this three-dimensional model offers a system to study the intersection of human aging and dementia.
Caveats
The findings are based on an in vitro model described in a preprint that has not yet undergone peer review. The study relies on cultured spheroids rather than intact tissue from patients.
The paper
An age-preserving neuronal iSpheroid platform for modeling human aging and Alzheimer disease
Alsolami S, Wang M, Sarraf Sabedot T et al.
bioRxiv
doi.org/10.64898/2026.09.30.755853