Groundbreaking studies are uncovering new mechanisms and interventions in neurodegeneration. Targeted activation of mitochondrial G-protein signaling (mitoDREADD-Gs) rejuvenates cognition in Alzheimer’s and frontotemporal dementia mouse models, revealing mitochondrial dysfunction as a causal factor. Meanwhile, a multimodal AI approach has revolutionized Alzheimer’s biomarker detection by integrating diverse data streams. Discovery of nuclear speckle modulation offers new therapeutic avenues against proteinopathies underlying neurodegenerative diseases. These advances deepen understanding and provide novel targets to slow or reverse neurological decline.