Translating the Biology of Aging into New Therapeutics for Alzheimer's Disease: Senolytics

The recent FDA-approval for amyloid lowering therapies reflects an unwavering commitment from the Alzheimer's disease (AD) research community to identify treatments for this leading cause of dementia. The clinical benefits achieved by reducing amyloid, though modest, provide evidence that disease modification is possible. Expanding the same tenacity to interventions targeting upstream drivers of AD pathogenesis could significantly impact the disease course. Advanced age is the greatest risk factor for developing AD. Interventions targeting biological aging offer the possibility of disrupting a foundational cause of AD. Senescent cells accumulate with age and contribute to inflammation and age-related diseases like AD. Senolytic drugs that clear senescent cells improve healthy aging, halt AD disease progression in animal models and are undergoing clinical testing. This review explores the biology of aging, the role of senescent cells in AD pathology, and various senotherapeutic approaches such as senolytics, dampening the SASP (senescence associated secretory phenotype), senescence pathway inhibition, vaccines, and prodrugs. We highlight ongoing clinical trials evaluating the safety and efficacy of the most advanced senolytic approach, dasatinib and quercetin (D+Q), including an ongoing Phase II senolytic trial supported by the Alzheimer's Drug Discovery Foundation (ADDF). Challenges in the field of senotherapy for AD, including target engagement and biomarker development, are addressed. Ultimately, this research pursuit may lead to an effective treatment for AD and provide the field with another disease-modifying therapy to be used, alone or in combination, with other emerging treatment options.