The authors of this open access paper consider the potential for regenerative medicine to treat Alzheimer's disease, such as by increasing production of new neurons, or delivering neurons via transplantation. While there has been something of an exodus from the amyloid hypothesis of late, given the litany of failure in clinical trials aiming to reduce amyloid in the brain, it still seems clear that protein aggregates (amyloid and tau) occupy a central position in the progression of neurodegeneration. Spurring greater brain tissue maintenance via generation of neurons is a beneficial goal in and of itself, but as a compensatory treatment, it can't be enough on its own to turn back neurodegeneration primarily caused by factors such as metabolic waste and chronic inflammation.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive cognitive decline. Tremendous efforts have been made to develop novel therapeutics to potentially reverse disease progression. Substantial neuronal loss is observed even in mild AD patients. Intuitively, increasing the number of neurons or replacing lost neurons are potential therapeutic strategies for AD. Stem cells are capable of renewing themselves continuously and differentiating into specialized cells, including neurons.

The process of generating new fate-specified, functional neurons from neural progenitor cells, which are functionally incorporated into a neural circuit, is defined as neurogenesis. Across different species, neural regeneration mainly takes place at the dentate gyrus of the hippocampus and the subventricular zone along the lateral ventricle. Notably, the dentate gyrus, which plays a crucial role in memory formation processes, is related to early memory loss in AD. Neurogenesis decline accompanies normal aging. For AD, accumulating evidence suggests that impaired neurogenesis plays a role in its pathogenesis. Multiple molecules involved in AD pathogenesis, such as ApoE, PS1, and APP were recognized to take part in neurogenesis modulation. Therefore, understanding the mechanism of neurogenesis dysfunction and intervening with neurogenesis represents an alternative AD therapeutic strategy.

Generally, neurogenesis can be modulated by multiple factors that are related to lifestyle, including learning, exercise, social interaction, caloric restriction, blood oxygen level, and even microbial colonization. In this regard, advocating a healthy lifestyle exerts at least a mild effect on preventing or controlling AD in the long run. Apart from lifestyle modification, which exerts mild effects, several pioneering studies identified key molecules or drugs that rescue or reverse NSC dysfunction in elderly animal models, such as via plasma exchange.

Transplanting stem cells to substitute for lost neurons is another intuitively feasible strategy. However, studies have confirmed that the main benefit of stem cell transplantation is a neurosecretory effect. Various neurotrophic factors involved in modulating multiple cellular functions that promote the amelioration of pathological features and cognition in animal models have been recognized. There has been increasing commercial interest to transform current advances in transplantation into clinical practice on human patients.