Background: With almost 47 million individuals worldwide suffering from some aspect
of dementia, it is clear that cognitive loss impacts a significant proportion of the global population.
Unfortunately, definitive treatments to resolve or prevent the onset of cognitive loss are limited. In
most cases such care is currently non-existent prompting the need for novel treatment strategies.
Methods: Mammalian forkhead transcription factors of the O class (FoxO) are one such avenue of
investigation that offer an exciting potential to bring new treatments forward for disorders that involve
cognitive loss. Here we examine the background, structure, expression, and function of FoxO
transcription factors and their role in cognitive loss, programmed cell death in the nervous system
with apoptosis and autophagy, and areas to target FoxOs for dementia and specific disorders such as
Results: FoxO proteins work in concert with a number of other cell survival pathways that involve
growth factors, such as erythropoietin and neurotrophins, silent mating type information regulation 2
homolog 1 (Saccharomyces cerevisiae) (SIRT1), Wnt1 inducible signaling pathway protein 1
(WISP1), Wnt signaling, and cancer-related pathways. FoxO transcription factors oversee proinflammatory
pathways, affect nervous system amyloid (Aβ) production and toxicity, lead to mitochondrial
dysfunction, foster neuronal apoptotic cell death, and accelerate the progression of degenerative
disease. However, under some scenarios such as those involving autophagy, FoxOs also can
offer protection in the nervous system and reduce toxic intracellular protein accumulations and
potentially limit Aβ toxicity.
Conclusion: Given the ability of FoxOs to not only promote apoptotic cell death in the nervous
system, but also through the induction of autophagy offer protection against degenerative disease
that can lead to dementia, a fine balance in the activity of FoxOs may be required to target cognitive
loss in individuals. Future work should yield exciting new prospects for FoxO proteins as new targets
to treat the onset and progression of cognitive loss and dementia.