TY - JOUR
T1 - Unveiling FOXO3's metabolic contribution to menopause and Alzheimer's disease
AU - O'Mahony, Christopher
AU - Hidalgo-Lanussa, Oscar
AU - Barreto, George E.
N1 - Publisher Copyright:
© 2025 The Authors
PY - 2025/2
Y1 - 2025/2
N2 - The increasing prevalence of Alzheimer's disease (AD) calls for a comprehensive exploration of its complex etiology, with a focus on sex-specific vulnerability, particularly the heightened susceptibility observed in postmenopausal women. Neurometabolic alterations during the endocrine transition emerge as early indicators of AD pathology, including reduced glucose metabolism and increased amyloid-beta (Aβ) deposition. The fluctuating endocrine environment, marked by declining estradiol levels and reduced estrogen receptor beta (ERβ) activity, further exacerbates this process. In this context, here we explore the potential of forkhead box O3 (FOXO3) as a critical mediator linking metabolic disturbances to hormonal decline. We propose that FOXO3 plays a key role in the intersection of menopause and AD, given its dysregulation in both AD patients and postmenopausal women, modulating cellular metabolism through interactions with the AMPK/AKT/PI3K pathways. This relationship highlights the intersection between hormonal changes and increased AD susceptibility. This review aims to open a discussion on FOXO3's contribution to the metabolic dysregulation seen in menopause and its impact on the progression of AD. Understanding the functional role of FOXO3 in menopause-associated metabolic changes could lead to targeted therapeutic strategies, offering novel insights for managing for this condition.
AB - The increasing prevalence of Alzheimer's disease (AD) calls for a comprehensive exploration of its complex etiology, with a focus on sex-specific vulnerability, particularly the heightened susceptibility observed in postmenopausal women. Neurometabolic alterations during the endocrine transition emerge as early indicators of AD pathology, including reduced glucose metabolism and increased amyloid-beta (Aβ) deposition. The fluctuating endocrine environment, marked by declining estradiol levels and reduced estrogen receptor beta (ERβ) activity, further exacerbates this process. In this context, here we explore the potential of forkhead box O3 (FOXO3) as a critical mediator linking metabolic disturbances to hormonal decline. We propose that FOXO3 plays a key role in the intersection of menopause and AD, given its dysregulation in both AD patients and postmenopausal women, modulating cellular metabolism through interactions with the AMPK/AKT/PI3K pathways. This relationship highlights the intersection between hormonal changes and increased AD susceptibility. This review aims to open a discussion on FOXO3's contribution to the metabolic dysregulation seen in menopause and its impact on the progression of AD. Understanding the functional role of FOXO3 in menopause-associated metabolic changes could lead to targeted therapeutic strategies, offering novel insights for managing for this condition.
KW - Alzheimer's disease
KW - FOXO3
KW - Gonadal hormones
KW - Menopause
KW - Mitochondria
KW - Steroid hormones
UR - http://www.scopus.com/inward/record.url?scp=85214336300&partnerID=8YFLogxK
U2 - 10.1016/j.exger.2025.112679
DO - 10.1016/j.exger.2025.112679
M3 - Short survey
AN - SCOPUS:85214336300
SN - 0531-5565
VL - 200
JO - Experimental Gerontology
JF - Experimental Gerontology
M1 - 112679
ER -