A substantial number of the more than 45 million postmenopausal US women will develop dementia or cognitive impairment. Our Perimenopause in Brain Aging and Alzheimer's Disease Program Project seeks to discover the biological transformations occurring in the brain during the perimenopausal transition which can result in phenotypes predictive of risk for development of Alzheimer's disease (AD) pathology and to identify the mechanisms by which these changes occur, and translate these discoveries to determine the optimal timing and strategies for preventing conversion to the perimenopausal at-risk phenotype. Project 4 will characterize biological profiles from the perimenopausal and postmenopausal periods, and evaluate the association of these profiles with cognition in women who are in eariy vs. late menopause. Project 4 will (1) determine whether biomarkers hypothesized to be important in the perimenopausal period and in AD characterize the postmenopausal human female in eariy vs. later menopause;(2) determine whether and to what extent these biomarkers are associated with cognition;and (3) evaluate whether administration of menopausal hormone therapy will modify these markers. Project 4 will use data and stored tissue samples from the NIA-funded Eariy versus Late Intervention Trial with Estrogen (ELITE) (R01AG-024154) trial to test four hypotheses: (1) The perimenopause transition results in the bioenergetic and inflammatory phenotype consistent with biomarkers of Alzheimer's disease risk;(2) the perimenopause transition will result in multiple phenotypes, subgroups of which will predict risk of developing biomarkers of Alzheimer's disease;(3) the perimenopause transition is a critical window that determines ovarian hormone response and their role in prevention vs. increased risk of developing eariy biomarkers of AD;and (4) ovarian hormone and bioenergetic interventions can modify development of biomarkers of Alzheimer's disease in the perimenopausal at-risk phenotype. This Project will work closely with Analytic Core and Administrative Core on processing samples and data, and with Projects 1-3 on bioenergetic, inflammatory, and dietary analyses.

Public Health Relevance

More than 60% of Alzheimer's disease (AD) patients are women. This phase of our Perimenopause Program Project seeks to evaluate, identify and prevent perimenopause-related brain changes predictive of increased AD risk. Project 4 will determine whether flushing and the timing and duration of perimenopause are associated with increased risk of cognitive decline. Project 4 will evaluate the impact of hormonal and dietary interventions on cognitive function, and identify a treatment window to reduce risk of cognitive decline.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Program Projects (P01)
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Special Emphasis Panel (ZAG1-ZIJ-8)
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University of Southern California
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Rettberg, Jamaica R; Yao, Jia; Brinton, Roberta Diaz (2014) Estrogen: a master regulator of bioenergetic systems in the brain and body. Front Neuroendocrinol 35:8-30
Finch, Caleb E; Beltrán-Sánchez, Hiram; Crimmins, Eileen M (2014) Uneven futures of human lifespans: reckonings from Gompertz mortality rates, climate change, and air pollution. Gerontology 60:183-8
Yin, Fei; Boveris, Alberto; Cadenas, Enrique (2014) Mitochondrial energy metabolism and redox signaling in brain aging and neurodegeneration. Antioxid Redox Signal 20:353-71
Finch, Caleb E; Tower, John (2014) Sex-specific aging in flies, worms, and missing great-granddads. Cell 156:398-9
Chang, Allen H K; Sancheti, Harsh; Garcia, Jerome et al. (2014) Respiratory substrates regulate S-nitrosylation of mitochondrial proteins through a thiol-dependent pathway. Chem Res Toxicol 27:794-804
Finch, Caleb E (2014) The menopause and aging, a comparative perspective. J Steroid Biochem Mol Biol 142:132-41
Sancheti, Harsh; Kanamori, Keiko; Patil, Ishan et al. (2014) Reversal of metabolic deficits by lipoic acid in a triple transgenic mouse model of Alzheimer's disease: a 13C NMR study. J Cereb Blood Flow Metab 34:288-96
Jayaraman, Anusha; Pike, Christian J (2014) Differential effects of synthetic progestagens on neuron survival and estrogen neuroprotection in cultured neurons. Mol Cell Endocrinol 384:52-60
Yin, Fei; Jiang, Tianyi; Cadenas, Enrique (2013) Metabolic triad in brain aging: mitochondria, insulin/IGF-1 signalling and JNK signalling. Biochem Soc Trans 41:101-5
Bali, N; Arimoto, J M; Morgan, T E et al. (2013) Progesterone antagonism of neurite outgrowth depends on microglial activation via Pgrmc1/S2R. Endocrinology 154:2468-80

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