Research

Research:

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that affects millions of people worldwide. Female sex is a major risk factor for AD; approximately two-thirds of individuals with AD are women. Moreover, compared with men, women show a greater burden of AD pathology, steeper cognitive decline prior to AD dementia diagnosis, and a more favorable clinical profile during prodromal disease, including a lower frequency of mild cognitive impairment (MCI). Our laboratory investigates the molecular mechanisms underlying these sex differences in AD. Using quantitative in vitro autoradiography and immunohistochemistry/immunofluorescence, we examine sex- and region-dependent differences in the density of AD-related biomarkers, including tau and amyloid deposition, neuroinflammation, and NMDARs, in postmortem hippocampal and cortical tissue from women and men. Future studies will investigate how neuroendocrine changes associated with menopause contribute to these sex differences. Ultimately, this work will help advance personalized, sex-specific approaches to the diagnosis and treatment of Alzheimer’s disease.

Fig. 1. Sex- and region-dependent increases in TSPO density in Alzheimer’s disease. Representative pseudocolored autoradiograms of the 18-kDa translocator protein (TSPO), a marker of neuroinflammation, labeled with [³H]-PK11195 in the hippocampus and entorhinal cortex of women and men who were cognitively normal (CN), had mild cognitive impairment (MCI), or Alzheimer’s disease (AD). Representative sections show higher TSPO density in AD compared with CN and MCI in both sexes, with particularly prominent signal in the representative AD woman. In AD participants, high TSPO density is apparent in the dentate gyrus (DG; asterisks) and subiculum (arrowheads). Quantitative analyses revealed significant main effects of diagnosis, region, and sex, with higher overall TSPO density in women than in men. Regional analyses showed that TSPO density in the subiculum was significantly higher in AD than in MCI and CN in both women and men, whereas MCI and CN did not differ. In women, AD-related increases in TSPO density were significant across all examined regions, whereas in men, significant AD-related increases were observed only in the CA1 and subiculum (quantitative data not shown). Autoradiograms were pseudocolored using the Gem lookup table shown at the bottom. CA1, cornu ammonis field 1; DG, dentate gyrus; CN, cognitively normal; MCI, mild cognitive impairment; AD, Alzheimer’s disease.

Acosta-Martínez M, Carter V, Nessim A, Murphy S, Dhawan, J, Beach TG, Serrano GE, Sundermann EE, Biegon A. Sex-divergent trajectories of hippocampal and cortical NMDA receptor density across the Alzheimer's disease continuum. (2026). Preprint: bioRxiv 2026.08.05.743051; doi:https://doi.org/10.64898/2026.08.05.743051

Sundermann EE, Banks SJ, Bondi MW, Acosta-Martínez M, Biegon A, Rotblatt LJ, Hildebrandt T. Sex differences in the relationship of biomarker change to memory decline in early Alzheimer’s disease: an observational cohort study. Biol Sex Differ. 2026;17(1):38, DOI 10.1186/s13293-025-00820-6, PMID 41540505

Acosta-Martínez M, Carter V, Nessim A, Panchal R, John D, Dhawan J, Beach TG, Serrano GE, Sundermann EE, Biegon A. (2025) Sex- and Region-Dependent Neuroinflammation in Alzheimer’s Disease.  Alzheimer’s Dement. 2025;21:e14603.

Acosta-Martínez M, Chandran L, Cohen S, Biegon A. (2023) Design, implementation, and evaluation of an intensive course on issues in women’s health and gender-based medicine. J of Med Educa Curric Dev. 10:1-9.

Acosta-Martínez, M. (2023). Hypothalamic-Pituitary-Gonadal Axis Disorders Impacting Fertility in Both Sexes and the Potential of Kisspeptin-Based Therapies to Treat Them. In: Tsirka, S.E., Acosta-Martinez, M. (eds) Sex and Gender Effects in Pharmacology. Handbook of Experimental Pharmacology, vol 282. Springer, Cham. https://doi.org/10.1007/164_2023_66

Acosta-Martínez M and Cabail MZ, (2022) The PI3K/Akt Pathway in Meta-Inflammation. Int. J. Mol. Sci., 23(23) 1-18.

Acosta-Martínez M. (2020) Shaping microglia phenotypes through estrogen receptors: Relevance to sex-specific neuroinflammatory responses to brain injury and disease. Journal of Pharmacology and Experimental Therapeutics (JPET) 375:223–236. 

Negrón, AL, Yu G., Boehm, U., Acosta-Martínez M. (2020). Targeted Deletion of PTEN in Kisspeptin Cells Results in Brain Region- and Sex-Specific Effects on Kisspeptin Expression and Gonadotropin Release International Journal of Molecular Sciences, 21(6): 2107.

Boughton Nelson, V*, Negrón, AL*, Yang L, Reid I, Thomas JA, Lin RZ, Acosta-Martínez M. (2017) Loss of PI3K p110α in the adipose tissue results in infertility and delayed puberty onset in male mice. BioMed Research International: Endocrinology, Volume 2017, Article ID 3756089, 13 pages

Negrón, AL, Beymer, M, Yu G, Warren KA, Yu G, Acosta-Martínez, M. (2015) Prolonged hyperglycemia and hyperinsulinemia increase BDNF mRNA expression in the posterior ventromedial hypothalamus and the dorsomedial hypothalamus of fed female rats. Neuroscience, 303 (10): 422-432

Dubois, SL, Acosta-Martínez M, DeJoseph MR, Wolfe A, Radovick S, Boehm U, Urban JH, and Levine, JE, (2015) Positive, but not negative feedback actions of estradiol in adult female mice require estrogen receptor a in kisspeptin neurons. Endocrinology, 156(3): 1111–1120

Beymer M, Negrón AL, Yu G, Wu S, Mayer C, Lin RZ, Boehm U, Acosta-Martínez M., (2014) Kisspeptin cell-specific PI3K signaling regulates hypothalamic kisspeptin expression and participates in the regulation of female fertility. American Journal of Physiology - Endocrinology and Metabolism 307 (11): E969-E982.

Aziz, R*, Beymer M*, Negrón AL, Newshan A, Yu G, Rosati B, McKinnon D, Fukuda M, Lin RZ, Mayer C, Boehm U, Acosta-Martínez M, (2014) Galanin-like peptide (GALP) neuron-specific PI3K signaling regulates GALP mRNA levels in the hypothalamus of males and LH levels in both sexes. J Neuroendocrinol. 26(7): 426-38.

Acosta-Martinez, M, (2012) PI3K: An attractive candidate for the central integration of metabolism and reproduction. Front. Endocrinology, 2(110): 1-15

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