Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer’s disease in midlife women

Nerattini, Matilde; Rubino, Federica; Jett, Steven; Andy, Caroline; Yepez, Camila Boneu; Zarate, Camila; Carlton, Caroline; Kodancha, Vibha; Loeb‐Zeitlin, Susan; Havryliuk, Yelena; Pahlajani, Silky; Williams, Schantel; Berti, Valentina; Dyke, Jonathan P.; Brinton, Roberta Dı́az; Mosconi, Lisa

doi:10.21203/rs.3.rs-2351642/v1

Cited by 2 publications

(2 citation statements)

References 61 publications

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“…We have shown that MS-Hu6 has an acceptable affinity to FSH, with a K D of 7.2 nM that approaches trastuzumab; a long half-life of 7.8 days in humanized Tg32 mice; limited, but measurable accumulation in the brain upon subcutaneous injection; and thermal, colloidal, monomeric, structural and accelerated stability in formulation, as evidence of durability and manufacturability 30,41,42 . However, supporting our core concept of inhibiting FSH to prevent MCI is a recent study in women between ages 40 to 65, of which 35% were peri-menopausal--documenting a strong positive correlation between serum FSH levels and Aβ load (measured on PET scans) and gray matter volume in AD-vulnerable regions 43 .…”

Section: Discussionmentioning

confidence: 71%

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Korkmaz,

Sims,

Sen

et al. 2024

Preprint

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Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post–menopausal levels of the pituitary gonadotropin follicle–stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampalFshrto drive AD–like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female3xTg;Fshr+/+, 3xTg;Fshr+/–and3xTg;Fshr-/-mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham–operated3xTg;Fshr-/-mice were implanted with 17β-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects ofFshrdepletion.3xTg;Fshr+/+mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in3xTg;Fshr-/-mice and, to a lesser extent, in3xTg;Fshr+/-mice–– thus documenting a clear gene–dose–dependent prevention of hippocampal–dependent spatial memory impairment. At 5 and 10 months, sham–operated3xTg;Fshr-/-mice showed better memory performance during the acquisition and/or retrieval phases, suggesting thatFshrdeletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10–month–old3xTg;Fshr-/-mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized3xTg;Fshr-/-mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene–dose–dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16–month–oldAPP/PS1mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH–blocking agent for the early prevention of cognitive decline in postmenopausal women.

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Section: Discussionmentioning

confidence: 71%

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Korkmaz,

Sims,

Sen

et al. 2024

Preprint

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“…This supports testing of therapies regulating serum gonadotropin levels for AD risk reduction. Estrogen therapy with or without a progestogen is the treatment of choice for menopausal symptoms (Santoro et al, 2021) and holds promise for AD prevention (Levin-Allerhand et al, 2002;Nerattini et al, 2023). Observational studies generally report favorable effects of MHT on AD risk, whereas clinical trials indicate null effects on cognition in early post-menopausal patients and null or negative effects in older post-menopausal women (Maki, 2008;Jett et al, 2022a,b).…”

Section: Discussionmentioning

confidence: 99%

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women

Nerattini,

Rubino,

Jett

et al. 2023

Front. Dement.

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IntroductionIn preclinical studies, menopausal elevations in pituitary gonadotropins, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), trigger Alzheimer's disease (AD) pathology and synaptic loss in female animals. Herein, we took a translational approach to test whether gonadotropin elevations are linked to AD pathophysiology in women.MethodsWe examined 191 women ages 40–65 years, carrying risk factors for late-onset AD, including 45 premenopausal, 67 perimenopausal, and 79 postmenopausal participants with clinical, laboratory, cognitive exams, and volumetric MRI scans. Half of the cohort completed 11C-Pittsburgh Compound B (PiB) amyloid-β (Aβ) PET scans. Associations between serum FSH, LH and biomarkers were examined using voxel-based analysis, overall and stratified by menopause status. Associations with region-of-interest (ROI) hippocampal volume, plasma estradiol levels, APOE-4 status, and cognition were assessed in sensitivity analyses.ResultsFSH levels were positively associated with Aβ load in frontal cortex (multivariable adjusted P ≤ 0.05, corrected for family wise type error, FWE), an effect that was driven by the postmenopausal group (multivariable adjusted PFWE ≤ 0.044). LH levels were also associated with Aβ load in frontal cortex, which did not survive multivariable adjustment. FSH and LH were negatively associated with gray matter volume (GMV) in frontal cortex, overall and in each menopausal group (multivariable adjusted PFWE ≤ 0.040), and FSH was marginally associated with ROI hippocampal volume (multivariable adjusted P = 0.058). Associations were independent of age, clinical confounders, menopause type, hormone therapy status, history of depression, APOE-4 status, and regional effects of estradiol. There were no significant associations with cognitive scores.DiscussionIncreasing serum gonadotropin levels, especially FSH, are associated with higher Aβ load and lower GMV in some AD-vulnerable regions of midlife women at risk for AD. These findings are consistent with preclinical work and provide exploratory hormonal targets for precision medicine strategies for AD risk reduction.

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Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer’s disease in midlife women

Cited by 2 publications

References 61 publications

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Elevated gonadotropin levels are associated with increased biomarker risk of Alzheimer's disease in midlife women

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