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

Abstract

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.

Gene–Dose–Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer’s Mice

“…We have shown that MS-Hu6 has an acceptable a nity 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 perimenopausal--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 .…”

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

“…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 .…”