Saturday, August 23, 2025 8/23/2025

Elevated FSH - A Driver for Sex Differences in Alzheimer's Disease

Award Number: R01AG074092
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Elevated FSH - A Driver for Sex Differences in Alzheimer's Disease - PROJECT SUMMARY Alzheimer’s disease (AD) stands out as notable in two respects––in not having a cure and in affecting women more than men. While declining estrogen has been thought to underpin post–menopausal AD, there is a clear clinical correlation of AD with rising levels of follicle–stimulating hormone (FSH). Most notably, there is a ‘spike’ in cognitive decline in women in the early years of the menopausal transition, when serum estrogen is normal and FSH levels begin to rise. Collaborative studies between the Mount Sinai and Emory groups have identified FSH as a potential driver for AD—and suggest that rising FSH levels may contribute to the disproportionate increase of AD in aging women. Notably, we find that FSH receptors (FSHRs) are expressed in both mouse and human brain, and that the injection of recombinant FSH or ovariectomy (that elevates serum FSH) aggravates AD pathology and cognitive decline in 3xTg mice. Inhibiting the action of FSH in 3xTg or APP/PS1 mice by an FSH–blocking antibody or downregulating Fshr expression in the hippocampus prevents onset of the AD phenotype. The Emory group also provides strong preliminary evidence that FSH upregulates C/EBPβ, which activates asparagine endopeptidase (AEP), a δ–secretase that cleaves amyloid precursor protein (APP) and Tau––resulting in neuritic plaques and neurofibrillary tangles, respectively. The goal of the transdisciplinary collaboration between the disciplines of endocrinology and neuroscience is to fully understand the mechanism of FSH action on AD–vulnerable brain regions. Thus, in Specific Aim 1, we will map the distribution and cellular localization of the FSHR and its signaling partners CEBPB and LGMN in human and mouse brain using single–transcript technologies. In Specific Aim 2, we will examine the function of the brain FSHR in driving AD pathology and cognitive decline. For this, we will downregulate or overexpress the Fshr in specific brain areas of 3xTg mice by stereotaxically injecting AAV expressing siFshr or Fshr. We will also study the effect of high FSH in 3xTg mice rendered haploinsufficient in Cebpb, and delineate the transcriptomic architecture of FSH–treated human neuronal cells by RNA–seq. In Specific Aim 3, we will determine whether deleting the Fshr or inhibiting FSH action by our murine FSH blocking antibody, Hf2, injected over the lifespan of 3xTg mice can prevent the onset of cognitive decline. To contemporaneously replicate our data, the Emory group will study the effect of treating established cognitive impairment with Hf2 in 18–month–old APP knock–in (KI) mice. In all, our proof–of–concept studies––conducted using our Good Laboratory Practices (GLP) Platform––should not only establish a role for high FSH in driving AD, but also provide a framework for the future testing of our humanized FSH–blocking antibody, Hu6, in aging women.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $1,242,150 )
2025	2025	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	5	8/6/2025	NON-COMPETING CONTINUATION	$1,242,150
														Subtotal = $1,242,150

Issue Date FY: 2024 ( Subtotal = $1,267,500 )
2024	2024	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	1 GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	4	7/31/2024	NON-COMPETING CONTINUATION	$1,267,500
														Subtotal = $1,267,500

Issue Date FY: 2023 ( Subtotal = $1,267,500 )
2023	2023	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	3	7/27/2023	NON-COMPETING CONTINUATION	$1,267,500
														Subtotal = $1,267,500

Issue Date FY: 2022 ( Subtotal = $1,267,500 )
2022	2022	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	2	8/17/2022	NON-COMPETING CONTINUATION	$1,267,500
														Subtotal = $1,267,500

Issue Date FY: 2021 ( Subtotal = $1,268,438 )
2021	2021	ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI	ONE GUSTAVE L LEVY PL	NEW YORK	NY	10029	NEW YORK	USA	Aging Research	000	1	9/24/2021	NEW	$1,268,438
														Subtotal = $1,268,438

Grand Total All Awards = $6,313,088

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Elevated FSH - A Driver for Sex Differences in Alzheimer's Disease

Award Number: R01AG074092

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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