# Peri-menopause as a neurological transition state that triggers Alzheimer's disease onset and accelerates disease progression

> **NIH NIH R21** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $211,875

## Abstract

ABSTRACT
Prevalence and rate of progression of Alzheimer’s disease are 2-3-fold higher in post-menopausal
women respect to age-matched men. Aside from the established vulnerability, the molecular mechanisms
underlying the increased risk of Alzheimer’s disease in women are largely unknown. Alzheimer’s has a
long prodromal phase which coincides with the menopause transition in women (peri-menopause, age
~45-54 years). Peri-menopausal women show higher levels of Alzheimer’s disease brain pathology
[amyloid b (Ab) plaques, neurofibrillary tangles, synaptic loss, and chronic inflammation] compared to
pre-menopausal women and men. This suggests that mechanisms unique to peri-menopause increase
the susceptibility to Alzheimer’s disease leading to earlier onset and faster progression of the disease.
The goal of this proposal is to elucidate the effects of peri-menopause on Alzheimer’s disease pathology
and cognitive decline, as well as to identify molecular pathways differentially expressed in peri-
menopausal females compared to young females, males, and ovariectomized females (as a mean of
comparison to previous published studies). We hypothesize that irregular estrogen cyclicity and estrogen-
estrogen receptor interactions during peri-menopause, rather than only loss of estrogen during post-
menopause, increase the susceptibility to Alzheimer’s by magnifying the pathology in vulnerable brain
regions leading to faster development of cognitive deficits. We will use a novel mouse model of
accelerated ovarian failure (AOF) which uniquely recapitulates human menopause including peri- and
post-menopause (peri- and post-AOF respectively). Two specific aims will test this hypothesis in the
hAPP-J20 (J20) mouse model of Alzheimer’s. Aim 1 will test the sub-hypothesis that irregular estrogen
fluctuations at peri-AOF will accelerate cognitive deficits, synaptic loss, and recruitment of microglia and
astrocytes in hippocampus and prefrontal cortex (PFC) of J20 mice compared to control mice. Aim 2 will
test the sub-hypothesis that peri-AOF disrupts neuronal pathways involved in Ab metabolism resulting in
increased deposition of Ab plaques in the hippocampus and PFC of our AD females compared to age-
matched controls. We will use a unique combination of sophisticated imaging and genomic analysis
including iDisco, which will allow the 3D quantification of whole brain Ab and glia activation, and
translational ribosomal profiling (TRAP) for sequencing the pool of actively transcribed mRNA in neurons.
Our research outcomes will provide novel insights into the influence of peri-menopause on molecular
mechanisms central to Alzheimer’s disease pathogenesis. Our findings will address NIA strategic goals:
understand the progression of Alzheimer’s (A), and identify potential therapeutic targets for the
development of precision medicine treatments for men and women (D).

## Key facts

- **NIH application ID:** 9979195
- **Project number:** 1R21AG064455-01A1
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Roberta Marongiu
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $211,875
- **Award type:** 1
- **Project period:** 2020-09-16 → 2022-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9979195

## Citation

> US National Institutes of Health, RePORTER application 9979195, Peri-menopause as a neurological transition state that triggers Alzheimer's disease onset and accelerates disease progression (1R21AG064455-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9979195. Licensed CC0.

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