# Sex Differences in Alzheimer's disease-Related Pathology: Role of Mitochondrial Function and Metabolic Health

> **NIH NIH K01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $128,496

## Abstract

Project Summary/Abstract
 My career goal is to become a leading researcher in the field of sex differences in Alzheimer’s disease
(AD), with a specific focus on metabolic mediators and mitochondrial function. To this end, my specific training
goals in this K01 proposal include: 1) Increasing expertise and knowledge around sex differences in the brain,
2) Expanding my knowledge in metabolic and mitochondrial function in relation to AD and obtain training in
biomarker research, and 3) Developing proficiency in translational research and biostatistics for data analysis.
The NIA K01 Mentored Research Scientist Development Award will support my training and provide me with
the knowledge base and skills needed to become an independent investigator. These training goals will be
achieved in conjunction with the testing of my specific aims, which are built on promising preliminary data
showing that metabolic health impacts memory circuitry function over the menopausal transition, potentially
through mechanisms of oxidative stress.
 Two-thirds of patients with AD are women. Beyond life expectancy rates, there are sex-specific and
sex-dependent genetic and physiologic factors that contribute to the higher frequency of AD in women. Midlife
metabolic dysfunction, which significantly differs by sex, has long been recognized as a risk factor for AD.
Despite this, the pathophysiology underlying this relationship remains largely unknown. I will test that
hypothesis that mitochondrial function plays a critical role in understanding sex differences in memory circuitry
function and the early emergence of AD-related pathology. Data will be leveraged from the unique New
England Family Study (NEFS) prenatal cohort (N=212; 106M:106F), born between 1959-1966 and followed for
>60 years. Detailed medical/reproductive histories, metabolic assessments, memory assessments, and stored
blood samples were collected from offspring at ages 45-55 (T1 in R01MH090291). These same individuals are
currently being assessed in an 8-year follow up, at ages 52-65 (T2 in R01AG067019), using the same T1
measures with additional brain imaging modalities. I have a unique window of opportunity to examine how
mitochondrial function affects memory circuitry and AD-related pathology in a sex-dependent manner. Further,
from T1 to T2, some women transitioned to menopause and thus I will be able to prospectively explore the
longitudinal impact of reproductive aging, metabolic health, and mitochondrial function on memory decline and
the accumulation of AD-related pathology. This proposal will examine mitochondrial function as a
pathophysiological mechanism for sex differences in memory circuitry and risk for AD. Findings will have
significant long-term implications for the co-occurrence of brain and metabolic disorders and highlight potential
mechanistic targets for therapeutic strategies.

## Key facts

- **NIH application ID:** 10820420
- **Project number:** 5K01AG081500-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Kyoko Konishi
- **Activity code:** K01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $128,496
- **Award type:** 5
- **Project period:** 2023-05-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10820420

## Citation

> US National Institutes of Health, RePORTER application 10820420, Sex Differences in Alzheimer's disease-Related Pathology: Role of Mitochondrial Function and Metabolic Health (5K01AG081500-02). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10820420. Licensed CC0.

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