# Aging of Emotion Circuitry and Risk for Alzheimer's disease: Impact of Sex, Immunity, and Fetal Origins

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2024 · $1,551,207

## Abstract

Summary
Symptomatology associated with emotion dysregulation (including depression) has been identified as a critical
early indicator of neurodegeneration preceding cognitive impairment in preclinical Alzheimer's disease (AD).
One of the primary symptoms is loss of inhibitory control of negative affective arousal in the absence of
significant cognitive complaints or dementia. When persistent and onsetting >age 50, it has been linked to
increased risk of AD and predictor of accelerated cognitive decline, particularly in women. In AG057505, we
have been investigating sex differences in the fetal immune programming of aging of brain regions associated
with depression and associated loss of inhibitory control of negative emotion. These include hypothalamus,
locus coeruleus (LC), amygdala, hippocampus, anterior cingulate, and prefrontal cortex, some of which are
shared with memory circuitry, vulnerable to early AD in midlife, and highly sexually dimorphic. In this competing
renewal of AG057505, we will test the hypothesis that neuroimmune and vascular pathways, in part, underlie
shared dysregulation of emotion/mood and memory circuitries, the former of which will begin prior to memory
decline and AD pathology, with women having greater risk for decline and AD pathology than men. We are
uniquely poised to examine this given that, in AG057505, we prospectively followed 160 offspring (equally
divided by sex) from our prenatal cohort from 2nd/3rd trimesters to ages 55-61. We will re-recruit over 5 years
the 160 offspring at ages 61-70 and relate maternal prenatal immune activity to sex differences in emotion
circuitry deficits/depression at ages 55-61 on memory circuitry, AD pathology, and neurovascular deficits at
ages 61-70, and cognitive decline over the 5 years. As in AG057507, the same multimodal imaging
(sMRI/fMRI/DTI) will be used coupled with hormones, autonomic and immune physiology, novel genomic
approach assessing innate immune gene expression, and emotion regulation and cognitive measures. Further,
we will add as outcomes an fMRI associative memory task, AD blood-based biomarkers, and novel ultra-high
field imaging of neurovascular structure/function, and PET amyloid imaging for half the sample to localize
amyloid accumulation. We predict that immune dysregulation, beginning prenatally, will lead to early alterations
in microvascular circulation of the LC (site of early amyloid and tau deposition) and associated emotion
circuitry dysregulation, that precedes development of AD pathology, neurovascular structural/functional
deficits, and memory decline, that we predict will be worse in women than men. There is a lack of studies that
can prospectively investigate the impact of emotion dysregulation/depression preceding cognitive decline and
AD pathology and uniquely investigate the impact of sex. Our approach is innovative and may identify potential
sex-selective targets (early risk modifiers) to attenuate disability and/or prevent memory decline...

## Key facts

- **NIH application ID:** 10881242
- **Project number:** 2R01AG057505-06A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** JILL M GOLDSTEIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,551,207
- **Award type:** 2
- **Project period:** 2018-06-15 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10881242

## Citation

> US National Institutes of Health, RePORTER application 10881242, Aging of Emotion Circuitry and Risk for Alzheimer's disease: Impact of Sex, Immunity, and Fetal Origins (2R01AG057505-06A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10881242. Licensed CC0.

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