Cholinergic Health After Menopause (CHAMP)

Summary

Women are at increased risk for Alzheimer's disease (AD). Notably at menopause, some women experience a change in cognition. However, not all women experience negative effects of menopause on cognition. The cognitive changes that occur at menopause have not yet been connected to late life risk for pathological aging including AD. Thus, understanding the neurobiological factors related to individual differences in cognition at menopause is critical for understanding normal cognitive aging and for determining risk for pathological aging. The challenge in understanding the role of estrogen loss on the risk for AD is the long lag time between the hormonal changes at menopause and the clinical manifestations of AD. Thus, identifying how the hormone changes after menopause are related to AD risk will alter the risk calculus for postmenopausal women in the future.

The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism that may also underlie cognitive changes after menopause. The investigators propose that the change in the hormonal milieu at menopause interacts with the cholinergic system and other brain pathologies to influence a woman's risk for cognitive decline. Preclinical studies have shown that estrogen is necessary for normal cholinergic functioning and its withdrawal leads to cholinergic dysfunction and cognitive impairment. It is important to determine whether menopause-related cognitive changes correlate with both cholinergic functional integrity and established AD biomarkers that portend increased risk for late-life cognitive impairment or dementia. This study will examine brain functioning following cholinergic blockade to separate individuals into those who are able to compensate for the hormone change after menopause and those who are not. The investigators hypothesize women with poor compensation have increased sensitivity to cholinergic blockade by showing poor performance on a cognitive task, altered brain activation, and decreased basal forebrain cholinergic system (BFCS) volume. These cholinergic markers will be related to menopausal factors associated with poor cognition and biomarkers of AD.

Specific Aim 1 is to examine cholinergic functional "integrity" by measuring working memory performance, functional brain activation, and BFCS structure in postmenopausal women. Specific Aim 2 will examine whether individual differences in menopause-relevant symptoms and known AD biomarkers are related to cognition and brain activation after anticholinergic challenge.

The public health significance of this study is that it will identify individual difference factors that are associated with cognitive performance changes after menopause and their relationship to structural, functional, and biomarker evidence of risk for later life cognitive dysfunction. Knowledge of these factors will serve to advance personalized future risk-mitigation strategies for women including hormonal, medication, cognitive remediation, etc. that will be the subject of further research.

Conditions

• Postmenopausal Symptoms
• Aging
• Alzheimer Disease

Interventions

DRUG

Cholinergic antagonist

The cholinergic antagonist drug mecamylamine will be administered as a a 20 mg oral pill and matching placebo

Sponsors & Collaborators

• Vanderbilt University Medical Center

  collaborator OTHER

• University of Vermont

  lead OTHER

Principal Investigators

• Julie A Dumas, Ph.D. · University of Vermont

• Paul A Newhouse, M.D. · Vanderbilt University

Study Design

Allocation

RANDOMIZED

Purpose

BASIC_SCIENCE

Masking

DOUBLE

Model

CROSSOVER

Eligibility

Min Age

50 Years

Max Age

70 Years

Sex

FEMALE

Healthy Volunteers

Yes

Timeline & Regulatory

Start

2020-03-15

Primary Completion

2024-12-16

Completion

2024-12-16

FDA Drug

Yes

Countries

• United States

Study Locations