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.