Health of the cholinergic system and risk for Alzheimer's disease in post-menopausal women

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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. The novel study proposed here will examine an established AD-related neurotransmitter-based mechanism that may also underlie cognitive changes after menopause. We 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 supplemental application will enhance the parent grant in two primary ways. First it will enable the acquisition of medicinal mecamylamine (our anticholinergic challenge drug) that has become exceedingly difficult to obtain in the last two years. Second, it will add a novel in-vivo cholinergic molecular imaging biomarker of the integrity/function of the cholinergic neurotransmission system. This approach will use a novel positron emission tomography (PET) radiotracer, [18F]Fluoroethoxybenzovesamicol ([18F]FEOBV), that was developed for in-vivo assessment of brain cholinergic function as it exhibits high binding affinity and specificity for the presynaptic vesicular acetylcholine transporter (VAChT). [18F]FEOBV PET imaging will be used to greatly enhance our abilities to evaluate the impact of early preclinical AD pathologies on the relationship between cholinergic integrity, early cognitive alterations, and reproductive history. 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.