Perspective: Estrogen and the Risk of Cognitive Decline: A Missing Choline(rgic) Link?

Factors that influence the risk of neurocognitive decline and Alzheimer's disease (AD) may provide insight into therapies for both disease treatment and prevention. Although age is the most striking risk factor for AD, it is notable that the prevalence of AD is higher in women, representing two-thirds of cases. To explore potential underlying biological underpinnings of this observation, the intent of this article is to explore the interplay between cognitive aging and sex hormones, the cholinergic system, and novel hypotheses related to the essential nutrient choline. Mechanistic evidence points toward estrogen's neuroprotective effects being strongly dependent on its interactions with the cholinergic system, a modulator of attentional functioning, learning, and memory. Estrogen has been shown to attenuate anticholinergic-induced impairments in verbal memory and normalize patterns of frontal and occipital cortex activation, resulting in a more young adult' phenotype. However, similar to estrogen replacement's effect in cardiovascular diseases, its putative protective effects may be restricted to early postmenopausal women only, a finding supportive of the critical window hypothesis.degrees Estrogen's impact on the cholinergic system may act both locally in the brain but also through peripheral tissues. Estrogen is critical for inducing endogenous choline synthesis via the phosphatidylethanolamine N-methyltransferase (PEMT) gene-mediated pathway of phosphatidylcholine (PC) synthesis. PEMT is dramatically induced in response to estrogen, producing not only a PC molecule and source of choline for the brain but also a key source of the long-chain omega-3 fatty acid, DHA. Herein, we highlight novel hypotheses related to hormone replacement therapy and nutrient metabolism aimed at directing future preclinical and clinical investigation.

Automated summary

This article discusses the factors influencing the risk of neurocognitive decline and Alzheimer's disease, with a focus on the interplay between cognitive aging, sex hormones, the cholinergic system, and essential nutrient choline. It highlights the neuroprotective effects of estrogen, particularly in interactions with the cholinergic system, and the potential impact on hormone replacement therapy and nutrient metabolism. The critical window hypothesis regarding estrogen's effects on the cholinergic system may have implications for future research in both preclinical and clinical settings.