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

Abstract

Factors that influence the risk of neurocognitive decline and Alzheimer's disease (AD) may provide insight into therapies for both disease treatment and prevention. While 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, supportive of the “critical window hypothesis.” 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) 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.

Postmenopausal Status Exacerbates Stress-Related Neurological Disorders in Rats

“…Results showed that social instability stress (SIS) linked to immobilization (IS) induced anxiogenic behavior more in ovariectomized than shamoperated animals, as reflected by OA parameters as well as GABA and serotonin levels assessments. Indeed, estrogens are known as potent modulators of neuronal physiology, although the exact mode of action by which estrogen exerts its diverse effects is not clear [42]. Nevertheless, it is almost certain that GABAergic and serotoninergic neurons are involved in estrogen modulators effects.…”

The impact of 17β-estradiol on the estrogen-deficient female brain: from mechanisms to therapy with hot flushes as target symptoms

“…Therefore, estrogen therapy (ET) should be beneficial in this regard. However, conventional ET carries risks, including but not limited to cardiovascular liabilities as well as enhanced chances for the development of breast and uterine cancers, especially if it is used around geripause ( 80 – 83 ). Timing of ET is one of the critical factors.…”

“…Notwithstanding, current ET carries contraindications due to the already mentioned risks for deep vein thrombosis and subsequent pulmonary embolism, estrogen-sensitive cancers, and additional adverse effects ( 40 , 80 , 82 , 83 ). This is, in large part, due to the significant peripheral exposure to the hormone and, thus, a significant increase in circulating estrogen(s) even when E2 is used for intervention instead of CEE.…”

Phosphatidylethanolamine N-methyltransferase: from Functions to Diseases

“…Several studies have indicated that PEMT plays a vital role in nervous system diseases [122][123][124], and choline can alter mitosis and neuronal protein expression during fetal brain development [125]. Zhu et al [122,126] reported that PEMT deficiency increases progenitor cell mitosis and protein methylation and decreases calretinin levels in the embryonic mouse hippocampus (Table 1).…”