Balchem Corporation, New Hampton, NY, USA.
Baylor College of Medicine, Houston, TX, USA.
Adv Nutr. 2022 Mar;13(2):376-387. doi: 10.1093/advances/nmab145. Epub 2023 Feb 10.
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." 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 ω-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.
影响神经认知衰退和阿尔茨海默病（AD）风险的因素可能为这两种疾病的治疗和预防提供治疗方法。尽管年龄是 AD 的最显著风险因素，但值得注意的是，女性 AD 的患病率更高，占病例的三分之二。为了探讨这种观察结果的潜在生物学基础，本文旨在探讨认知老化与性激素、胆碱能系统之间的相互作用，以及与必需营养素胆碱相关的新假说。机制证据表明，雌激素的神经保护作用强烈依赖于其与胆碱能系统的相互作用，胆碱能系统是注意力功能、学习和记忆的调节剂。雌激素已被证明可减轻抗胆碱能药物引起的言语记忆损伤，并使额皮质和枕皮质激活模式正常化，从而呈现出更“年轻成年”的表型。然而，与雌激素替代疗法在心血管疾病中的作用类似，其潜在的保护作用可能仅限于绝经后早期的女性，这一发现支持“关键窗口期假说”。雌激素对胆碱能系统的影响既可以在大脑局部发挥作用，也可以通过外周组织发挥作用。雌激素对于通过磷酸乙醇胺 N-甲基转移酶（PEMT）基因介导的途径诱导内源性胆碱合成至关重要，该途径涉及磷酸胆碱（PC）的合成。PEMT 对雌激素的反应非常强烈，不仅产生 PC 分子和大脑的胆碱来源，还产生长链 ω-3 脂肪酸 DHA 的重要来源。在此，我们强调了与激素替代疗法和营养代谢相关的新假说，旨在指导未来的临床前和临床研究。
