Enhancing cognition through the menopausal transition in at-risk 'APOE4' carriers by fatty acid and hormonal modulation.

痴呆症是一组与年龄相关的大脑功能下降有关的症状。它会影响记忆、推理、交流和情绪。英国有85万痴呆症患者，预计到2050年将增加到200万。因此，未来25年，英国痴呆症护理成本预计将翻一番以上。阿尔茨海默病(AD)是痴呆症最常见的形式。几乎三分之二的AD患者是女性。女性患病率较高的原因被认为与更年期的影响和APOE4基因风险因素对大脑功能的影响有关。更年期被定义为卵巢功能的永久停止。绝经前的几年被称为绝经过渡期，或围绝经期。这一时期目前被认为是关键时期，雌激素水平的下降与大脑(认知)功能的下降有关。最近有限的研究表明，在绝经过渡期间引入雌激素替代疗法(ERT)可以为有AD风险的女性提供认知方面的好处。然而，对ERT在大脑中的影响和作用机制还知之甚少，值得研究。我们基因的变异会影响我们身体产生功能蛋白质的能力。这可能会随后改变身体新陈代谢和阿尔茨海默病等疾病的风险。载脂蛋白E基因的变异导致了该蛋白的三个版本，即E2、E3或E4。我们每个人都有每个基因的两个副本，我们中那些APOE3/E4(25%英国人)或APOE4/E4(2%英国人)的人患AD的风险是那些最常见的APOE3/E3人(60%英国人)的3倍和15倍。最近的研究表明，在绝经过渡期开始的APOE4-女性比APOE4-男性患AD的风险更高。在小鼠和人类的研究中，我们和其他人证明，APOE4女性AD风险的增加可能是由于脑部炎症增加和脑细胞末端(神经元突触区域)的性能降低，这两者都会影响脑细胞的正常运作能力，随着时间的推移，这可能会导致认知能力下降。大脑，特别是突触区域，富含一种在油性鱼类中发现的omega-3脂肪酸，称为DHA。在人群观察研究和动物实验中，增加DHA摄入量与改善认知和降低AD风险有关。我们假设DHA和雌激素替代将共同提高APOE4高危女性的大脑DHA水平，改善认知和降低痴呆症发病率。我们将通过分析来自英国生物库的更年期女性的饮食、激素和认知测试数据来测试这一点。此外，我们将测试饮食DHA和激素干预对我们成熟的更年期小鼠模型认知功能的影响。在UK Biobank分析中，我们将受益于一个包含50万英国参与者(其中26万为女性，随访期为12年以上)的大型数据库，以观察DHA摄入量和状态、激素使用和APOE4状态对认知功能、AD发病率和脑体积的个人和集体影响。在小鼠模型中，我们将用DHA喂养表达人APOE3和APOE4基因的小鼠，然后诱导类似人类的更年期，并在更年期过渡的早期或后期给予雌激素。将对小鼠的认知功能进行评估，然后提取脑组织以评估大脑的完整性，并进行基因、蛋白质和脂肪酸的分析。从公共卫生的角度来看，这项研究将有助于确定APOE4高危女性(她们约占总人口的13%，但几乎占全部AD患者的40%)在关键更年期窗口的饮食和激素替代策略。这有助于提高老年女性的生活质量，减少不断增加的痴呆症护理国家预算。

Dementia is a group of symptoms associated with age-related decline in brain function. It affects memory, reasoning, communication, and mood. There are 850,000 in the UK living with dementia, with an expected rise to two million by 2050. As a result, the cost of dementia care in the UK is expected to more than double in the next 25 years. Alzheimer's disease (AD) is the most common form of dementia. Almost two-thirds of AD patients are women. The reason behind the higher female prevalence is thought to be related to the effects of menopause and the impact of the APOE4 genetic risk factor on brain function. Menopause is defined as the permanent cessation of ovarian function. The years leading up to menopause are called the menopausal transition, or perimenopause. This period is currently considered critical, where estrogen decline has been linked to a decline in brain (cognitive) functions. Limited recent studies suggest that the introduction of estrogen replacement therapy (ERT) during the menopausal transition could provide cognitive benefits to women at risk of AD. However, it is poorly understood and worthy of investigation to look at the impact and mechanism of action of ERT in the brain.Variation in our genes can affect our body's ability to produce functional proteins. This may subsequently change body metabolism and risk of diseases such as AD. Variation in the APOE gene results in three versions of the protein, namely E2, E3 or E4. We all have two copies of each gene and those of us who are APOE3/E4 (25% UK population) or APOE4/E4 (2% UK population) are at 3- and 15-fold increased risk of AD compared to those with the most common APOE3/E3 (60% UK population). Recent studies show that the risk of AD is higher in APOE4-women compared to APOE4-men, which begins during the menopausal transition. In mice and human studies, we and others demonstrated that the increased risk of AD in APOE4 females is likely due to increased brain inflammation and lower performance of the end of brain cells (neuronal synaptic regions), both of which affects the ability of brain cells to function properly which over time can lead to cognitive decline. The brain, and in particular the synaptic region, is rich in an omega-3 fatty acid found in oily fish, called DHA. In population observational studies and animal experiments increased DHA intake is associated with improved cognition and reduced AD risk.We hypothesise that DHA and estrogen replacement will together increase brain DHA levels, improve cognition and reduce dementia incidence in at-risk APOE4 females. We will test this by analysing dietary, hormonal, and cognitive test datasets of menopausal women from the UK BIOBANK. In addition, we will test the impact of dietary DHA and hormonal intervention on the cognitive function of our well-established menopausal mouse model.In the UK BIOBANK analysis, we will benefit from a large-scale database of half a million UK participants (of which 260,000 are females, with a follow-up period of 12 years+), to look at the individual and collective effect of DHA intake and status, hormone use, and APOE4 status on cognitive function, AD incidence, and brain volume. In the mouse model, we will feed mice that express the human APOE3 and APOE4 gene with DHA, then induce a human-like menopause and administer estrogen early or late during the menopausal transition. The cognitive function of the mice will be assessed, then the brain tissue will be extracted for evaluating brain integrity, and for gene, protein, and fatty acids profiling. From a public-health point of view, this study will help in identifying dietary and hormonal replacement strategies for at-risk APOE4 women (who represent about 13% of the general population but almost 40% of total AD patients) at a critical menopausal window. This can assist in improving the quality of life of older females and in reducing the rising national budget for dementia care.