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脑功能衰退相关的症状。它会影响记忆、推理、沟通和情绪。英国有85万人患有痴呆症，预计到2050年将增加到200万。因此，在未来25年里，英国治疗痴呆症的费用预计将增加一倍以上。阿尔茨海默病（AD）是最常见的痴呆症。几乎三分之二的阿尔茨海默病患者是女性。女性患病率较高的原因被认为与更年期的影响以及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，在更年期过渡期间引入雌激素替代疗法（ERT）可以为有AD风险的妇女提供认知益处。然而，ERT在大脑中的作用及其影响机制尚不清楚，值得进一步研究。基因的变异会影响我们身体产生功能性蛋白质的能力。这可能随后改变身体代谢和AD等疾病的风险。APOE基因的变异导致三种版本的蛋白质，即E2， E3或E4。我们每个人都有两个基因副本，APOE3/E4（25%的英国人）或APOE4/E4（2%的英国人）的人患AD的风险是最常见的APOE3/E3（60%的英国人）的3倍和15倍。最近的研究表明，与apoe4 -男性相比，apoe4 -女性患阿尔茨海默病的风险更高，这种风险开始于更年期过渡时期。在小鼠和人类研究中，我们和其他人证明APOE4女性患AD的风险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）性能降低，这两者都会影响脑细胞正常运作的能力，随着时间的推移会导致认知能力下降。大脑，尤其是突触区域，富含一种富含ω -3脂肪酸的DHA，这种脂肪酸存在于油性鱼类中。在人群观察研究和动物实验中，DHA摄入量的增加与认知能力的提高和AD风险的降低有关。我们假设DHA和雌激素替代将共同增加APOE4高危女性脑DHA水平，改善认知并降低痴呆发病率。我们将通过分析来自英国生物银行的绝经期妇女的饮食、激素和认知测试数据集来验证这一点。此外，我们将测试膳食DHA和激素干预对我们建立的绝经小鼠模型认知功能的影响。在UK BIOBANK分析中，我们将受益于50万英国参与者的大型数据库（其中26万是女性，随访期为12年以上），以观察DHA摄入量和状态、激素使用和APOE4状态对认知功能、AD发病率和脑容量的个人和集体影响。在小鼠模型中，我们将给表达人类APOE3和APOE4基因的小鼠喂食DHA，然后诱导类似人类的更年期，并在更年期过渡期间早或晚给予雌激素。将评估小鼠的认知功能，然后提取脑组织以评估大脑完整性，并进行基因、蛋白质和脂肪酸分析。从公共卫生的角度来看，这项研究将有助于确定处于关键绝经期的APOE4高危妇女（约占总人口的13%，但几乎占AD患者总数的40%）的饮食和激素替代策略。这有助于提高老年妇女的生活质量，并减少日益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.