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下降相关的症状。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200万人。因此，英国痴呆症护理的成本预计将在未来25年内增加一倍以上。阿尔茨海默病（AD）是痴呆症最常见的形式。近三分之二的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以及APOE 4遗传风险因素对脑功能的影响有关。绝经是指卵巢功能的永久性停止。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的，雌激素下降与大脑（认知）功能下降有关。最近有限的研究表明，在绝经过渡期引入雌激素替代疗法（ERT）可以为有AD风险的女性提供认知益处。然而，我们对ERT在大脑中的作用和机制知之甚少，值得研究。我们基因的变异会影响我们身体产生功能蛋白的能力。这可能随后改变身体代谢和疾病的风险，如AD。APOE基因的变异导致蛋白质的三个版本，即E2，E3或E4。我们每个基因都有两个拷贝，与最常见的APOE 3/E3（60%英国人口）相比，APOE 3/E4（25%英国人口）或APOE 4/E4（2%英国人口）的AD风险增加了3倍和15倍。最近的研究表明，与APOE 4-男性相比，APOE 4-女性的AD风险更高，这在绝经过渡期间开始。在小鼠和人类研究中，我们和其他人证明，APOE 4女性AD风险增加可能是由于大脑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，随着时间的推移可能导致认知能力下降。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。在人群观察性研究和动物实验中，DHA摄入量的增加与认知能力的改善和AD风险的降低有关。我们假设DHA和雌激素替代品将共同增加大脑DHA水平，改善认知能力，降低APOE 4高危女性的痴呆发病率。我们将通过分析来自英国BIOBANK的更年期妇女的饮食，激素和认知测试数据集来测试这一点。此外，我们将测试膳食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。在英国BIOBANK分析中，我们将受益于拥有50万英国参与者的大规模数据库（其中260，000人为女性，随访期为12年以上），以观察DHA摄入量和状态的个体和集体影响，激素使用和APOE 4状态对认知功能、AD发病率和脑体积的影响。在小鼠模型中，我们将用DHA喂养表达人类APOE 3和APOE 4基因的小鼠，然后诱导类似人类的绝经期，并在绝经过渡期的早期或晚期给予雌激素。将评估小鼠的认知功能，然后提取脑组织用于评价脑完整性，以及用于基因、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饮食和激素替代策略的风险APOE 4妇女（谁代表约13%的一般人群，但近40%的总AD患者）在一个关键的绝经窗口。这有助于提高老年女性的生活质量，并减少用于痴呆症护理的国家预算的增加。

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.