UCL School of Pharmacy, University College London, 29-39 Brunswick Square, London WC1N 1AX, UK.
Int J Mol Sci. 2024 May 9;25(10):5169. doi: 10.3390/ijms25105169.
Dementia exists as a 'progressive clinical syndrome of deteriorating mental function significant enough to interfere with activities of daily living', with the most prevalent type of dementia being Alzheimer's disease (AD), accounting for about 80% of diagnosed cases. AD is associated with an increased risk of comorbidity with other clinical conditions such as hypertension, diabetes, and neuropsychiatric symptoms (NPS) including, agitation, anxiety, and depression as well as increased mortality in late life. For example, up to 70% of patients diagnosed with AD are affected by anxiety. As aging is the major risk factor for AD, this represents a huge global burden in ageing populations. Over the last 10 years, significant efforts have been made to recognize the complexity of AD and understand the aetiology and pathophysiology of the disease as well as biomarkers for early detection. Yet, earlier treatment options, including acetylcholinesterase inhibitors and glutamate receptor regulators, have been limited as they work by targeting the symptoms, with only the more recent FDA-approved drugs being designed to target amyloid-β protein with the aim of slowing down the progression of the disease. However, these drugs may only help temporarily, cannot stop or reverse the disease, and do not act by reducing NPS associated with AD. The first-line treatment options for the management of NPS are selective serotonin reuptake inhibitors/selective noradrenaline reuptake inhibitors (SSRIs/SNRIs) targeting the monoaminergic system; however, they are not rational drug choices for the management of anxiety disorders since the GABAergic system has a prominent role in their development. Considering the overall treatment failures and side effects of currently available medication, there is an unmet clinical need for rationally designed therapies for anxiety disorders associated with AD. In this review, we summarize the current status of the therapy of AD and aim to highlight novel angles for future drug therapy in our ongoing efforts to alleviate the cognitive deficits and NPS associated with this devastating disease.
痴呆是一种“进行性临床综合征，精神功能逐渐恶化，严重到足以干扰日常生活活动”，最常见的痴呆类型是阿尔茨海默病（AD），约占确诊病例的 80%。AD 与其他临床疾病（如高血压、糖尿病和神经精神症状（NPS））的合并症风险增加有关，包括激越、焦虑和抑郁，以及晚年死亡率增加。例如，多达 70%的 AD 患者受到焦虑的影响。由于衰老是 AD 的主要危险因素，这代表着老龄化人口中巨大的全球负担。在过去的 10 年中，人们做出了巨大努力来认识 AD 的复杂性，了解疾病的病因和病理生理学以及早期检测的生物标志物。然而，早期的治疗选择，包括乙酰胆碱酯酶抑制剂和谷氨酸受体调节剂，都受到限制，因为它们通过靶向症状起作用，只有最近获得 FDA 批准的药物旨在针对淀粉样蛋白-β 蛋白，目的是减缓疾病的进展。然而，这些药物可能只是暂时有效，不能阻止或逆转疾病，也不能通过减少与 AD 相关的 NPS 起作用。管理 NPS 的一线治疗选择是针对单胺能系统的选择性 5-羟色胺再摄取抑制剂/选择性去甲肾上腺素再摄取抑制剂（SSRIs/SNRIs）；然而，由于 GABA 能系统在其发展中具有突出作用，它们不是管理焦虑障碍的合理药物选择。考虑到目前可用药物的整体治疗失败和副作用，针对与 AD 相关的焦虑障碍进行合理设计的治疗方法存在未满足的临床需求。在这篇综述中，我们总结了 AD 治疗的现状，并旨在强调未来药物治疗的新角度，以努力减轻这种毁灭性疾病相关的认知缺陷和 NPS。
