阿茲海默症藥物治療的現在與未來

阿茲海默症是一種在已開發國家老年人盛行率最高的退化型失智症。根據WHO估計目前全球罹患阿茲海默症人口高達三千多萬人。因其退化性疾病之特徵，所耗費的社會資源成本實不容小覷。即便如此，在FDA通過donezepil上市已超過了15年的今天，及至目前仍無任何一種藥物可有效抑制疾病的病程進展或者預防疾病的發生。不僅如此，因許多病程調節藥物在第三階段臨床實驗的失敗，讓我們對於阿茲海默症可能的單一致病機轉及原理產生了動搖與懷疑。目前FDA 通過的上市藥物包含了四種膽鹼藥物（acetylcholine esterase inhibitors）藥物以及一種N-甲基-D-天門冬胺酸（N-methyl-D-aspartic acid, NMDA）受體拮抗劑。目前的研究發展多認為阿茲海默症是由多重致病因子及機轉所組合串聯，許多臨床前期及臨床試驗藥物正是針對不同的致病因子為假設而蓬勃發展。包含了：γ-secretase抑制劑減少類澱粉（β-amyloid）蛋白的生成、免疫療法幫助類澱粉的清除、抑制tau蛋白過磷酸化（hyper-phosphorylation）及增加微管（microtubule）穩定性的藥物、增加粒腺體穩定性的抗氧化物質，其它甚至像是鼻腔吸入的胰島素。由單一藥物治療阿茲海默症已是不適切的想法。本篇文獻即回顧整理了阿茲海默症治療的現況與未來發展。

Alzheimer's disease (AD) is the most common progressive dementing disease in elder population. According to the World Health Organization, there are estimated 34 millions of people with Alzheimer's disease worldwide. More then a decade after the first approval of donezepil, we still do not have a single treatment that can effectively stop the relentless progression of disease or can help prevent the disease. Several failures in disease-modifying therapies in phase III clinical trials led to debates about our understanding of the pathogenesis of AD. Until now, there are four acetylcholine esterase inhibitors and one NDMA antagonist under the approval of FDA. Many experimental and clinical studies are ongoing, based on targeting the pathogenesis of AD which should be composed of multi-factors and those closely related. These include gamma secretase inhibitors for reducing beta amyloid formation, immunotherapies for enhancing clearance of the amyloid plaques, therapies targeting hyperphosphorylated tau protein, microtubules stabilizing drugs, antioxidant agents, and others such like insulin are also tackled with. A single cure for Alzheimer's disease is unlikely to be found. Thus, the need to better understand the pathogenesis of AD is warranted. This article presents current practice and future developments of treatment for AD.