From the first described AD case in 1901 to the current year 2022, understanding the pathogenesis of Alzheimer’s disease (AD) and dementia has undergone a long and tortuous journey. Many mechanisms of AD etiology have been proposed and studied. However, current medications and FDA-approved treatments cannot cure AD and AD-related dementias (AD/ADRD). Recently, brain hypoperfusion associated with neurovascular dysfunction was recognized as one of the causal factors in the development of AD dementia. Arteriosclerotic changes were observed in the first AD case. A recent study reported that the functional hyperemic response to whisker stimulation was reduced in 9–12 months old atherosclerotic mice. Interestingly, they found that evoked hemodynamic responses were not altered in age-matched AD mice or AD mice with superimposed atherosclerosis using 2D-optical imaging spectroscopy in chronic studies. However, functional hyperemia was impaired in AD mice using the same approach in an acute study. It is essential to scrutinize the available data critically since different genetic backgrounds, ages, sexes of studied animal models, and different approaches used for the same function even structural examination may provide opposite information. We certainly are closer to truly understanding the pathogenesis of dementia. We expect positive results from using aducanumab (Aduhelm®) as the first FDA-approved anti-amyloid monoclonal antibody as a treatment for AD/ADRD. We hope to identify and develop new drugs targeting other potential contributing mechanisms such as the cerebral vascular pathways.

从1901年首次描述AD病例到如今的2022年，了解阿尔茨海默病（AD）和痴呆症的发病机制经历了漫长而曲折的旅程。 AD病因学的许多机制已经被提出和研究。然而，目前的药物和 FDA 批准的治疗方法无法治愈 AD 和 AD 相关痴呆症 (AD/ADRD)。最近，与神经血管功能障碍相关的脑灌注不足被认为是 AD 痴呆发生的原因之一。在第一例 AD 病例中观察到动脉硬化变化。最近的一项研究报告称，9-12 个月大的动脉粥样硬化小鼠对胡须刺激的功能性充血反应有所降低。有趣的是，他们在慢性研究中使用二维光学成像光谱发现，在年龄匹配的 AD 小鼠或叠加动脉粥样硬化的 AD 小鼠中，诱发的血流动力学反应没有改变。然而，在一项急性研究中，使用相同方法的 AD 小鼠的功能性充血受到损害。必须严格审查现有数据，因为所研究动物模型的遗传背景、年龄、性别不同，以及用于同一功能的不同方法，甚至结构检查也可能提供相反的信息。我们无疑更接近真正了解痴呆症的发病机制。我们预计使用 aducanumab (Aduhelm®) 作为 FDA 批准的第一个抗淀粉样蛋白单克隆抗体治疗 AD/ADRD 会产生积极结果。我们希望识别和开发针对其他潜在贡献机制（例如脑血管通路）的新药。