Neuroinflammation and progress in clinical trials for the treatment of Alzheimer’s disease and related dementias: An update

According to the latest report in 2024 by the World Health Organization, based on global data from 2021, Alzheimer’s disease (AD) and other forms of dementia rank seventh among the leading causes of death worldwide, with an estimated 1.8 million deaths. This alarming number underscores the urgent requirement for effective treatments. AD and other dementias also severely affect the global economy. Unfortunately, no cure has been found, and effective treatments remain limited. Over the past two decades, thousands of disease-modifying drugs have been developed for AD treatment. However, most have failed to progress beyond phase I clinical trials, with only a few reaching phase III. To date, lecanemab (sold under the brand name Leqembi) is the only drug to receive full approval from the United States Food and Drug Administration for slowing AD progression. This drug is specifically designed to target and clear amyloid-beta (Aβ) plaques. Apart from targeting Aβ aggregation and tau tangles, neuroinflammatory regulatory pathways have emerged as promising therapeutic targets. With advancing research, neuroinflammation has been considered one of the core characteristics of AD and the third major pathological hallmark of the disease after Aβ plaques and neurofibrillary tau tangles. In this review, we summarize key research findings in neuroinflammatory regulation of AD and related dementias that are promising for treatments. We also provide an overview of clinical trials targeting the immune system or neuroinflammatory regulatory pathways, analyzing their challenges and potential successes.