Multi-target-directed therapeutic strategies for Alzheimer's disease: Controlling amyloidb aggregation, metal ion homeostasis, and enzyme inhibition

Alzheimer's disease (AD) is the most prevalent neurodegenerative dementia, marked by progressive cognitive decline and memory impairment. Despite advances in therapeutic research, single-targetdirected treatments often fall short in addressing the complex, multifactorial nature of AD. This arises from various pathological features, including amyloid-b (Ab) aggregate deposition, metal ion dysregulation, oxidative stress, impaired neurotransmission, neuroinflammation, mitochondrial dysfunction, and neuronal cell death. This review illustrates their interrelationships, with a particular emphasis on the interplay among Ab, metal ions, and AD-related enzymes, such as b-site amyloid precursor protein cleaving enzyme 1 (BACE1), matrix metalloproteinase 9 (MMP9), lysyl oxidase-like 2 (LOXL2), acetylcholinesterase (AChE), and monoamine oxidase B (MAOB). We further underscore the potential of therapeutic strategies that simultaneously inhibit Ab aggregation and address other pathogenic mechanisms. These approaches offer a more comprehensive and effective method for combating AD, overcoming the limitations of conventional therapies.