Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β 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-target-directed treatments often fall short in addressing the complex, multifactorial nature of AD. This arises from various pathological features, including amyloid-β (Aβ) 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 Aβ, metal ions, and AD-related enzymes, such as β-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 Aβ aggregation and address other pathogenic mechanisms. These approaches offer a more comprehensive and effective method for combating AD, overcoming the limitations of conventional therapies.