Pathological mechanisms and treatment progression of Alzheimer's disease

Abstract

Alzheimer's disease (AD) represents the most prevalent neurodegenerative disorder and leading cause of dementia worldwide, with its incidence rising dramatically in aging populations. This progressive disease is neuropathologically characterized by extracellular amyloid-β (Aβ) plaques, intracellular neurofibrillary tau tangles, and chronic neuroinflammation, leading to synaptic dysfunction and neuronal loss. Despite extensive research efforts, the complex and multifactorial nature of AD pathogenesis has prevented the development of truly disease-modifying therapies. Current therapeutic approaches, including recently approved anti-amyloid immunotherapies, demonstrate limited clinical efficacy and significant adverse effects, highlighting the need for alternative treatment strategies. This comprehensive review systematically evaluates recent advances in understanding AD pathophysiology, emphasizing the interplay between genetic risk factors (particularly APOE ε4), proteostasis imbalance, metabolic dysfunction, and neurovascular contributions. We critically analyze emerging diagnostic biomarkers, including novel neuroimaging techniques and cerebrospinal fluid/blood-based biomarkers, that enable earlier and more accurate detection. The review provides an in-depth assessment of both pharmacological interventions (such as tau-targeting therapies, anti-inflammatory agents, and neurotransmitter modulators) and non-pharmacological approaches (including lifestyle modifications and cognitive training). Special attention is given to personalized medicine strategies that account for disease heterogeneity and individual risk profiles. By synthesizing evidence from molecular studies, animal models, and clinical trials, we identify key challenges in therapeutic translation and propose future research directions. Our analysis underscores the importance of multimodal interventions targeting multiple pathological processes simultaneously, combined with early detection methods, to effectively combat this devastating disease. This review aims to provide researchers and clinicians with an updated framework for understanding AD pathogenesis and developing more effective treatment paradigms.

Keywords: Alzheimer’s disease; Pathomechanism; Treatment progression.