Neurodegeneration in Alzheimer’s disease: A narrative review of mechanistic insights and emerging therapeutic approaches

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder responsible for 50–75% of dementia cases worldwide, primarily affecting individuals over 65 years of age. It is characterized by cognitive decline, memory loss, and behavioral abnormalities. Key pathological features include extracellular β-amyloid (Aβ) plaques, intracellular neurofibrillary tangles of hyperphosphorylated tau protein, mitochondrial dysfunction, and cholinergic system impairment. Despite extensive research, the precise etiology remains unclear, and current treatments only alleviate symptoms without halting disease progression. A comprehensive literature review was conducted using peer-reviewed articles from PubMed, Scopus, and Google Scholar, emphasizing recent studies on molecular mechanisms, risk factors, diagnostics, and therapies. Major pathogenic mechanisms identified include oxidative stress, tau hyperphosphorylation, Aβ aggregation, and synaptic degeneration. Non-modifiable risk factors such as aging, genetic mutations in amyloid precursor protein, phosphatidylinositol-binding clathrinid assembly protein, presenilin 1/2, and the apolipoprotein E ε4 allele play significant roles, whereas modifiable risks involve lifestyle factors and comorbidities such as diabetes. Diagnostic advancements highlight the promise of blood-based biomarkers, although current practices rely heavily on cerebrospinal fluid markers and neuroimaging. Approved pharmacological interventions, including cholinesterase inhibitors and N-methyl-D-aspartate receptor antagonists, provide limited symptomatic relief. Ongoing research into Aβ- and tau-targeted therapies has yielded mixed results. In addition, novel approaches such as tripartite motif-containing protein 2-mediated tau clearance and deep cervical lymphatic-venous anastomosis are being explored for their potential in targeting intracellular aggregates and enhancing brain waste clearance. AD emerges as a multifactorial condition driven by a complex interplay of biological, genetic, and environmental factors. Although substantial progress has been made in understanding its pathophysiology, effective disease-modifying therapies remain elusive. Continued advances in biomarker discovery and personalized therapeutic strategies offer hope for improved early detection and targeted treatment approaches.