Unveiling Alzheimer's disease (1901-2025): Historical insights, global burden, biological mechanisms, diagnostics, and therapeutic strategies.

Alzheimer's disease (AD), first identified by Dr. Alois Alzheimer in 1906, has evolved from a rare presenile dementia to a global health crisis affecting over 58 million people as of 2020, with projections reaching 152 million by 2050. Manuscript offers a comprehensive overview of AD, tracing its historical origins, epidemiological trends, pathophysiological mechanisms, diagnostic advancements, and therapeutic strategies. The pathogenesis of AD is multifactorial, involving amyloid-β plaque accumulation, tau protein hyperphosphorylation, cholinergic deficits, oxidative stress, and metal ion dyshomeostasis. These mechanisms converge to cause progressive neurodegeneration, cognitive decline, and behavioral disturbances. Clinically, AD manifests through a spectrum of neuropsychiatric symptoms, progressing from mild cognitive impairment to severe dementia, with distinct phenotypes and overlapping features with other dementias like DLB and VaD. Diagnostic approaches have advanced from clinical observation to biomarker-based precision, incorporating CSF and plasma tau assays, neuroimaging modalities (MRI, PET, SPECT), and AI-driven models for early detection. Despite these innovations, definitive diagnosis remains challenging due to symptom heterogeneity and overlap with other conditions. Therapeutically, the landscape has shifted from symptomatic treatments (e.g., cholinesterase inhibitors, memantine) to disease-modifying agents. Recent FDA approvals of monoclonal antibodies like Aducanumab, Lecanemab, and Donanemab mark a new era in targeted immunotherapy. However, many candidates targeting amyloid and tau pathways have failed in trials, underscoring the complexity of AD. Emerging drug delivery systems, including nanocarriers and intranasal formulations, aim to overcome the BBB and enhance therapeutic efficacy. The manuscript emphasizes the urgent need for integrative, personalized, and scalable solutions to manage AD's growing burden.