BACKGROUND: Alzheimer's disease (AD) is the most common cause of dementia worldwide, affecting over 55 million individuals and projected to rise drastically in the coming decades. Characterized by progressive cognitive decline and memory impairment, AD involves complex pathological mechanisms including amyloid-beta (Aβ) plaque accumulation, neurofibrillary tangles (NFTs) of hyperphosphorylated tau, and chronic neuroinflammation.
OBJECTIVE: This comprehensive review aims to provide a foundational understanding of the molecular, genetic, and immunological underpinnings of AD, with a focus on pathogenic proteins, glial cell responses, and current monoclonal antibody (mAb)-based therapeutic strategies.
METHODS: Literature on key pathological players such as Aβ, tau, microglia, and astrocytes was mentioned to explain their roles in neurodegeneration. The impact of key genetic mutations (APP, PSEN1, PSEN2, APOE, BACE1, MAPT) was outlined. Additionally, recent clinical trial data of anti-Aβ monoclonal antibodies (aducanumab, lecanemab, donanemab) were reviewed, with comparative analysis of efficacy, safety, and trial outcomes.
RESULTS: Neuroinflammation, mediated by activated microglia and astrocytes, exacerbates Aβ and tau pathology, contributing to synaptic loss and neuronal death. Genetic mutations alter APP processing and promote plaque formation. Monoclonal antibodies show promise in reducing Aβ burden and slowing cognitive decline: donanemab achieved 60% slower decline in mild cognitive impairment, while lecanemab showed 27% cognitive benefit in early AD. Aducanumab, despite initial promise, was discontinued in 2024 due to limited efficacy and safety concerns. Adverse events like amyloid-related imaging abnormalities (ARIA), particularly in APOE-4 carriers, remain significant.
CONCLUSION: AD pathology is multifactorial, involving an interplay between protein aggregation, immune dysregulation, and genetic risk. While mAb therapies mark progress in disease modification, their success depends on patient stratification, early intervention, and safety profiling. Future directions must emphasize combinatorial and personalized approaches incorporating early biomarkers, neuroimaging, and emerging technologies to effectively combat the rising global burden of AD.
