Lecanemab

To assess the long-term effects of lecanemab plus standard of care (SoC) compared with SoC alone in a cohort of patients with early Alzheimer's disease (AD; mild cognitive impairment [MCI] due to AD, or mild AD dementia) using different modeling approaches and data from Clarity AD (NCT0388745538).

A Markov model was employed using health states based on disease severity, long-term institutionalization, and death, with disease severity defined using the Clinical Dementia Rating - Sum of Boxes (CDR-SB) classification for MCI due to AD, and Mild, Moderate, and Severe AD. State transitions during the first 18 months of treatment were estimated using either patient count data (Approach 1) or multistate survival analysis (Approach 2). Transition probabilities beyond 18 months for the lifetime of the cohort were informed by longitudinal natural history data for the SoC arm with a hazard ratio for time-to-worsening health state applied to estimate outcomes in the lecanemab arm.

Over a lifetime horizon, the model predicted a delayed time to Mild, Moderate, and Severe AD for patients treated with lecanemab compared to SoC by 1.31, 1.85, and 2.04 years, respectively when using Approach 1. Patients treated with lecanemab experienced a survival benefit of 1.36 years, comprised of an additional 1.85 years in early AD and 0.49 years less in moderate and severe AD, compared to patients treated with SoC alone. The model also predicted that compared to SoC, lecanemab increased the time in community care and reduced time spent in institutional care. Results were similar when using Approach 2.

Long-term disease progression was informed by constant annual transition probabilities derived from the published literature.

Patients treated with lecanemab experience delayed progression to Moderate and Severe AD, resulting in additional life-years (LYs) and reduced time in institutional care.

Alzheimer's disease (AD) is a multifactorial and progressive neurodegenerative disorder characterized by complex interactions among amyloid-β (Aβ) deposition, tau protein hyperphosphorylation, neuroinflammation, oxidative stress, metal dyshomeostasis, and impaired autophagy. Increasing evidence positions neuroinflammation not merely as a secondary response but as a central driver of disease progression, dynamically interacting with amyloid and tau protein pathology and contributing to synaptic dysfunction and neuronal loss. Among inflammatory mechanisms, microglial activation pathways-particularly TREM2 signaling, NLRP3 inflammasome activation, and complement cascade dysregulation-are currently the most clinically actionable targets, supported by genetic, biomarker, and therapeutic evidence. Emerging data suggest that modulation of innate immune pathways is most likely to confer benefit during the prodromal and early symptomatic stages of AD, when neuroinflammatory responses remain partially adaptive and neuronal networks retain functional reserve. Despite decades of drug development, many candidates have failed due to limited efficacy or safety concerns. Recent FDA approvals of anti-amyloid monoclonal antibodies, including aducanumab and lecanemab, represent important advances toward disease-modifying therapy, although their long-term clinical impact and safety profiles remain under evaluation. These developments underscore the importance of biomarker-guided patient selection, disease-stage stratification, and vigilant safety monitoring, particularly regarding amyloid-related imaging abnormalities. Therapeutic strategies are increasingly shifting toward multi-target approaches that integrate amyloid modulation, tau protein-directed interventions, and attenuation of maladaptive neuroinflammatory responses. Concurrently, inflammatory mediators and peripheral metabolic biomarkers are gaining recognition as tools for early detection, risk stratification, and therapeutic response monitoring, potentially enabling precision-based intervention. This review synthesizes current understanding of AD pathogenesis through an inflammation-centered framework, highlighting clinically actionable immune pathways and stage-specific therapeutic windows. By integrating mechanistic insights with biomarker-driven strategies, we aim to delineate translational paths toward more precise, safe, and clinically meaningful disease modification.