Last Updated on 2026 年 3 月 16 日 by 総合編集組
Global Alzheimer’s Disease Treatment Paradigm Shift: From Symptom Management to Disease Modification – Key Highlights and Pipeline Overview
In 2025, the field of Alzheimer’s disease (AD) and broader dementia treatment has reached a pivotal turning point. With the global population aging rapidly, AD remains one of the most pressing biomedical challenges. This year marks a clear transition from purely symptomatic relief to true disease-modifying therapies (DMTs) that target underlying pathologies such as amyloid-beta (Aβ) plaques, tau neurofibrillary tangles, neuroinflammation, and synaptic loss.
Core Pathological Mechanisms and Evolving Targets Modern understanding centers on the amyloid cascade hypothesis, where abnormal accumulation of Aβ – in forms ranging from monomers and oligomers to protofibrils and mature plaques – initiates the disease process. Recent clinical evidence strongly supports clearing protofibrils and plaques to meaningfully slow cognitive decline. Meanwhile, tau pathology shows even stronger correlation with clinical symptom severity due to its prion-like seeding and spread between neurons. Research in 2025 increasingly focuses on blocking tau propagation using monoclonal antibodies, antisense oligonucleotides (ASOs), and vaccines.
Approved Disease-Modifying Therapies Leading the Way Two anti-amyloid monoclonal antibodies dominate the current landscape:
- Lecanemab (Leqembi): A humanized IgG1 antibody targeting Aβ protofibrils. The pivotal Phase 3 Clarity AD trial demonstrated a 27% reduction in cognitive decline on the CDR-SB scale over 18 months compared to placebo. FDA granted full approval in 2023, and Taiwan’s TFDA approved it on March 28, 2025, for mild cognitive impairment (MCI) and mild AD. A major advancement came in August 2025 with FDA approval of a subcutaneous maintenance formulation, enabling home or outpatient administration after initial intravenous infusions, significantly easing healthcare burden. Long-term modeling suggests continued treatment could delay progression to severe dementia by several years, introducing the valuable “time saved” metric.
- Donanemab (Kisunla): Targets fibrillar Aβ plaques with phosphorylated modifications. The TRAILBLAZER-ALZ 2 Phase 3 trial showed up to 35% slowing of decline in early patients with low-to-medium tau burden. Its unique “treat-to-clear” approach allows discontinuation once amyloid PET confirms plaque removal to near-negative levels, offering economic and convenience advantages. Updated labeling in 2025 introduced gentler titration to reduce amyloid-related imaging abnormalities (ARIA), particularly ARIA-E (edema).
Management of Neuropsychiatric Symptoms (NPS) Beyond core cognition, agitation, hallucinations, and sleep disturbances drive much of the caregiver burden and institutionalization. Brexpiprazole (Rexulti) became the first FDA-approved agent specifically for AD-related agitation, showing good tolerability and improvements in aggression and irritability while requiring careful monitoring for mortality risk in elderly patients using antipsychotics. Dual orexin receptor antagonists (DORAs) like suvorexant improve sleep quality without exacerbating daytime cognitive fog and may indirectly support glymphatic clearance of brain waste.
Traditional Symptomatic Agents Remain Foundational Cholinesterase inhibitors (ChEIs) and memantine continue as first-line options:
- Donepezil: Now widely available as a weekly transdermal patch to minimize gastrointestinal side effects.
- Galantamine: Enhanced formulations like Zunveyl improve bioavailability.
- Memantine: Often combined with ChEIs for moderate-to-severe stages.
- Rivastigmine: Expanded use in Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB).
Robust 2025 Clinical Trial Pipeline According to Jeffrey L. Cummings’ annual report, the AD pipeline features 182 active clinical trials evaluating 138 novel agents – a record level of diversity and activity.
Phase 3 highlights include:
- HMTM (Hydromethylthionine mesylate): An oral tau aggregation inhibitor from TauRx, advancing toward potential approval in regions like the UK and EU.
- Semaglutide (GLP-1 agonist): EVOKE and EVOKE+ trials missed primary cognitive endpoints but showed benefits on neuroinflammation markers, sparking interest in metabolic-neurodegenerative links and preventive/combination strategies.
- Remternetug: Eli Lilly’s next-generation anti-amyloid antibody designed for subcutaneous delivery with higher affinity.
- Mirodenafil: A PDE5 inhibitor in the POLARIS-AD trial, exploring non-protein targets via enhanced cerebral blood flow and neuroregeneration.
Phase 2 candidates span multiple mechanisms:
- Blarcamesine (ANAVEX 2-73): Sigma-1 receptor agonist with promising long-term cognitive protection in specific genotypes and no ARIA risk.
- Trontinumab: Roche’s BrainShuttle technology enabling efficient plaque clearance at low doses with ARIA rates below 5%.
- ALZ-801: Oral small molecule preventing Aβ oligomer formation, particularly effective in APOE ε4/ε4 homozygotes.
Gene therapy breakthroughs include:
- LX1001: AAV-mediated delivery of protective APOE2 to APOE ε4 homozygotes, with Phase 1/2 data showing successful CSF expression and tau biomarker reduction.
- BIIB080: Tau-targeted ASO from Biogen/Ionis to reduce tau production upstream.
Diagnostic Revolution: Blood-Based Biomarkers and AI Integration Early precise diagnosis is crucial for DMT success. In 2025, plasma p-tau217 has emerged as the gold standard blood biomarker, correlating strongly with brain amyloid and achieving diagnostic accuracy over 90%. The Alzheimer’s Association released its first clinical practice guideline for blood-based biomarkers (BBMs), recommending their use to initiate anti-amyloid therapy in patients with objective cognitive impairment. Large cohort studies indicate p-tau217 abnormalities can appear 20–25 years before symptoms, opening doors to true preclinical intervention. Complementary markers like NfL (neuronal damage) and GFAP (astrocytic activation) enable multi-omic models. Artificial intelligence now integrates digital biomarkers – voice patterns, gait analysis, wearable sleep/activity data – for low-cost, longitudinal risk detection in preclinical stages.
Non-Pharmacological and Neuromodulation Approaches Comprehensive care in 2025 emphasizes synergy between drugs and non-drugs:
- Repetitive transcranial magnetic stimulation (rTMS): High-frequency targeting of dorsolateral prefrontal cortex improves executive function, enhanced by closed-loop EEG synchronization.
- Transcranial direct current stimulation (tDCS): Affordable, safe home-use trials show enhanced neuroplasticity with daily 30-minute sessions.
- Digital therapeutics (DTx): Taiwan-approved platforms like CogMate deliver structured cognitive training to delay regional atrophy.
- 40Hz sensory stimulation: Gamma entrainment to activate microglial clearance, advancing in Phase 3.
Differential Diagnosis and Management Across Dementia Types While AD accounts for 60–70%, other forms progress:
- Vascular dementia: Focus on vascular risk control (hypertension, diabetes, lipids) and antiplatelet therapy; rTMS explored for cerebral perfusion.
- Dementia with Lewy bodies (DLB) and PDD: Extreme sensitivity to antipsychotics; rivastigmine mainstay, with p38 MAPK inhibitor neflamapimod in Phase 3.
- Frontotemporal dementia (FTD): SSRIs for behavioral symptoms; GRN-targeted gene therapy (DNL593) in early trials.
Taiwan-Specific Landscape and Challenges Taiwan entered its “precision era” in 2025 with TFDA approvals including Lecanemab (March 28), Donanemab (H1), Brexpiprazole, Donepezil patch, and CogMate. Estimated annual self-pay for Lecanemab is around NT$700,000. National health insurance faces pressure but implements strict prior authorization requiring APOE ε4 genotyping and amyloid confirmation (PET/CSF). Efforts include expanding p-tau217 blood testing to rural areas and regional ARIA referral networks for MRI monitoring.
Future Directions and Societal Impact The next 5–10 years may see combination regimens akin to hypertension management: initial amyloid clearance, followed by tau suppression and anti-inflammatory agents. Preclinical treatment ethics arise as blood tests enable 20-year; ongoing trials like AHEAD 3-45 address asymptomatic high-risk intervention. Economically, delaying severe dementia by even one year could save billions in care costs, making digital monitoring, subcutaneous formulations, and early screening national priorities.
In summary, 2025 represents the dawn of hope in dementia care. With Lecanemab and Donanemab as anchors, revolutionary blood diagnostics, a diverse pipeline, and multimodal approaches, the field is shifting toward manageable chronic disease status – provided early detection, personalized plans, and lifestyle interventions (MIND diet, exercise) remain central.
