Review shows lecanemab and donanemab slow decline and explains who should get them

By Priyanjana Pramanik, MSc.Reviewed by Susha Cheriyedath, M.Sc.Sep 24 2025

A Lancet review finds modest yet meaningful slowing with lecanemab and donanemab, highlighting plasma p-tau217 as a scalable triage marker. While ARIA risk, eligibility limits, and payer decisions will determine the real-world impact, these findings are promising.

Alzheimer's Disease Outlook: Controversies and Future Directions. Image Credit: Burdun Iliya / Shutterstock

In a recent review in The Lancet, researchers examined the results of recent clinical trials of anti-β-amyloid monoclonal antibodies for Alzheimer’s disease, comparing differing expert opinions on their place in personalized medicine, costs, risks, and overall clinical value through three complementary perspectives: disease-centered, patient-centered, and population-centered.

They concluded that these drugs show unprecedented reductions in β-amyloid, with about 27 percent (lecanemab) and 36 percent (donanemab) less decline on CDR-SB over 18 months, accompanied by slower declines in function and cognition. Both the treated and placebo groups declined over 18 months, with less decline in the treatment group. However, concerns remain about the risks, including symptomatic amyloid-related imaging abnormalities (ARIA) in ~3–6 percent, and treatment-related deaths reported in trials. Warnings highlight potential interactions with anticoagulants and thrombolytics.

Burden of Alzheimer’s Disease

Alzheimer’s disease differs from cancers, multiple sclerosis (MS), and rheumatoid arthritis (RA) in many respects. Unlike cancers, MS, and RA, Alzheimer’s typically emerges after age 65, when patients frequently have comorbidities, frailty, and mixed brain pathologies.

While monoclonal antibodies for Alzheimer’s modestly slow decline in cognition and function, other conditions, such as cancers, MS, and RA, show more direct and measurable outcomes, such as improved survival in cancers, reduced relapses (periods when symptoms worsen) in MS, and better physical function in RA.

Adverse effects also differ between therapies, with amyloid treatments linked to amyloid-related imaging abnormalities (ARIA), brain scan changes such as swelling or bleeding, whereas other biologics may provoke severe infections, heart failure, or rare immune complications.

The societal and economic impact of Alzheimer’s is disproportionately large. Although each patient loses fewer life-years than with cancer or MS, the sheer prevalence of dementia makes it the leading cause of years lived with disability. One of the costliest global health conditions, with total annual costs ≈ estimated at approximately €442 billion in GBD 2021, and in high-income countries, about 90 percent of costs arise from informal care and non-medical support. Only 8–15 percent of people with early Alzheimer’s meet treatment eligibility under trial-like criteria, and if US-like pricing were adopted in Europe, annual system costs could exceed €133 billion.

Early Alzheimer’s Drug Developments

The history of Alzheimer’s research reflects a slow trajectory from its recognition in the early 20th century to more recent therapeutic trials. After Alzheimer’s disease was classified as a major condition in 1976, the first drug, tacrine, was introduced in 1993 but withdrawn due to toxicity.

Later, memantine and cholinesterase inhibitors became widely used, though their benefits were modest, offering only temporary slowing of decline. By the 2010s, enthusiasm for drug-based management had waned, and debates about the cost-effectiveness of therapies and the high cost of biomarkers intensified.

Biologic therapies have transformed treatment in conditions such as MS, cancer, and RA. Recently, the monoclonal antibodies lecanemab and donanemab showed clear evidence of slowing cognitive and functional decline in Alzheimer’s disease, marking a milestone in a field where progress has long been limited.

Yet, their arrival sparked contrasting reactions, ranging from optimism about a breakthrough to concerns about safety, costs, and the modest benefits compared to the risks.

The Role of Monoclonal Antibodies

Monoclonal antibodies represent the first class of drugs to demonstrate clear and replicable effects on slowing cognitive and functional decline in Alzheimer’s disease. They act by targeting and removing β-amyloid plaques (abnormal protein deposits in the brain), one of the hallmark brain pathologies of the disease.

Early controversy surrounded aducanumab, which received accelerated approval from the US regulatory agency in 2021, primarily based on amyloid clearance despite mixed trial outcomes. More recent agents, lecanemab and donanemab, have shown more consistent results, with patients on treatment experiencing a slower rate of decline compared to those on placebo over 18 months.

Importantly, evidence suggests a direct link between the degree of amyloid removal and the extent of clinical benefit. However, these drugs also carry risks, with around 3–6% of patients developing brain swelling or bleeding. In comparative trial tables, serious ARIA-E occurred in approximately 0.3 percent with lecanemab and 1.5 percent with donanemab, a narrower subset of overall symptomatic ARIA.

Concerningly, some treatment-related deaths have been reported, especially in combination with anticoagulants or thrombolytic therapies. The long-term effects of asymptomatic brain changes in treated patients remain uncertain.

Alongside monoclonal antibodies, blood-based biomarkers such as Aβ42/40 ratios and phosphorylated tau (p-tau217) are transforming diagnosis by offering scalable, less invasive alternatives to positron emission tomography (PET) scans and cerebrospinal fluid (CSF) testing, with plasma p-tau217 showing >90 percent accuracy for detecting amyloid pathology, dual-threshold strategies can cut CSF and PET testing by 80–85 percent. However, thresholds should be adjusted in primary care where PPV is lower.

Future of Alzheimer’s Treatments

The future of Alzheimer’s care is shifting toward earlier, more accurate diagnosis, broader therapeutic targets, and prevention strategies. Blood-based biomarkers such as plasma p-tau217 and neurofilament light show high accuracy in detecting amyloid and tau pathology, offering scalable alternatives to PET and CSF tests.

Combined with digital biomarkers, such as speech analysis, wearable sensors, and cognitive tests, these tools may enable earlier detection and continuous monitoring, though ethical and privacy concerns remain.

On the treatment front, research is expanding beyond amyloid to target inflammation, vascular health, synaptic function, and other pathways. Over 182 randomised trials are underway, with only ~33 percent targeting amyloid or tau, while many explore inflammation, vascular, synaptic, and metabolic pathways.

Secondary prevention programs are testing risk assessment, lifestyle modification, and cognitive training in people without impairment but at high risk. Meanwhile, primary prevention trials aim to stop Alzheimer’s before pathology begins, using monoclonal antibodies, metabolic drugs such as metformin, and genetic therapies.

Beyond pharmacology, population-level strategies, such as reducing vascular risk factors, improving diet, promoting physical activity, and addressing social determinants, offer cost-effective means to reduce dementia burden.

Health-system capacity and payer models will shape implementation, and cost-effectiveness depends on lower drug and delivery prices, as well as which budget bears the costs.

The Series also maps three complementary perspectives: disease, patient, and population-centred, to balance individual benefits with equity, feasibility, and population health impact.

Conclusions

Alzheimer’s research and clinical practice are becoming increasingly aligned, with biomarkers, treatments, and prevention strategies being more integrated into care.

However, challenges remain around defining the disease, designing trials, and addressing skepticism toward therapies.

Continued debate, alongside advances in biomarkers and preventive approaches, is expected to strengthen efforts to improve cognitive health and quality of life.