Anti-Amyloid Finally Worked. What Comes Next?
How Leqembi and Kisunla are reshaping the scientific and investment landscape in Alzheimer’s disease
Published by RichStorm.co
Key Takeaways
Leqembi and Kisunla changed the amyloid debate. Both substantially reduced brain amyloid and significantly slowed cognitive and functional decline in Phase III trials, showing that amyloid can be a therapeutically actionable target in early Alzheimer’s disease.
Their success also exposed the limits of current anti-amyloid therapy. Patients continued to decline despite substantial plaque removal, while amyloid-related imaging abnormalities (ARIA) created additional safety and monitoring requirements.
The next opportunity may be broader than a better antibody. Earlier diagnosis, safer amyloid removal, improved brain delivery, simpler administration, and treatments targeting disease beyond amyloid could all shape what comes next.
1. After decades of failure, amyloid finally worked
For decades, Alzheimer’s drug development has been shaped by the amyloid hypothesis: the idea that amyloid-beta accumulation is an early driver of a disease process that ultimately contributes to tau pathology, neuronal damage, and cognitive decline. If amyloid helps initiate the disease, removing it could potentially slow progression.
For years, trials failed to demonstrate that clearly. Bapineuzumab, one of the first anti-amyloid antibodies to reach Phase III trials, failed to slow cognitive or functional decline. Aducanumab, approved by the FDA in 2021 and discontinued in 2024, substantially reduced amyloid but produced conflicting Phase III results. Gantenerumab treated patients with early, amyloid-confirmed disease and substantially reduced amyloid burden, yet still failed its two primary clinical endpoints. Then came lecanemab (Leqembi) and donanemab (Kisunla). Both substantially reduced amyloid and significantly slowed cognitive and functional decline in large Phase III trials of early symptomatic Alzheimer’s disease. [1,2]
There was no single breakthrough that explains why these drugs succeeded where others failed. Earlier treatment and biomarker confirmation appear important, but previous trials had incorporated both and failed. The degree of plaque removal may matter, but amyloid reduction alone has not consistently translated into clinical benefit.
What Leqembi and Kisunla established is narrower but important: under the right conditions, removing amyloid can slow Alzheimer’s progression.
The harder question is why it does not slow it down more.
2. Amyloid removal works… But only so far
The success of Leqembi and Kisunla came with an important limitation: both drugs substantially reduced amyloid, but neither stopped patients from declining.
In CLARITY-AD, Leqembi reduced brain amyloid by 59.1 centiloids relative to placebo and slowed cognitive and functional decline by 27% over 18 months. Kisunla produced an approximately 87-centiloid reduction in TRAILBLAZER-ALZ 2 and slowed decline by 22% in the broader trial population. [1,2] These percentages come from different trials and outcome measures, so they should not be compared directly.
The gap between amyloid removal and clinical benefit raises a bigger question about what continues to drive disease by the time symptoms appear. Patients can already have tau pathology, neuroinflammation, synaptic dysfunction, and neuronal loss alongside amyloid. In the Kisunla trial, patients with lower levels of tau pathology experienced greater slowing of decline, raising the possibility that the stage at which amyloid is removed may matter. [2]
So the question for the next generation is no longer simply whether amyloid can be removed. Do we need to clear it better, clear it earlier, or look beyond amyloid?
3. The vascular price of clearing amyloid
Amyloid removal also comes with a distinct safety challenge: amyloid-related imaging abnormalities, or ARIA.
ARIA includes edema or effusion (ARIA-E) and hemorrhagic findings such as microhemorrhages and superficial siderosis (ARIA-H). Most events are asymptomatic, but serious and occasionally life-threatening events can occur.
The strongest current mechanistic models place cerebral amyloid angiopathy (CAA) at the center of ARIA. Amyloid in Alzheimer’s disease is not confined to plaques in brain tissue; it can also accumulate within cerebral blood-vessel walls. Vascular amyloid may therefore become a direct site of antibody-mediated inflammation or receive amyloid mobilized from plaques during treatment. [3]
The precise sequence remains unresolved, but proposed mechanisms include antibody interaction with vascular amyloid, increased perivascular clearance, local immune activation, and temporary disruption of vessel-wall integrity.
Several clinical risk factors reinforce this vascular connection:
POE4 is particularly striking. In the pivotal lecanemab study, ARIA occurred in 45% of APOE4 homozygotes, compared with 19% of heterozygotes and 13% of noncarriers. Symptomatic ARIA-E occurred in 9% of homozygotes compared with 2% and 1%, respectively. [4]
Baseline vascular findings matter too. The FDA label identifies pre-treatment microhemorrhages and superficial siderosis as factors associated with greater ARIA risk. [4]
This makes ARIA more than a side-effect percentage. It shapes the treatment pathway. Patients undergo baseline and follow-up MRIs, APOE genotyping can inform risk, and ARIA may require additional monitoring or treatment interruption.
The unresolved question is whether vascular toxicity is tightly coupled to effective amyloid removal or can be reduced without sacrificing clinical benefit.
If it can, lowering ARIA could do more than make the drugs safer. It could make anti-amyloid treatment substantially easier to deliver.
4. The antibody is only part of the treatment
Leqembi and Kisunla also show that an effective drug is only one part of making Alzheimer’s treatment scalable.
Symptoms → early diagnosis → amyloid confirmation → safety assessment → treatment → ARIA monitoring
Patients have to be identified while they are still in the early stages represented in the pivotal trials. Amyloid pathology then needs to be confirmed before treatment, followed by additional safety assessment and monitoring.
That makes blood biomarkers particularly relevant. In May 2025, the FDA cleared the first blood test intended to aid assessment of amyloid pathology associated with Alzheimer’s disease, offering a less invasive alternative to PET imaging and cerebrospinal-fluid testing for appropriate patients. [5] More blood-based tests are now entering the field, although their impact on real-world treatment access remains to be seen.
Administration is changing too. Lecanemab initially required IV infusions every two weeks. In July 2026, the FDA approved once-weekly subcutaneous Leqembi IQLIK from treatment initiation, with at-home patient or caregiver administration possible after supervised training. [6]
Neither development guarantees greater uptake. But both target identifiable friction in the current treatment pathway.
This also broadens the commercial opportunity beyond the antibody itself. If disease-modifying treatment becomes more widely used, value could emerge from technologies that help identify eligible patients earlier, make treatment safer or easier to deliver, or improve the magnitude of clinical benefit. Which of these ultimately becomes commercially meaningful will depend on whether it can demonstrate an improvement in the real-world treatment pathway.
5. What the next generation has to improve
Leqembi and Kisunla have made the remaining problems easier to define.
The important distinction is between designing a technology to solve a problem and proving that it actually does.
Roche’s trontinemab, for example, uses a “Brainshuttle” designed to improve antibody transport across the blood-brain barrier. Early clinical data have shown rapid amyloid removal, but whether that translates into better clinical efficacy or a meaningfully improved safety profile still requires Phase III evidence. [7]
Combination approaches are earlier still. Trials are beginning to test whether targeting amyloid alongside tau can produce greater benefit than targeting amyloid alone. The biological rationale is compelling; the clinical answer is not yet known. [8]
There may therefore be no single “next” Alzheimer’s technology. The opportunity could emerge from improving the antibody itself, finding patients earlier, reducing treatment burden, or addressing disease biology that amyloid removal leaves behind.
6. What to watch next
Three questions now matter more than whether another drug can lower amyloid on a PET scan:
Can earlier or more complete amyloid removal produce a larger clinical effect?
Can ARIA be reduced without sacrificing efficacy?
Can targeting disease beyond amyloid materially increase clinical benefit?
Leqembi and Kisunla turned amyloid removal into a reproducible disease-modifying strategy. But their importance may extend beyond the drugs themselves. Their success has made the remaining bottlenecks in Alzheimer’s treatment much easier to see.
ABOUT THE AUTHOR
Ilina Navani
Ilina Navani is pursuing a master's degree in Biotechnology at the University of Pennsylvania. With a background in computer science, neuroscience and academic research, she is keen to bridge disciplines to drive innovation in science and healthcare. She is particularly interested in exploring how scientific ideas and technologies can be evaluated, positioned, and translated into real-world products, partnerships and business opportunities.
References
[1] van Dyck CH, et al. Lecanemab in Early Alzheimer’s Disease. New England Journal of Medicine. 2023;388:9–21.
[2] Sims JR, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512–527.
[3] Greenberg SM, et al. Amyloid-related imaging abnormalities: manifestations, metrics and mechanisms. Nature Reviews Neurology. 2025.
[4] U.S. Food and Drug Administration. LEQEMBI (lecanemab-irmb) Prescribing Information. Current FDA labeling.
[5] U.S. Food and Drug Administration. FDA Clears First Blood Test Used in Diagnosing Alzheimer’s Disease. May 16, 2025.
[6] U.S. Food and Drug Administration. LEQEMBI IQLIK (lecanemab-irmb) Prescribing Information. July 2026.
[7] Roche. Phase Ib/IIa trontinemab clinical data and TRONTIER Phase III development update. 2025.
[8] UCSF Alzheimer’s Tau Platform / ClinicalTrials.gov. Combination studies of tau-directed therapies with donanemab in early Alzheimer’s disease.
