Alzheimer's Disease: The Landmark Breakthroughs of 2025

 

 

Alzheimer's in Numbers

Alzheimer's disease (AD) is the most common cause of dementia, accounting for 60–70% of
the 55 million people living with dementia worldwide. It is a progressive neurodegenerative
disease characterised by the accumulation of amyloid-beta (Aβ) plaques and tau
neurofibrillary tangles in the brain, leading to neuronal death, cognitive decline, and
eventually loss of independent function. AD affects an estimated 10% of people over age 65
and nearly 50% of those over age 85.
For over three decades, every attempt to develop disease-modifying therapy for Alzheimer's
— treatments that address the underlying biology rather than merely managing symptoms —
failed. That changed between 2023 and 2025, when the FDA approved the first-ever drugs
to actually slow the progression of Alzheimer's disease.

 

 

The Amyloid Hypothesis: Finally Validated

The dominant hypothesis in AD research has been the "amyloid cascade hypothesis" — the
idea that toxic accumulation of amyloid-beta protein in the brain initiates a cascade that
leads to tau tangle formation, neuroinflammation, and neuronal death. This hypothesis has
guided drug development but also been highly controversial after numerous failed clinical
trials.
The approvals of lecanemab and donanemab in 2023–2024 validated the amyloid
hypothesis in a fundamental way. Both drugs clear amyloid from the brain — and both slow
cognitive decline. The correlation between amyloid clearance and slowed decline is the
clinical proof that amyloid causally drives the disease.

 

Lecanemab (Leqembi): The First Approved Disease-Modifying Treatment

Lecanemab received traditional FDA approval in July 2023 and European Medicines Agency
approval in late 2024. It is a humanised monoclonal antibody that targets aggregated soluble
amyloid-beta protofibrils — the most neurotoxic form of amyloid.
The pivotal CLARITY-AD Phase 3 trial (18 months, double-blind, placebo-controlled)
demonstrated that lecanemab slowed cognitive decline by 27% as measured by the CDR-
SB (Clinical Dementia Rating Sum of Boxes) and achieved a 59-centiloid reduction in
amyloid burden on PET imaging. In simpler terms: patients on lecanemab had more than 5
months of additional time at a better cognitive level compared to those on placebo over 18
months.
Critically, 2025 brought major accessibility advances. The FDA approved monthly IV
maintenance dosing in January 2025, and — in a landmark August 2025 approval — weekly
subcutaneous (under-the-skin) self-injection maintenance dosing using an autoinjector,
allowing patients to manage their treatment at home rather than making frequent hospital
visits. Lecanemab has now been approved in 51 countries.

 

Donanemab (Kisunla): A Finite Course of Treatment

Donanemab received FDA approval in July 2024. It targets a specific modified form of
amyloid-beta (pyroGlu-Aβ) found in mature plaques. The TRAILBLAZER-ALZ 2 Phase 3 trial
(76 weeks) showed that donanemab slowed clinical progression by 29% compared to
placebo across all cognitive and functional measures.
A unique and clinically important feature of donanemab is that treatment can be paused or
discontinued once amyloid PET imaging confirms sufficient plaque clearance — effectively a
finite course of therapy. Long-term extension data presented at AAIC 2025 confirmed that

patients who began donanemab early continued to experience meaningful benefit for up to 3
years, with more than 75% achieving amyloid clearance within 76 weeks.
However, the European Medicines Agency rejected donanemab's marketing authorisation
application in 2025 based on an unfavourable benefit-risk assessment — a difference from
the FDA's decision that highlights ongoing regulatory and scientific debate about the
magnitude of clinical benefit relative to safety risks.

 

Safety: The ARIA Challenge

Both lecanemab and donanemab carry a risk of Amyloid-Related Imaging Abnormalities
(ARIA) — brain swelling (ARIA-E) and microhemorrhages (ARIA-H) — that occur in 21–37%
of patients and are serious or symptomatic in 2–3%. These risks are higher in patients
carrying the APOE-ε4 genetic variant (which also increases AD risk). Anti-amyloid therapies
are contraindicated in patients taking anticoagulants. Regular MRI monitoring is required.
These safety requirements have prompted active research into less toxic delivery systems
— Eli Lilly is developing a brain-shuttle technology for donanemab to reduce ARIA
incidence.

 

What Is Coming Next

Both drugs slow, but do not stop, decline — slowing progression by 25–30% over 18
months, with uncertain long-term effects. The next frontier is targeting tau pathology in
parallel with amyloid — researchers believe that combination therapy (anti-amyloid + anti-
tau) may produce dramatically greater benefits than either approach alone. Tau-targeting
drugs including etalanetug (E2814, Eisai) are currently in Phase 3 trials. Prevention trials
(AHEAD study, TRAILBLAZER-ALZ 3) are now testing anti-amyloid drugs in cognitively
normal people who have elevated amyloid — the hope being to prevent Alzheimer's before
symptoms begin. In August 2025, the 18th CTAD Conference reported 138 drugs in 182
active global trials — the most robust pipeline in AD history.

 

References

[1] van Dyck CH et al. Lecanemab in Early Alzheimer's Disease (CLARITY-AD). NEJM. 2023;388:9-21.
doi:10.1056/NEJMoa2212948.
[2] Sims JR et al. Donanemab in Early Symptomatic Alzheimer Disease: TRAILBLAZER-ALZ 2. JAMA.
2023;330(6):512-527. doi:10.1001/jama.2023.13239.
[3] Wang H, Pan J et al. Re-evaluation of anti-Aβ monoclonal antibodies in early AD. Front Pharmacol.
2025;16:1599048. doi:10.3389/fphar.2025.1599048.
[4] Alzheimer's Association. Lecanemab (Leqembi). alz.org, August 2025.
[5] ALZ-NET. New results from TRAILBLAZER-ALZ 2 long-term extension. alz-net.org, August 2025.
[6] Alzheimer's Research UK. CTAD 2025: Six highlights from the latest clinical trials. December 2025.
[7] Loera-Valencia R et al. Anti-Amyloid Therapies for Alzheimer's: Progress, Pitfalls, and the Path
Ahead. PMC12524931. 2025.