The New Alzheimer's Drugs Are Approved. Are They Working?

When the FDA approved lecanemab (Leqembi) in 2023 and donanemab (Kisunla) in 2024, the announcements were framed as major turning points: the first disease-modifying treatments for Alzheimer's disease. The clinical evidence behind these drugs tells a more complicated story, and the gap between statistical significance and clinical meaning is wide enough that approval shouldn't be treated as the end of the analysis.

Leqembi and Kisunla are anti-amyloid monoclonal antibodies, approved specifically for patients with mild cognitive impairment or mild dementia due to Alzheimer's, not moderate or severe disease. The goal is to delay progression, not cure it.

In trials, both drugs slowed cognitive decline compared to placebo, but the magnitude matters. Clinicians use a threshold called the minimal clinically important difference, the smallest change a patient or caregiver would actually notice, generally 2 to 3 points on the cognitive scales used in these trials. The observed improvement was around 1 point over 76 weeks, below that threshold. Both drugs appear to delay progression by a matter of months, meaningful, but short of what the approval headlines implied.

A Cochrane Collaboration systematic review covering 17 randomized controlled trials and more than 20,000 participants found these drugs probably result in little to no difference in cognitive function or dementia severity at 18 months. NICE, the UK's health technology assessment body, declined to recommend reimbursement, citing benefit too small to justify cost. Independent reviewers in multiple markets, evaluating the same data the FDA approved, have arrived at the same conclusion.

Safety is a meaningful consideration. Both drugs are associated with ARIA (amyloid-related imaging abnormalities), brain swelling and microbleeds, most asymptomatic but occasionally serious. Managing that risk requires repeated MRI monitoring throughout treatment. Patients with the APOE ε4 genetic variant face substantially higher ARIA risk, a factor worth identifying before initiating therapy where testing is available. A recently approved self-injectable maintenance option for Leqembi may reduce administration burden after an initial IV period, but doesn't change the drug's clinical or safety profile.

Clinical takeaway: FDA approval reflects statistical significance, not necessarily a clinically meaningful benefit for an individual patient. For patients being considered for therapy, confirm they meet the specific mild-stage criteria the trials studied, screen for APOE ε4 status where available, and ensure MRI monitoring capacity is in place before initiating treatment, not after. The field is also actively questioning whether amyloid is the right therapeutic target at all, so this is a category worth watching for guidance changes rather than treating current evidence as settled.