What are the current FDA‑approved and controversial treatments for Alzheimer’s and their evidence bases?
Executive summary
Two classes of Alzheimer’s treatments exist today: longstanding symptomatic drugs that modestly delay decline (cholinesterase inhibitors and memantine) and a new wave of anti‑amyloid immunotherapies that reduce brain amyloid but offer only modest and debated clinical benefit while carrying significant safety, cost and regulatory controversy (notably aducanumab/Aduhelm and lecanemab/Leqembi) [1] [2] [3]. Regulators, payers and many clinicians remain divided because trial results are mixed, side effects include brain swelling and bleeding, and long‑term functional benefit is still uncertain [4] [5] [6].
1. Traditional symptomatic drugs: what they do and the evidence
For decades the backbone of Alzheimer’s pharmacotherapy has been cholinesterase inhibitors (donepezil, rivastigmine) and the NMDA antagonist memantine, which consistently show small but clinically relevant delays in cognitive and functional decline across mild to severe stages in systematic reviews and guideline summaries; these drugs do not target disease biology but improve symptoms and remain standard of care [1].
2. Anti‑amyloid antibodies: mechanism, approvals and trial results
A new generation of monoclonal antibodies targets amyloid‑beta plaques — a hallmark of Alzheimer’s pathology — and clearly reduces amyloid burden on PET scans, which became the biomarker basis for accelerated and conditional FDA approvals beginning in 2021 (aducanumab) and continued with lecanemab (and related agents) after larger trials [2] [3] [6]. Aducanumab’s trial record was inconsistent — one phase III showed benefit while another did not — yet it received accelerated approval in 2021 on the surrogate endpoint of plaque removal, a decision many experts and an FDA advisory committee questioned because clinical benefit was not clearly demonstrated [4] [7] [8]. Lecanemab’s 18‑month randomized trial in nearly 1,800 people reported a modest slowing of cognitive decline versus placebo and reduction in amyloid, prompting regulatory clearance and further submissions for full approval, though authors and observers stressed that longer trials are needed to confirm meaningful, sustained functional benefit [3] [9].
3. Safety signals, deaths and the ARIA problem
Anti‑amyloid therapies carry a distinctive safety liability called ARIA (amyloid‑related imaging abnormalities) — brain swelling or microhemorrhages — which can produce stroke‑like symptoms and, in some post‑marketing reports, deaths potentially linked to treatment; this risk profile has shadowed both regulatory enthusiasm and clinical uptake [2] [5] [9]. Trial protocols require imaging surveillance to detect ARIA, and clinicians weigh modest cognitive gains against these nontrivial risks, especially in older, comorbid populations where trial participants may not reflect real‑world frailty [2] [5].
4. Cost, coverage and the politics of approval
Price and payer policy magnify the controversy: aducanumab was initially priced at roughly $56,000 per year and met CMS restrictions that limited coverage to clinical‑trial settings, reflecting payer skepticism about value given uncertain clinical benefit [2] [10] [11]. Lecanemab’s approval also triggered scrutiny about whether CMS will reimburse broadly or impose limits pending further evidence, a decision that will determine real‑world access and the financial consequences for Medicare and patients [3] [11]. Hidden incentives shape the debate — companies’ commercial interests, regulators’ use of accelerated pathways for unmet needs, and advocacy groups’ pressure for options all intersect and color interpretations of the same trial data [4] [12].
5. Emerging agents, remaining gaps and what to watch
Beyond the two headline antibodies, other anti‑amyloid agents (and different targets such as tau) are in development and some formulations (e.g., subcutaneous lecanemab autoinjectors) aim to change delivery and uptake, but systematic reviews and updated guidance emphasize that long‑term functional outcomes, safety in broader populations, cost‑effectiveness and head‑to‑head comparisons remain unresolved — areas regulators and clinicians are actively monitoring [13] [1] [6]. Where reporting is thin, this account does not claim undisclosed trial results exist; it sticks to published trial outcomes, regulator statements and payer decisions, all of which show progress but also clear, unresolved controversies [3] [2].