What peer‑reviewed treatments currently exist for Alzheimer’s and how are they evaluated?
Executive summary
Two families of peer‑reviewed, routinely cited treatments exist today: symptomatic agents (cholinesterase inhibitors and memantine) that modestly improve cognition or behavior, and more recently developed anti‑amyloid monoclonal antibodies that reduce brain amyloid and have small but statistically significant effects on clinical decline; both are evaluated through randomized controlled trials using clinical endpoints (eg, CDR‑SB, iADRS) and biomarker outcomes (amyloid PET, CSF/blood markers) while safety—most notably amyloid‑related imaging abnormalities (ARIA)—remains a limiting factor [1] [2] [3].
1. Standard symptomatic drugs: what they are and how good they perform
Three cholinesterase inhibitors—donepezil, galantamine and rivastigmine—plus the NMDA antagonist memantine are established, peer‑reviewed treatments recommended for mild to moderate Alzheimer’s disease because randomized trials show modest improvements in cognitive scales and some behavioral measures, but these drugs do not alter long‑term disease progression and effect sizes are small-to-moderate on standard instruments [1] [4].
2. Anti‑amyloid monoclonal antibodies: mechanism, approvals and limits
Monoclonal antibodies such as aducanumab, lecanemab and donanemab target aggregated amyloid‑β, have demonstrated robust clearance of brain amyloid on PET, and received regulatory attention—aducanumab and lecanemab were approved by the FDA and donanemab has shown positive phase 3 results or regulatory submissions—yet clinical benefits have been statistically significant but generally below commonly accepted minimal clinically important differences on scales like the CDR‑SB or iADRS [1] [2] [5] [6].
3. How clinical trials and biomarkers are used to judge efficacy
Drug candidates are evaluated in randomized phase 2/3 trials measuring clinical endpoints such as the Clinical Dementia Rating–Sum of Boxes (CDR‑SB), integrated AD Rating Scale (iADRS) and cognitive batteries, and increasingly incorporate biomarker endpoints—amyloid PET, tau PET, CSF and blood Aβ/p‑tau/NfL—to demonstrate target engagement and disease‑modifying potential; regulators and journals weigh both clinical change and biomarker shifts when judging approval and meaningful benefit [2] [3] [7].
4. Safety evaluation and the ARIA problem
Safety assessment is central: anti‑amyloid antibodies reliably increase the risk of amyloid‑related imaging abnormalities—vasogenic edema and microhaemorrhages (ARIA) —which are usually asymptomatic but can be severe or fatal in rare cases, prompting trial monitoring protocols, MRI requirements, and careful risk–benefit discussions in peer‑reviewed reports and guidance documents [1] [2].
5. Emerging and non‑pharmacological approaches under peer review
An active, peer‑reviewed pipeline includes small molecules (eg, ALZ‑801, GV‑971), tau‑targeting agents, neuroinflammation modulators and non‑pharmacological therapies—exercise, cognitive training, cell and nanoparticle approaches—whose early trials show promise for symptom relief or biomarker change but lack definitive phase‑3 evidence of slowing clinical progression; the literature emphasizes that many of these strategies remain investigational and need rigorous randomized trials to establish clinical efficacy [8] [9] [10].
6. How to read the evidence: statistical significance vs clinical meaningfulness
Peer‑reviewed meta‑analyses and trial reports emphasize a persistent gap between statistical significance and real‑world benefit: monoclonal antibodies can produce statistically significant reductions in decline on CDR‑SB (eg, group differences of ~0.4–0.5 points) yet these fall short of published minimal clinically important differences, meaning clinicians, patients and regulators must judge modest average effects against cost, monitoring burden and safety profiles [1] [4].