Cognitive-enhancing drugs in Phase II clinical trials for Alzheimer's disease: emerging therapeutic candidates

Expert Opin Investig Drugs. 2026 Jul 30. doi: 10.1080/13543784.2026.2710112. Online ahead of print.

ABSTRACT

INTRODUCTION: Alzheimer's disease (AD) is biologically defined by amyloid-β (Aβ) and tau pathology but clinically manifests as progressive synaptic dysfunction and cognitive decline. Although anti-amyloid and anti-tau therapies modestly slow disease progression, they do not directly restore cognition or synaptic function.

AREAS COVERED: Phase II trials of cognition‑enhancing therapies in AD and prodromal AD were reviewed to identify factors behind success or failure. Trials from ClinicalTrials.gov and the EU Clinical Trials Register with cognitive endpoints were assessed by mechanism, design, population, and outcomes. Strategies included synaptic, inflammatory, metabolic, vascular, and regenerative approaches.Most therapies showed limited or inconsistent cognitive effects, and many trials did not demonstrate clear efficacy.

EXPERT OPINION: Phase II cognition‑enhancing trials in AD show biological plausibility but remain methodologically limited. Cognitive signal detection depends on the fit between mechanism, disease stage, and trial design, and on the statistical approach used to capture subtle change. Outcome variability highlights the need for sensitive cognitive measures and adequate power. Progress will require precision‑enriched designs, with biomarker‑defined populations, cognitive‑trajectory modeling, and integrated cognitive and functional endpoints.

PMID:42530559 | DOI:10.1080/13543784.2026.2710112