Neurology. 2026 Aug 25;107(4):e218373. doi: 10.1212/WNL.0000000000218373. Epub 2026 Jul 23.
ABSTRACT
BACKGROUND AND OBJECTIVES: Regulatory guidance has long emphasized clinically meaningful outcomes in Alzheimer disease (AD) drug trials. No contemporary review has examined the efficacy measures used for clinical trials of AD therapies. The objective of this study was to evaluate the clinical relevance and heterogeneity of efficacy measures used in phase II-IV AD drug trials over the past decade.
METHODS: We systematically searched PubMed, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov. All phase II-IV clinical trials of pharmacologic therapies in individuals with mild cognitive impairment due to AD or mild-to-moderate AD that were published, completed, or terminated between January 1, 2015, and November 15, 2025, or still ongoing as of November 15, 2025, were eligible for inclusion. We summarized the proportion of trials using clinical outcomes or biomarkers as primary or secondary efficacy measures, key clinical domains addressed, and the number of distinct measures using descriptive statistics. This study is registered with PROSPERO (CRD420251032087).
RESULTS: Among 238 included trials, 95.4% (227/238) used at least one clinical outcome and 73.5% (175/238) used at least one biomarker as efficacy measures. Cognitive abilities (87.0%, 207/238), global status (76.9%, 183/238), and functional ability (71.4%, 170/238) were the most frequently measured clinical domains, whereas patient (16.0%, 38/238) and caregiver (8.8%, 21/238) quality of life and significant disease-related life events (2.5%, 6/238) were less frequent. Only 21.8% (52/238) of trials adopted regulatory-recommended co-primary measures of cognition with either function or global status, whereas 8.4% (20/238) used biomarkers as the sole primary efficacy measure. We identified 318 distinct clinical outcome measures and 219 distinct biomarkers used across all trials, 6.9% (22/318) and 6.8% (15/219) of which were used in more than 5% of trials.
DISCUSSION: Efficacy measures in AD drug trials primarily focused on cognition, global status, and functional outcomes, which are important indicators of AD progression. However, other clinical domains that may also be meaningful to patients and caregivers were far less frequently assessed, while biomarker use is widespread. Substantial heterogeneity in efficacy measure use limits comparability across trials and highlights the need for standardized, consensus-based, clinically meaningful core measure sets for AD drug trials.
PMID:42492033 | DOI:10.1212/WNL.0000000000218373
