Minimal clinically important difference in Alzheimer's disease: Rapid review

Ryan T Muir; Michael D Hill; Sandra E Black; Eric E Smith

doi:10.1002/alz.13770

Minimal clinically important difference in Alzheimer's disease: Rapid review

Alzheimers Dement. 2024 Apr 1. doi: 10.1002/alz.13770. Online ahead of print.

Authors

Ryan T Muir^{1

2}, Michael D Hill^{1

2}, Sandra E Black^{3

4}, Eric E Smith^{1

2}

Affiliations

¹ Department of Clinical Neurosciences and Department of Community Health Sciences, Calgary, Alberta, Canada.
² Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.
³ Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
⁴ L.C Campbell Cognitive Neurology Research Unit, Dr Sandra Black Centre for Brain Resilience and Recovery, and Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.

PMID: 38561021
DOI: 10.1002/alz.13770

Abstract

Introduction: We conducted a rapid systematic review of minimal clinically important differences (MCIDs) for Alzheimer's disease (AD) trial endpoints.

Methods: Two reviewers searched EMBASE, MEDLINE, and PubMed from inception to June 4, 2023.

Results: Ten articles were retrieved. For mild cognitive impairment (MCI), a change of +2 to +3 points on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), +1 points on the Clinical Dementia Rating scale sum of boxes (CDR-SB), -5 points on the integrated Alzheimer's Disease Rating Scale (iADRS), or -1 to -2 points on the Mini-Mental State Examination (MMSE) was considered meaningful. For patients with mild AD, a change of +3 on the ADAS-Cog, +2 points on CDR-SB, -9 points on the iADRS, or -2 points on the MMSE was considered meaningful. For patients with moderate to severe AD, a change of +2 points on the CDR-SB or a change of -1.4 to -3 points on the MMSE was considered meaningful.

Conclusion: This review identified previously published MCIDs for AD trial endpoints. Input from patients and caregivers will be needed to derive more meaningful endpoints and thresholds.

Highlights: This systematic rapid review identified thresholds for minimal clinically important differences (MCIDs) for recently used Alzheimer's disease (AD) trial endpoints: Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating scale sum of boxes (CDR-SB), integrated Alzheimer's Disease Rating Scale (iADRS), Mini-Mental State Examination (MMSE). MCIDs were higher for more severe stages of AD. Average treatment effects in recent trials of anti-amyloid disease modifying monoclonal antibodies are lower than previously published MCIDs. In future trials of disease modifying treatments for AD, the proportion of participants in each treatment group that experienced a clinically meaningful decline could be reported. More work is needed to incorporate the values and preferences of patients and care partners in deriving MCIDs.

Keywords: Alzheimer's disease; clinical trial; minimal clinically important difference.