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

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.

FIGURE 1

Study selection.

FIGURE 2

Summary of minimal clinically important differences for Alzheimer's disease trial endpoints. Values indicate the minimal clinically important difference (MCID) for decline. AD, Alzheimer's disease; ADAS‐Cog, Alzheimer's Disease Assessment Scale‐Cognitive; CDR‐SB, Clinical Dementia Rating scale sum of boxes; iADRS, integrated Alzheimer's Disease Rating scale; MCI, mild cognitive impairment; MMSE, Mini‐Mental State Examination; Mod, moderate.