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. 2025 Sep 24;11(3):e70160.
doi: 10.1002/trc2.70160. eCollection 2025 Jul-Sep.

Clinically meaningful changes in cognitive and functional outcomes in a population-based study of cognitive aging

Jeremiah A Aakre  1 , Anna M Castillo  1 , Jonathan Graff-Radford  2 , Prashanthi Vemuri  3 , Mary M Machulda  4 , Clifford R Jack Jr  3 , David S Knopman  2 , Ronald C Petersen  1   2 , Maria Vassilaki  1
Affiliations

Clinically meaningful changes in cognitive and functional outcomes in a population-based study of cognitive aging

Jeremiah A Aakre et al. Alzheimers Dement (N Y). .

Abstract

Introduction: Research is limited regarding meaningful change thresholds for individual patients on clinical outcome assessments (COAs) frequently used in clinical trials for Alzheimer's disease and related dementias (ADRD), particularly in population-based studies early in the disease course.

Methods: There were 646 study participants in the population-based Mayo Clinic Study of Aging (MCSA), 54-99 years old (47% females), who developed the clinical syndromes of mild cognitive impairment (MCI) with complete data to establish clinically meaningful within-patient change thresholds in cognitive and functional COAs.

Results: Using the diagnosis of incident MCI as the anchor, mean (95% confidence interval [CI]) annualized estimates of change were: Clinical Dementia Rating (CDR) scale Sum of Boxes (SB) 0.49 (0.43, 0.55), Mini-Mental State Examination (MMSE) -1.01 (-1.12, -0.91), and Functional Activities Questionnaire (FAQ) score 1.04 (0.82, 1.26).

Discussion: This study provides within-patient estimates of clinically meaningful change early in disease progression in a community-based sample.

Highlights: We studied incident mild cognitive impairment (MCI) participants from a population-based study.Within-patient change thresholds were estimated for clinical outcome assessments (COAs) used in clinical trials for Alzheimer's disease and related dementia (ADRD).These estimates may be used to plan and evaluate clinical trials involving disease-modifying therapies (DMTs).

Keywords: clinical outcome assessments; clinically meaningful decline; mild cognitive impairment; within‐patient change.

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Conflict of interest statement

Jeremiah A. Aakre has no disclosures. Anna M. Castillo has no disclosures. Jonathan Graff‐Radford receives support from the NIH and serves on the DSMB for StrokeNET and is an investigator in clinical trials sponsored by Esai, Cognition therapeutics, and the Alzheimer's Treatment and Research Institute at USC. He is an associate editor for JAMA neurology. Prashanthi Vemuri receives research funding from NIH. Mary M. Machulda receives research funding from NIH. Clifford R. Jack Jr. has no financial conflicts to disclose; he receives research support from NIH and the Alexander Family Alzheimer's Disease Research Professorship of the Mayo Clinic. David S. Knopman serves on a Data Safety Monitoring Board for the Dominantly Inherited Alzheimer Network Treatment Unit study sponsored by Washington University St Louis, and for the SMART‐HS clinical trial (Univ of Kentucky). He was an investigator in Alzheimer clinical trials sponsored by Biogen, Lilly Pharmaceuticals and the University of Southern California, both of which have ended, and is currently an investigator in a trial in frontotemporal degeneration with Alector. He has served as a consultant for Roche, AriBio, Linus Health, Biovie and Alzeca Biosciences but receives no personal compensation. He receives funding from the NIH. Ronald C. Petersen serves as a consultant for Roche, Inc., Genentech, Inc., Eli Lilly and Co., Novo Nordisk, Eisai, Inc. (no funding), receives royalties from Oxford University Press and UpToDate, contributes to Medscape education and receives NIH funding. Maria Vassilaki consulted for F. Hoffmann‐La Roche Ltd, unrelated to the current study; she currently receives research funding from NIH and has equity ownership in Johnson and Johnson, Merck and Amgen. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Performance on COAs as a function of time to incident MCI (for progressors) or in the past 36 months of assessments (for non‐progressors). Cubic splines were used to allow non‐linear trends to emerge. COA, clinical outcome assessment; MCI, mild cognitive impairment.
See this image and copyright information in PMC

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