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Table 2 Outcome measures in early phases of the AD continuuma

From: Meaningful benefits: a framework to assess disease-modifying therapies in preclinical and early Alzheimer’s disease

Domain Preclinical ADb MCI due to AD
Cognition Preclinical Alzheimer Cognitive Composite (PACC)
 • Composite cognitive measure that assesses episodic memory, timed executive function, and global cognition
 • In several studies, has reliably identified cognitive decline in individuals with preclinical AD over a 2- to 3-year observation period [17]
 • Primary endpoint in first interventional trial in cognitively normal individuals identified as “at-risk” for progression to AD dementia—the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s (A4) study [18]
Alzheimer’s Prevention Initiative Composite Cognitive Test (APCC)
 • Composite instrument of word recall, naming, praxis, orientation, and abstract reasoning [19]
 • Primary outcome measure in Alzheimer’s Prevention Initiative (API) [19]
 • Sensitivity has been independently confirmed in a cohort of cognitively normal older adults who progressed to late-onset AD [20]
Alzheimer’s Disease Assessment Scale, Cognitive Subscale (ADAS-Cog)
 • 11 subtests related to memory, praxis, and language [12]
 • Standard tool in pivotal clinical trials to detect therapeutic efficacy in cognition [21]
 • Best for patients with symptomatic AD; although often used in earlier AD, ceiling effects may limit its utility unless the assessment is modified (e.g., adding one or more tests) [21, 22]
Neuropsychological Test Battery (NTB)
 • Uses widely available tests with known reliability and validity to overcome some of the limitations of the ADAS-Cog
 • Assesses 5 cognitive domains: attention, language, memory, spatial, and executive function
 • High degree of reliability for characterizing individuals with mild to moderate AD [2325]
 • More sensitive to change in mild AD dementia than the ADAS-Cog [2325]
Global/composite None Clinical Dementia Rating (CDR) – GS or SB
 • Clinician rating scale widely used in clinical trials in MCI due to AD and mild AD dementia
 • Can yield global score (CDR-GS) or sum of boxes (CDR-SB)
 • CDR-GS supports trial eligibility and staging: score of 0.5 corresponds to MCI; score of 1 corresponds to mild dementia [26]
 • CDR-SB is often the primary outcome; has both cognitive (e.g., memory, orientation, judgment, and problem solving) and functional (community affairs, home and hobbies, personal care) aspects and serves as a composite measure
Alzheimer’s Disease Composite Score (ADCOMS)
 • Composite scoring approach designed as outcome measure for trials in patients with MCI due to AD and mild AD dementia [27]
 • Based on weighted scores from 4 ADAS-Cog subscale items, 2 Mini-Mental State Examination (MMSE) items, and all 6 CDR items
 • Demonstrated improved sensitivity over individual scales to detect clinical decline in people with amnestic MCI and those individuals with mild AD dementia
 • Also detected treatment effects associated with the use of cholinesterase inhibitors in these populations
Integrated Alzheimer’s Disease Rating Scale (iADRS)
 • Combines scores from the ADAS-Cog and the Alzheimer’s Disease Cooperative Study—Instrumental Activities of Daily Living (ADCS-iADL)
 • Across all phase 3 trials of the anti-amyloid treatment, solanezumab, in mild AD dementia, the iADRS differentiated between active treatment and placebo [28]
Function Emerging options
 • Performance-based assessment of functional capacity as demonstrated by:
  o A performance-based assessment of everyday function [29] like the University of California San Diego Performance-Based Skills Assessment (UPSA), or
  o Navigating an interactive voice response system, as in the Harvard Automated Phone Task, [30] or
  o Demonstrating skills in a virtual setting, such as the Virtual Reality Functional Capacity Assessment Tool (VRFCAT) [31]
 • Brief performance measure of financial skills, such as with the Financial Capacity Instrument [32]
 • Informant- and/or patient-reported ratings of everyday function, such as
  o The Everyday Cognition (ECog) scale [33]
  o The Cognitive Function Index (CFI) [34, 35]
  o The ADCS-ADL Prevention Instrument (ADCS ADL-PI) [36, 37]
 • Widely used endpoint in clinical trials [38]
 • Inventory of ADL elements rated based on the extent of assistance the individual needs with each activity (e.g., going shopping or keeping appointments or meetings) [38]
 • Successfully distinguishes those with MCI from those with unimpaired function [39]
Amsterdam IADL Questionnaire
 • Study partner report about the individual’s ability to perform a range of everyday activities, including cooking, finances, and everyday technology use [40]
 • Correlates longitudinally with cognitive decline [41]
 • Detects difficulties with IADLs in preclinical AD compared to healthy controls [42]
  1. Abbreviations: AD Alzheimer’s disease, MCI mild cognitive impairment
  2. aA more comprehensive review of a range of composite batteries developed for secondary prevention trials in AD, as well as their strengths and weaknesses, was recently provided by Schneider and Goldberg [16]
  3. bFDA has suggested an integrated scale that adequately and meaningfully assesses both daily function and cognitive effects. This scale may be acceptable as a single primary efficacy outcome in trials of preclinical AD