. 2022 Apr 19;14:54. doi: 10.1186/s13195-022-00984-y

Table 2.

Outcome measures in early phases of the AD continuum^a

Domain	Preclinical AD^b	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 [23–25] • More sensitive to change in mild AD dementia than the ADAS-Cog [23–25]
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]	ADCS-ADL-MCI Scale • 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]

Domain

Preclinical AD^b

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 [23–25]

• More sensitive to change in mild AD dementia than the ADAS-Cog [23–25]

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]

ADCS-ADL-MCI Scale

• 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]

Abbreviations: AD Alzheimer’s disease, MCI mild cognitive impairment

^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]

^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