ADAS-Cog (Alzheimer's Disease Assessment Scale — Cognitive Subscale)

Type: Clinician-administered cognitive outcome measure Purpose: Quantify cognitive function in Alzheimer's disease clinical trials Developer: Rosen, Mohs, and Davis (1984)[@rosen1984] Current use: Primary endpoint in LY-3372689 MAGNOLIA trial, Phase 3 anti-amyloid trials (Aducanumab), and most AD therapeutic trials

Overview

Type: Clinician-administered cognitive outcome measure Purpose: Quantify cognitive function in Alzheimer's disease clinical trials Developer: Rosen, Mohs, and Davis (1984)[@rosen1984] Current use: Primary endpoint in LY-3372689 MAGNOLIA trial, Phase 3 anti-amyloid trials (Aducanumab), and most AD therapeutic trials

Overview

The Alzheimer's Disease Assessment Scale — Cognitive Subscale (ADAS-Cog) is the gold-standard cognitive outcome measure in Alzheimer's disease clinical trials. It was developed in 1984 by Rosen et al. as a comprehensive assessment tool specifically for AD trials["@rosen1984"]. The scale measures multiple domains of cognition including memory, language, praxis, and visuospatial function.

ADAS-Cog has become the most widely used primary endpoint in AD drug trials, with a large body of validation data across diverse populations. Its sensitivity to change over time and ability to distinguish between AD patients and healthy controls has made it the benchmark for regulatory approval studies["@mohs2000"].

Versions

ADAS-Cog 11 (Original)

• Word recall (3 trials, 10 words each): Immediate word recall score
• Naming: Identifies objects and fingers
• Commands: Follows written commands
• Constructional praxis: Draws geometric figures
• Ideational praxis: Reproduces sequences
• Orientation: Date, day, time, place
• Word recognition: 12-word delayed recognition
• Language: Spontaneous speech, comprehension

ADAS-Cog 13

• Delayed word recall: Separate delayed recall trial
• Number cancellation: Attention and visual scanning

ADAS-Cog 14 (Most commonly used in recent trials)

• Concentration/distractibility item
• Improves ceiling/floor properties

Scoring

Interpretation

• 0–5: Normal cognitive function
• 5–12: Mild cognitive impairment range
• 12–30: Mild-to-moderate AD range
• 30–50+: Moderate-to-severe AD range

Minimum Clinically Important Difference (MCID)

• 1–3 points: Often cited as MCID in mild AD
• 4+ points: Generally considered clinically meaningful change
• Trial designs typically power for 25–50% slowing of decline vs. placebo

Advantages

• Widely validated across hundreds of AD trials
• Strong regulatory acceptance (FDA, EMA)
• Sensitive to change in mild-to-moderate AD (MMSE 10–26)
• Detailed cognitive profile across multiple domains

Limitations

• Ceiling effects in very mild AD (preclinical)
• Floor effects in moderate-to-severe AD
• Administration time: 30–45 minutes
• Training required for reliable administration
• Cultural/language adaptations needed for global trials

Domains Assessed

| Domain | Items | Max Points | Description |
|--------|-------|------------|-------------|
| Memory | Word recall, recognition | 25 | Immediate and delayed verbal memory |
| Language | Naming, commands, comprehension, speech | 25 | Verbal abilities and comprehension |
| Praxis | Constructional, ideational | 10 | Visuospatial and motor execution |
| Orientation | Time, place | 8 | Temporal and spatial awareness |
| Concentration | Number cancellation | 5 | Attention and processing speed |

Use in OGA Inhibitor Trials

MAGNOLIA Trial (LY-3372689 in Early AD)

• Population: Early symptomatic AD (amyloid-confirmed)
• Primary endpoint: Change from baseline in ADAS-Cog 13 at 18 months
• Expected change: Treatment group expected to show ~30–40% slowing of decline
• Context: OGA inhibition aims to reduce tau phosphorylation, potentially slowing cognitive decline by protecting synaptic and neuronal function

Why ADAS-Cog for OGA inhibitor trials

• OGA inhibitors target tau pathology, which correlates with cognitive decline progression
• ADAS-Cog captures the cognitive domains most affected by tau pathology (memory, executive function)
• Strong baseline-to-follow-up sensitivity in the mild AD population being studied
• Regulatory precedent: FDA has accepted ADAS-Cog as primary endpoint for tau-targeting therapies

Validation and Historical Use

Landmark Trials Using ADAS-Cog

| Trial | Drug | Primary Endpoint | Result |
|-------|------|-----------------|--------|
| Aducanumab EMERIAN | Aducanumab | ADAS-Cog 13 | Mixed (high-dose showed slowing) |
| ENGAGE | Aducanumab | ADAS-Cog 13 | Did not meet primary |
| CLARITY AD | Lecanemab | ADAS-Cog 14 | -27% slowing at 18 months |
| TRAILBLAZER-ALZ | Donanemab | ADAS-Cog 13 | Met primary endpoint |
| MAGNOLIA | LY-3372689 | ADAS-Cog 13 | Pending (expected Q3 2026) |

Cross-Reference with Other Outcome Measures

ADAS-Cog is typically used alongside:

• [ADCS-MCI-ADL](/entities/adcs-mci-adl): Functional outcome measure (co-primary)
• MMSE: Brief screening tool for baseline stratification
• CDR-SB: Clinical staging and global change
• CSF/blood biomarkers: Tau phosphorylation, A-beta, neurodegeneration

OGA Inhibitor Context

The OGA inhibitor therapeutic approach targets tau hyperphosphorylation by increasing [O-GlcNAcylation](/mechanisms/protein-o-glcna-cylation-pathway) on tau proteins. This is based on the [Yin-Yang Hypothesis](/mechanisms/yin-yang-hypothesis) — that O-GlcNAcylation and phosphorylation compete for the same serine/threonine sites on tau.

If OGA inhibition successfully reduces tau phosphorylation:

The key question in MAGNOLIA is whether sufficient target engagement (CSF O-GlcNAc increase) translates into measurable cognitive benefit at 18 months — a question that will inform the entire OGA inhibitor field.

Cross-Links

• [ADCS-MCI-ADL](/entities/adcs-mci-adl) — functional outcome measure
• [O-GlcNAcylation Pathway](/mechanisms/protein-o-glcna-cylation-pathway) — target of OGA inhibitors
• [Yin-Yang Hypothesis](/mechanisms/yin-yang-hypothesis) — mechanism linking O-GlcNAc and phosphorylation
• [LY-3372689 MAGNOLIA Trial](/clinical-trials/ly3372689-magnolia-phase2-ad) — primary endpoint
• [PSP Rating Scale](/entities/psp-rating-scale) — analogous measure in PSP trials
• [Tau Pathology](/proteins/tau) — target of OGA inhibitor intervention
• [Alzheimer's Disease](/diseases/alzheimers-disease) — primary disease context

Pathway Diagram

The following diagram shows the key molecular relationships involving ADAS-Cog (Alzheimer's Disease Assessment Scale — Cognitive Subscale) discovered through SciDEX knowledge graph analysis: