Cognitive heterogeneity in probable Alzheimer disease: Clinical and neuropathologic features

Abstract

Objective: To identify heterogeneity in cognitive profiles of patients with probable Alzheimer disease (AD) who have mild to moderate dementia and satisfy inclusion and exclusion criteria for a typical AD clinical trial, and to determine whether cognitive profiles are systematically related to the clinical course and neuropathologic features of the disease.

Methods: Neuropsychological test data from patients with mild to moderate probable AD (n = 4,711) were obtained from the National Alzheimer's Coordinating Center. Inclusion and exclusion criteria usually used in AD clinical trials were applied. Principal component analysis and model-based clustering were used to identify cognitive profiles in a subset of patients with autopsy-verified AD (n = 800) and validated in the overall (nonautopsy) sample and an independent cohort with similar test data. Relationships between cognitive profile, clinical characteristics, and rate of decline were examined with mixed-effects models.

Results: In the autopsy-confirmed sample, 79.6% of patients had a typical AD cognitive profile (greater impairment of episodic memory than other cognitive functions), and 20.4% had an atypical profile (comparable impairment across cognitive domains). Similar results were obtained in the overall (typical 79.8%, atypical 20.2%) and validation (typical 71.8%, atypical 28.2%) samples. Atypicality was associated with younger age, male sex, lower probability of APOE ε4, less severe global dementia, higher depression scores, lower Braak stage at autopsy, and slower cognitive decline.

Conclusion: We can reliably identify distinct cognitive profiles among patients with clinically diagnosed probable AD that are associated with tangle pathology and with different rates of decline. This may have implications for clinical trials in AD, especially therapies targeting tau.

Figure 1. Results of model-based clustering and z scores on neuropsychological test measures

Clustering results and z scores on neuropsychological test measures for participants from the neuropathologically confirmed subsample of (A and B) sample 1, (C and D) overall sample 1, and (E and F) independent sample 2. In panels A, C, and E, each ellipse is the estimated 95th percentile for each cluster (95% of the estimated population lies within this ellipse). In panels B, D, and F, test measures were grouped as episodic/semantic memory (left) and nonmemory (right) cognitive domains. Because normative data were not available to compute z scores for Trail-Making rate, time to completion is displayed. AD = Alzheimer disease; BENS-I = Benson Figure Delayed Recall; BENS-II = Benson Figure Copy; BNT = Boston Naming Test; CatFlu = Category Fluency; CRFT-I = Craft 21 Story Immediate Recall; CRFT-II = Craft 21 Story Delayed Recall; Dig sym = Wechsler Adult Intelligence Scale–Revised Digit Symbol; LM-I = Logical Memory Immediate Recall; LM-II = Logical Memory Delayed Recall; MINT = Multilingual Naming Test; Span-B = Digit Span Backward; Span-F = Digit Span Forward; Trail A Time = Trail-Making Test Part A—time to completion; Trail B Time = Trail-Making Test Part B—time to completion; Letter Flu = Letter Fluency.

Figure 2. Proportion of typical and atypical participants by Braak and CERAD rating

Distribution of cognitive subtype by Braak stage and Consortium to Establish a Registry for Alzheimer’s Disease (CERAD) plaque density rating (A and B) for all sample 1 participants with autopsy (n = 976) and (C and D) restricted to those with pathologically confirmed Alzheimer disease (AD) (n = 800). Number over each bar is the sample size for that stage/level. Classification was based on clustering results of sample 1.

Figure 3. Model fitted lines comparing rate of change over 2 years for typical and atypical AD

Predicted rate of decline over 2 years for typical vs atypical Alzheimer disease (AD) cognitive subtypes based on mixed effects models from sample 1 for (A) Mini-Mental State Examination (MMSE), (B) Clinical Dementia Rating (CDR) global rating, and (C) CDR Sum of Boxes (SOB). (D) Differences in proportion of 2-year decline between typical and atypical AD with 95% confidence interval bars.