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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.
Glossary
- AD=
- Alzheimer disease;
- ADC=
- Alzheimer’s Disease Center;
- CDR=
- Clinical Dementia Rating;
- CERAD=
- Consortium to Establish a Registry for Alzheimer’s Disease;
- CVD=
- cardiovascular disease;
- DLB=
- dementia with Lewy bodies;
- FAQ=
- Functional Assessment Questionnaire;
- FTLD=
- frontotemporal lobar degeneration;
- GDS=
- Geriatric Depression Scale;
- MMSE=
- Mini-Mental State Examination;
- MoCA=
- Montreal Cognitive Assessment;
- NACC=
- National Alzheimer's Coordinating Center;
- PCA=
- principal component analysis;
- PC1=
- first principal component;
- PC2=
- second principal component;
- UDS=
- Uniform Data Set
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
- Received October 18, 2018.
- Accepted in final form March 28, 2019.
- © 2019 American Academy of Neurology
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