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Abstract
Background and Objectives Given prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories.
Methods Cluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data.
Results Five clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy.
Discussion We identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline.
Glossary
- Aβ1–42=
- β-amyloid peptide 1–42;
- AD=
- Alzheimer disease;
- ADRC=
- Alzheimer's Disease Research Center;
- aMCI=
- amnestic mild cognitive impairment;
- ANOVA=
- analysis of variance;
- CDR=
- clinical dementia rating;
- CN=
- cognitively normal;
- DLB=
- dementia with lewy bodies;
- FDR=
- false discovery rate;
- FTLD=
- frontotemporal lobal degeneration;
- HR=
- hazard ratio;
- HSD=
- honestly significant difference;
- MCI=
- mild cognitive impairment;
- mMCI=
- mixed mild cognitive impairment;
- MMSE=
- mini-mental state examination;
- NACC=
- National Alzheimer's Coordinating Center;
- naMCI=
- nonamnestic mild cognitive impairment;
- NIA=
- National Institute on Aging;
- NINCDS-ADRDA=
- National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer’s Disease and Related Disorders Association;
- oCN=
- optimal cognitively normal;
- PDD=
- Parkinson disease dementia;
- UCSD=
- University of California San Diego;
- tCN=
- typical cognitively normal
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.
Podcast: NPub.org/8r0hcr
- Received February 5, 2021.
- Accepted in final form July 1, 2021.
- © 2021 American Academy of Neurology
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