Data-driven versus consensus diagnosis of MCI: enhanced sensitivity for detection of dementia progression, biomarker status, and neuropathological outcomes

Objective: 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 (UCSD) Alzheimer’s
Disease Research Center (ADRC) in order to identify cognitive subgroups
within nondemented ADRC participants, and to examine cognitive, biomarker,
and neuropathological 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 AD biomarker status and neuropathological 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, non-amnestic 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. Conclusions: We identified subtypes of MCI and CN with
differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and
neuropathological 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 neuropathological
signatures. Findings indicate that data-driven algorithms enhance
diagnostic sensitivity relative to consensus diagnosis for identifying
older adults at risk for cognitive decline.