Factors Predictive of Mild Cognitive Impairment in Healthy Individuals

Brain DNA
Brain DNA
Investigators sought to examine factors that influence a cognitively normal individual's risk for developing symptoms of mild cognitive impairment due to Alzheimer disease.

Education, age, APOE ε4, cerebrospinal fluid (CSF) phosphorylated tau (p-tau) and amyloid-β, right hippocampus volume, and right entorhinal cortex thickness are specific biomarkers that offer potential value for predicting the risk for development of symptoms of mild cognitive impairment (MCI) from Alzheimer disease (AD) at 5 years in a person with normal cognition, according to study findings published in Brain.

Investigators enrolled participants who were considered “cognitively normal,” a designation attributed to normal results obtained from an electrocardiogram, a physical and neurological examination, neuropsychological testing, and standard laboratory studies. In total, 224 participants without cognitive impairment were included in this trial. Specific biomarkers, including education, age, CSF p-tau, and CSF amyloid-β were studied to determine whether changes correlated with the progression to the onset of AD-related MCI symptoms at 5 years.

The first analysis demonstrated that there was a significant association between the onset of MCI symptoms and APOE ε4 (hazard ratio [HR] 1.862; 95% CI, 1.013-3.424; P =.045), right hippocampus volume (HR 0.728; 95% CI, 0.552-0.961; P =.025), right entorhinal cortex thickness (HR 0.668; 95% CI, 0.492-0.905; P =.009), and p-tau (HR 1.391; 95% CI, 1.069-1.812; P =.014).

An analysis of the full model demonstrated that age (HR 1.364; 95% CI, 1.014-1.834; P =.040), APOE ε4 (HR 1.904; 95% CI, 1.024-3.541; P =.042), Paired Associates Immediate Recall scores (HR 0.617; 95% CI, 0.469-0.812; P <.001), Digit Symbol Substitution (HR 0.454; 95% CI, 0.315-0.655; P <.001), CSF p-tau (HR 1.779; 95% CI, 1.355-2.336; P <.001), right hippocampus volume (HR 0.699; 95% CI, 0.526-0.930; P =.014), and right entorhinal cortex thickness (HR 0.594; 95% CI, 0.429-0.821; P =.002) held significant value for predicting the 5-year progression of onset of MCI symptoms in cognitively normal individuals (area under the curve 0.85; 95% CI, 0.807-0.913, model sensitivity = 0.804).

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In this study, investigators measured p-tau in CSF, which does not provide an accurate demonstration of its distribution in the brain. Additionally, participants in this study were generally well educated, had a family history of AD or dementia, and were mostly white, all variables that limit the generalizability of the findings.

The researchers commented that the incremental predictive benefit “generated by adding each of the domains consecutively to one another provides information that might be particularly useful for designing a screening strategy for a clinical trial” focused on patients with preclinical AD.


Albert M, Zhu Y, Moghekar A, et al. Predicting progression from normal cognition to mild cognitive impairment for individuals at 5 years [published online January 19, 2018]. Brain. doi:10.1093/brain/awx365