Cognitive changes preceding clinical symptom onset of mild cognitive impairment and relationship to ApoE genotype

Abstract

Background: This study had two goals (1) to evaluate changes in neuropsychological performance among cognitively normal individuals that might precede the onset of clinical symptoms, and (2) to examine the impact of Apolipoprotein E (ApoE) genotype on these changes.

Methods: Longitudinal neuropsychological, clinical assessments and consensus diagnoses were completed prospectively in 268 cognitively normal individuals. The mean duration of follow-up was 9.2 years (+/- 3.3). 208 participants remained normal and 60 developed cognitive decline, consistent with a diagnosis of MCI or dementia. Cox regression analyses were completed, for both baseline scores and rate of change in scores, in relation to time to onset of clinical symptoms. Analyses were completed both with and without ApoE-4 status included. Interactions with ApoE-4 status were also examined.

Results: Lower baseline test scores, as well as greater rate of change in test scores, were associated with time to onset of clinical symptoms (p<0.001). The mean time from baseline to onset of clinical symptoms was 6.15 (+/- 3.4) years. The presence of an ApoE-4 allele doubled the risk of progression. The rate of change in two of the test scores was significantly different in ApoE-4 carriers vs. non-carriers.

Conclusions: Cognitive performance declines prior to the onset of clinical symptoms that are a harbinger of a diagnosis of MCI. Cognitive changes in normal individuals who will subsequently decline may be observed at least 6.5 years prior to symptom onset. In addition, the risk of decline is doubled among individuals with an ApoE-4 allele.

Figure 1

Approximate timeline of BIOCARD study indicating the types of measurements obtained each year when the study was at the NIH and since the study has been at Johns Hopkins.

Figure 2

The survival plot for the Digit Symbol Test , based on the Cox regression model. This is one of the measures that was associated with time to onset of clinical symptoms (both with respect to the baseline score and the rate of change over time). The solid line represents scores below the median at baseline, and the dashed line represents scores above the median at baseline. The lines in black represent the scores of those who were ApoE-4 negative and the lines in red represent the scores of those who were ApoE-4 positive. The y axis represents the proportion of subjects who remained without symptoms. The plot starts at age 50 and is truncated at 75 years of age, since few participants remained unimpaired after this age, making the estimates unreliable after that age. Note that this survival curve is not age adjusted.