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.
Keywords: Apolipoprotein E genotype, cognitive decline, episodic memory, longitudinal follow-up, mild cognitive impairment,
preclinical Alzheimer’s disease.
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