Relationship of medial temporal lobe atrophy, APOE genotype, and cognitive reserve in preclinical Alzheimer's disease

Abstract

This study evaluated the utility of baseline and longitudinal MRI measures of medial temporal lobe brain regions collected when participants were cognitively normal and largely in middle age (mean age 57 years) to predict the time to onset of clinical symptoms associated with mild cognitive impairment (MCI). Furthermore, we examined whether the relationship between MRI measures and clinical symptom onset was modified by Apolipoprotein E (ApoE) genotype and level of cognitive reserve (CR). MRI scans and measures of CR were obtained at baseline from 245 participants who had been followed for up to 18 years (mean follow-up 11 years). A composite score based on reading, vocabulary, and years of education was used as an index of CR. Cox regression models showed that lower baseline volume of the right hippocampus and smaller baseline thickness of the right entorhinal cortex predicted the time to symptom onset independently of CR and ApoE-ε4 genotype, which also predicted the onset of symptoms. The atrophy rates of bilateral entorhinal cortex and amygdala volumes were also associated with time to symptom onset, independent of CR, ApoE genotype, and baseline volume. Only one measure, the left entorhinal cortex baseline volume, interacted with CR, such that smaller volumes predicted symptom onset only in individuals with lower CR. These results suggest that MRI measures of medial temporal atrophy, ApoE-ε4 genotype, and the protective effects of higher CR all predict the time to onset of symptoms associated with MCI in a largely independent, additive manner during the preclinical phase of AD.

Cognitive reserve and neuropsychiatric disorders

“…Longitudinal studies agree that indices of cognitive reserve do not modify the impact of the APOE e4 allele on increased risk of Alzheimer's disease [27,31,32] although one study found that cognitive reserve interacted to enhance the protective effect of the APOE e2 allele [32], an effect in a relative small number of participants that requires replication.…”

Entorhinal cortex: a good biomarker of mild cognitive impairment and mild Alzheimer’s disease

“…In another longitudinal study by Burggren et al (2011), the authors found that cortical thickness in EC was highly correlated with memory encoding and that subjects at greater risk of progressing to AD usually had a thinner EC. The atrophy rates in the volumes of the bilateral EC and amygdala were also associated with the time of symptom onset (Soldan et al, 2015). Patients with mild to moderate AD had a thinner EC than those with MCI (Shibuya et al, 2013;Velayudhan et al, 2013).…”

“…de Toledo-Morrell et al (2000) also found that the right EC may be more vulnerable to the aging process than the left because it was smaller in elderly subjects. A recent longitudinal study showed that a smaller thickness in the right EC predicted the onset of symptoms (Soldan et al, 2015). The measurement of changes in the right EC thus provides better predictive value compared with measurements of the left side for disease progression in individuals with early AD (de Toledo-Morrell et al, 2004).…”

Brain‐derived neurotropic factor polymorphisms, traumatic stress, mild traumatic brain injury, and combat exposure contribute to postdeployment traumatic stress

“…2012; Soldan et al. 2015). Outcome after TBI also is influenced by APOE genotype, in both humans and laboratory models, with risk for poor outcome in the order ε 4 >  ε 3 >  ε 2.…”