Journal
CEREBRAL CORTEX
Volume 33, Issue 6, Pages 2748-2760Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhac239
Keywords
Alzheimer's disease; APOE-epsilon 4; resting-state connectivity; compensation
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The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-epsilon 4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the epsilon 4 allele. Yet, no study has assessed APOE-epsilon 4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. Our data indicate that APOE-epsilon 4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.
The investigation of resting-state functional connectivity (rsFC) in asymptomatic individuals at genetic risk for Alzheimer's disease (AD) enables discovering the earliest brain alterations in preclinical stages of the disease. The APOE-epsilon 4 variant is the major genetic risk factor for AD, and previous studies have reported rsFC abnormalities in carriers of the epsilon 4 allele. Yet, no study has assessed APOE-epsilon 4 gene-dose effects on rsFC measures, and only a few studies included measures of cognitive performance to aid a clinical interpretation. We assessed the impact of APOE-epsilon 4 on rsFC in a sample of 429 cognitively unimpaired individuals hosting a high number of epsilon 4 homozygotes (n = 58), which enabled testing different models of genetic penetrance. We used independent component analysis and found a reduced rsFC as a function of the APOE-epsilon 4 allelic load in the temporal default-mode and the medial temporal networks, while recessive effects were found in the extrastriate and limbic networks. Some of these results were replicated in a subsample with negative amyloid markers. Interaction with cognitive data suggests that such a network reorganization may support cognitive performance in the epsilon 4-homozygotes. Our data indicate that APOE-epsilon 4 shapes the functional architecture of the resting brain and favor the idea of a network-based functional compensation.
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