Genotypic effects of APOE-epsilon 4 on resting-state connectivity in cognitively intact individuals support functional brain 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.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Neurologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Neurology (hsv//eng)

Keyword

Alzheimer's disease

APOE-epsilon 4

resting-state connectivity

compensation

default-mode network

apolipoprotein-e genotype

alzheimers-disease

glucose-metabolism

genetic risk

apoe

age

dementia

carriers

burden

Neurosciences & Neurology

Publication and Content Type

ref (subject category)

art (subject category)