Distinct patterns of brain activity in young carriers of the APOE -ε4 allele

Abstract

The APOE 4 allele is a risk factor for late-life pathological changes that is also associated with anatomical and functional brain changes in middle-aged and elderly healthy subjects. We investigated structural and functional effects of the APOE polymorphism in 18 young healthy APOE 4-carriers and 18 matched noncarriers (age range: 20 -35 years). Brain activity was studied both at rest and during an encoding memory paradigm using blood oxygen level-dependent fMRI. Resting fMRI revealed increased ''default mode network'' (involving retrosplenial, medial temporal, and medial-prefrontal cortical areas) coactivation in 4-carriers relative to noncarriers. The encoding task produced greater hippocampal activation in 4-carriers relative to noncarriers. Neither result could be explained by differences in memory performance, brain morphology, or resting cerebral blood flow. The APOE 4 allele modulates brain function decades before any clinical or neurophysiological expression of neurodegenerative processes.hippocampus ͉ memory ͉ neuroimaging ͉ resting connectivity A polipoprotein E (apoE, protein; APOE, gene) is a very-lowdensity lipoprotein that removes cholesterol from the blood and carries it to the liver for processing (1). In the central nervous system, apoE has a key role in coordinating the mobilization and redistribution of cholesterol, phospholipids, and fatty acids, and it is implicated in mechanisms such as neuronal development, brain plasticity, and repair functions (2). The human APOE gene, which is encoded on chromosome 19, has 3 allelic variants ( 2, 3, and 4). The 4 allele has been associated with a higher risk of cardiovascular disease (3), both early-onset (4) and late-onset (5) Alzheimer's disease (AD), poor outcome from traumatic brain injury (6), and age-related cognitive impairment (7).Neuroimaging studies of the APOE polymorphism in healthy subjects have largely focused on gray matter (GM) alterations in middle or late life, particularly in brain regions associated with the greatest AD pathological findings. Even in asymptomatic subjects, hippocampal and frontotemporal GM reduction has been observed in APOE 4-carriers relative to noncarriers (8). Moreover, a reduction of resting glucose metabolism was reported in young and middle-aged cognitively normal APOE 4-carriers in brain regions known to be affected by AD, including the posterior cingulate, parietal, temporal, and prefrontal cortices (9-11). fMRI task-based studies (mainly investigating memory processes) have shown greater activation in middle-aged and elderly APOE 4-carriers relative to noncarriers (12-16). Although these studies suggest an influence of the APOE 4 allele on brain structure and metabolism, they do not make clear at what age these influences initially manifest. Furthermore, although differences in structure, resting metabolism, and function have each been reported in 4-carriers relative to noncarriers, it remains to be established to what extent these characteristics interact.Thus far, reports of structural and functional eff...

Functional brain network centrality is related to APOE genotype in cognitively normal elderly

“…The regions of changed centrality partially coincide with previous work that reported brain regions with default mode network (DMN)‐related changes in APOE‐ε4 carriers (Filippini et al., 2009), most markedly the precuneus. Those did not include the visual cortex as the statistical analyses were limited to changes inside the DMN.…”

“…Overall, the most frequently reported changes are weakened DMN connectivity in middle‐aged and older subjects (Goveas et al., 2013; Machulda et al., 2011; Reiman et al., 1996; Sheline et al., 2010; Wang et al., 2012) and, less frequently, increased DMN connectivity in young adults (Filippini et al., 2009; Fleisher et al., 2009). Our results demonstrate early visual effects in a population study with realistic proportions of carriers and noncarriers, which shows the applicability of functional measures in a community setting.…”

“…The “canonical” pattern of the DMN is the precuneus, superior lateral parietal lobes, and the ACC. When analyses are limited to the DMN regions, this is where the changes are found (Binnewijzend et al., 2012; Filippini et al., 2009). Analyses of AD‐related functional brain network differences associated with the DMN but not part of the DMN report changes in superior parietal and occipital regions (Agosta et al., 2012; Lee et al., 2016).…”

“…The high vulnerability of hubs for AD is also found in RS‐fMRI studies (Buckner et al., 2009; Qi et al., 2010). The default mode network (DMN) and other resting‐state networks, that is, regions with synchronized fMRI activity, have been studied as markers for AD progression (Binnewijzend et al., 2012; Filippini et al., 2009; Sheline et al., 2010). Functional brain connectivity changes in healthy adults are related to amyloid depositions (Hedden et al., 2009; Sperling et al., 2009), and carriers of the APOE‐ε4 allele show increased co‐activation with the DMN in young adults (Bookheimer et al., 2000; Filippini et al., 2009), indicating that functional connectivity is sensitive to AD‐related alterations of the brain.…”

Time related effects on functional brain connectivity after serotonergic and cholinergic neuromodulation

“…RS‐fMRI networks were thereafter extracted from each individual denoised RS‐fMRI dataset (12 subjects × 3 days × 6 scans = 216 datasets) applying a dual regression analysis [Beckmann et al, 2009; Filippini et al, 2009] based on 10 predefined standard network templates as used in our previous research [Klaassens et al, 2015]. Confound regressors of time series from white matter (measured from the center of the corpus callosum) and cerebrospinal fluid (measured from the center of lateral ventricles) were included in this analysis to account for non‐neuronal signal fluctuations [Birn, 2012].…”