Alzheimer's Disease Genetic Risk Factor APOE-ε4 Also Affects Normal Brain Function

Abstract

APOE-ε4 is the strongest genetic risk factor for Alzheimer’s disease (AD), and is associated with an increase in the levels of amyloid deposition and an early age of onset. Recent data demonstrate that AD pathological changes occur decades before clinical symptoms, raising questions about the precise onset of the disease. Now a convergence of approaches in mice and humans has demonstrated that APOE-ε4 affects normal brain function even very early in life in the absence of gross AD pathological changes. Normal mice expressing APOE4 have task-specific spatial learning deficits, as well as reduced NMDAR-dependent signaling and structural changes to presynaptic and postsynaptic compartments in neurons, particularly in hippocampal regions. Young humans possessing APOE-ε4 are more adept than APOE-ε4 negative individuals at some behavioral tasks, and functional magnetic resonance imaging has shown that inheritance of APOE-ε4 has specific effects on medial temporal brain activities. These findings suggest that inheritance of APOE-ε4 causes life long changes to the brain that may be related to the late risk of AD. Several possible mechanisms of how APOE-ε4 could affect brain neurochemistry, structure, and function are reviewed.

Transcriptional signatures of brain aging and Alzheimer’s disease: What are our rodent models telling us?

“…The Down’s cases shared moderate concordance with idiopathic AD, including a large block of downregulated genes, suggesting that genetic AD in humans shares more similarity with idiopathic cases than with mouse models. Alternatively, analysis of more recently developed animal models of late onset Alzheimer’s disease [45–48] that appreciate chronic age-related changes [49] may importantly shed light on molecular processes associated with the development of idiopathic AD.…”

Adverse Effects of the Apolipoprotein E ε4 Allele on Episodic Memory, Task Switching and Gray Matter Volume in Healthy Young Adults

“…Unlike studies in human beings, studies using mice consistently show that, at an early age, ApoE ε4 is associated with altered brain biochemistry, reduced dendritic spine density, structural changes to presynaptic and postsynaptic compartments in neurons, and deficits in behavior and memory (Di Battista et al, 2016). The inconsistent conclusions arising from human studies may relate to the numerous compounding factors in human studies along with methodological issues.…”

Exosome Production Is Key to Neuronal Endosomal Pathway Integrity in Neurodegenerative Diseases

“…Multiple mechanisms appear to drive the pathogenic effects of the APOE4 allele in the brain, including enhancing Aβ deposition while reducing Aβ clearance and degradation; modulating synaptic integrity; modulating cholesterol levels in the brain and the availability of cholesterol and other lipids to neurons; and inducing changes in reactive O 2 scavenging in the CNS Ma et al, 1994;Bales et al, 1997;Higgins et al, 1997;Haan et al, 1999;Holtzman et al, 2000;Shibata et al, 2000;Bu, 2009;Kim et al, 2009;Kolovou et al, 2009;Andrews-Zwilling et al, 2010;Verghese et al, 2011;Villemagne et al, 2011;Leung et al, 2012;Mahley and Huang, 2012;Andrews et al, 2013;Liu et al, 2013;Reinvang et al, 2013;Zlokovic, 2013;Rodriguez et al, 2014). In the absence of a dementia diagnosis, human APOE4-carriers still display structural and functional differences within regions of the hippocampus and cortex, and cognitive decline compared to age-matched non-carriers (Bookheimer and Burggren, 2009;Filippini et al, 2009;Olofsson et al, 2010;Sheline et al, 2010;Wisdom et al, 2011;Liu et al, 2013;Di Battista et al, 2016), and mouse models show cognitive deficits linked to APOE4 expression without AD pathology (Leung et al, 2012;Peng et al, 2017;East et al, 2018).…”