Date Published: January 31, 2019
Publisher: Impact Journals
Author(s): Diego Iacono, Gloria C. Feltis.
The central nervous system (CNS) is the cellular substrate for the integration of complex, dynamic, constant, and simultaneous interactions among endogenous and exogenous stimuli across the entire human lifespan. Numerous studies on aging-related brain diseases show that some genes identified as risk factors for some of the most common neurodegenerative diseases – such as the allele 4 of APOE gene (APOE4) for Alzheimer’s disease (AD) – have a much earlier neuro-anatomical and neuro-physiological impact. The impact of APOE polymorphism appears in fact to start as early as youth and early-adult life. Intriguingly, though, those same genes associated with aging-related brain diseases seem to influence different aspects of the brain functioning much earlier actually, that is, even from the neonatal periods and earlier. The APOE4, an allele classically associated with later-life neurodegenerative disorders as AD, seems in fact to exert a series of very early effects on phenomena of neuroplasticity and synaptogenesis that begin from the earliest periods of life such as the fetal ones.
Some genes identified as risk factors for aging-related neurodegenerative diseases – such as the allele 4 of Apolipoprotein E gene (APOE4) for Alzheimer’s disease (AD) – can have an early impact on different neuronal and non-neuronal features of the human brain, even starting from the perinatal periods or earlier. The possible early influence of APOE polymorphism on various cognitive and non-cognitive aspects through the entire human lifespan [1–8] poses the biological rationale for a wider re-consideration on how identical genes – for example, the ones identified as risk factors for aging-related diseases – could differently interact with other genes and environmental factors from the beginning of the human life until the advanced or extreme age.
In humans, the apolipoproteins E (ApoE2, ApoE3 and ApoE4) are molecules expressed in peripheral tissues (liver, spleen, kidneys, and macrophages) [32,33] and within the CNS . ApoE is an essential apolipoprotein for the catabolism of triglyceride-rich lipoprotein constituents and it is found in chylomicron, low- and very low-density lipoproteins (LDLs, VLDLs) . While liver and macrophages are the primary peripheral tissues where ApoE is produced, astrocytes are the main, and apparently the only cells within the CNS, that produce ApoE. Functionally, in the peripheral tissues, ApoE is part of cholesterol metabolism, while in the CNS it has been recognized as the principal carrier of cholesterol . ApoE transfers cholesterol to neurons and represents an essential molecule for neuronal growth, synaptic plasticity, and membrane reparative processes . The transfer of ApoE (cholesterol) to neurons occurs through the interaction of ApoE receptors . These receptors such as LDLR, VLDLR, ApoER2, and LRP1 receptors belong to the low-density lipoprotein receptor gene family . While the different chemical differences across the three isoforms of ApoE proteins started to be lately better defined , their different roles and effects in each cellular type remain to be completely understood yet [41,42].
ApoE, the protein, is codified by a gene localized on the long arm (“q” arm) of the chromosome 19 in the sub-band 32 of region 13 (19q13.32): APOE gene (APOE). The APOE has three alleles (genetic polymorphism): APOEpsilon2 (APOE2), APOEpsilon3 (APOE3), and APOEpsilon4 (APOE4). Each allele codifies to corresponding protein isoforms (ApoE2, ApoE3, ApoE4) that differ in amino acid sequence at the residue 112 (also called “site A”) and 158 (also called “site B”). Specifically, APOE2, APOE3, APOE4 (the alleles) codify respectively for ApoE2, ApoE3, ApoE4 (the proteins), which at the position 112 and 158 of their amino acidic sequence, contain respectively cysteine/ cysteine, cysteine/arginine, and arginine/arginine . These amino acid differences in the primary sequence of each ApoE protein determine a different number of charges (0, 1+, 2+) and account for their variant tertiary and quaternary conformations and electrophoretic differences . Four individual mutations give electrophoretically separated bands at the E2 position. Using the isoelectric focusing techniques  at least four different bands (corresponding to different ApoE2 conformational status) have been identified: E2 (arg158-to-cys) , E2 (lys146-to-gln) , E2 (arg145-to-cys), and E2-Christchurch (arg136-to-ser) . E2 (arg158-to-cys) is the most common of all four. In general, these “minimal” physical-chemical differences among ApoE proteins determine massive metabolic and structural consequences at tissue and metabolic level, especially within the human CNS [49,50].
In the general population, the distribution of APOE alleles can vary across different ethnic groups . These variations seem to be related to different non-genetic factors such as geographical latitude , local temperature and altitude, metabolic rate , hypoxia , “local” availability of lipophilic nutrients , climate  and others [57–60].
APOE began to appear as one of the best examples of genetic “antagonistic pleiotropy” (AP), a concept applicable to human traits and diseases, and to human cognition, neurodegenerative diseases, and brain diseases in general [67–71]. AP is defined as a genetic phenomenon existing when a gene can control for more than one trait (pleiotropy) with at least one possible trait beneficial and another detrimental (antagonistic) to the fitness of that same organism [72,73]. Once considered a rare genetic phenomenon, AP seems rather to be a much more frequent event, especially when considering human diseases , and in particular aging-related diseases and human longevity [75–77]. Among the APOE polymorphism-associated traits that appear to have AP characteristics are included the different biochemical consequences that ApoE2, ApoE3, ApoE4 proteins have on the metabolism of cholesterol, which have important implications, among others, on the metabolism of β-amyloid and synaptogenesis resistance in younger vs. aged mammalians, and could so explain the “paradoxical” beneficial effects of APOE4 on specific cognitive skills (e.g. verbal memory in schizophrenic patients , memory performance , and attention in young ), and the observation that APOE4 is an advantageous factor on survival and infertility in infectious environments [81,82], or that APOE alleles are associated with conscientiousness personality-trait in relationship to gray matter volume  and greater cortical connectivity . Figure 1 shows graphs describing the antagonistic pleiotropy concept applied to APOE polymorphism.
In general, APOE4 and its association with different measurable clinical variables such as dementia severity , neuropsychological scores , pathology burdens , cortical morphometry , morphometric-MRI [87,88], functional-MRI [89–91], electroencephalographic (EEG) [92,93] and magnetoencephalographic (MEG) signals , evoked potentials (EPs) changes [95,96], and other methods  has been investigated much more extensively than APOE2 [98–100]. In fact, studies focusing on APOE2 and its association to different clinical and subclinical parameters and possible molecular mechanisms of brain protection have been historically, less numerous than investigations comparing APOE4 vs. APOE3 for example. Furthermore, although APOE4 and APOE2 appear to have divergent effects on cognitive outcomes during aging, their corresponding protective or deleterious effects on other periods or conditions of life as brain development, birth prematurity, infancy, childhood cognitive and behavioral outcomes, as well as early-adult and mid-adult life predisposition for neurodegeneration have been generally much less investigated.
As described earlier in this review, only few studies have focused on the relative impact, including possible molecular mechanisms, of APOE4 vs. APOE2 in terms of different cognitive outcomes during normal or cognitively successful aging [228–231]. Those few studies that have attempted to verify the possible associations between cognitively normal older subjects and APOE polymorphism have shown that the protective effect of APOE2 is not directly associated with mechanisms linked, for example, to the extracellular β-amyloid accumulation into the brain or to the alterations of synaptic and neuroinflammatory levels in the CNS [232,233]. These latter observations are of special interest since they could open other and different views on the possible protective mechanisms of APOE2 independent on the “classic” AD pathology [234,235]. These more recent findings allow hypothesizing that the protective effects of APOE2 on the brain and its functions are intrinsic to the molecular features of APOE alleles and its protein products. In fact, the beneficial effects of APOE2 later in life can be only partially, or indirectly, related to the reduction of those pathologic factors currently considered as the “pathogenetic” causes of AD: extracellular accumulation of β-amyloid pathology, hyperphosphorylated-tau formation and spreading, increased levels of neuroinflammation and synaptic loss [236,237]. Therefore, these more recent findings imply that also other factors linked to the intrinsic molecular advantage of APOE2 need to be taken in account [228,238,239]. However, the new molecular aspects of APOE2 need future confirmation by analyzing data from very large prospective studies aiming to measure the real effect of APOE2 protein in a large multi-factorial statistical model that would include both biological (genetic) and non-biological (environmental) factors [240,241]. These studies should include human brain donations to increase the chance to quantifying ratios between residual (normal/still-functional) and pathologic tissues (dysfunctional neuronal or non-neuronal) that could directly derive from the action of APOE2 vs. APOE4 on the neural tissue through probably its biochemical interaction with cholesterol metabolism. Therefore, it could be possible to hypothesize that the APOE2-related action on the cholesterol metabolism would be capable to delay the cognitive decline during normal aging by specific molecular mechanisms that could be modulated using pharmacological compounds or non-pharmacological treatments, or alternatively, offer the opportunity to potentiate their beneficial action in a more preventive or protective manner. Unfortunately, the specific APOE2 molecular mechanisms are currently not completely known . Nonetheless, some molecular mechanisms have been proposed based on new and unexpected metabolic links between different biochemical pathways. For example, new possible links between homeostatic pathways of iron and lipids metabolism  or between APOE2 and disease-onset of other mutations through the interaction of APOE2 and genes involved in cellular proliferation, protein degradation, apoptotic and immune dysregulation processes has been shown . Moreover, differential phenomena of neuroplasticity as based on APOE4 vs. APOE3 have been proposed . Furthermore, as for possible differences across the three APOE proteins, recent pilot investigations started to show that APOE genotypes is associated with different plasmatic levels of APOE2 vs. APOE3 and APOE4 proteins as hourly measured in human subjects . These newer biochemical findings on APOE have been made possible by recent methodological advancement especially those based on mass spectrometry  and highly complex techniques .
APOE2 in older subjects, even in the presence of high levels AD pathology and clinically silent dementia, have shown a significant association with higher language skills acquired early in life . Furthermore, recently, MRI findings showed that specific spectroscopy signals are associated with cognitive and language development at term-equivalent period in some of the identical brain areas (e.g. hippocampus) that are later often affected by aging-related diseases such as AD [250,251]. However, it is not known, yet, if these imaging findings are also directly linked to APOE or to other genetic polymorphisms. Nonetheless, it is highly possible that language skills, as well as other higher cognitive human functions, could be connected to more specific gene-environmental interactions during either in-utero life and during the very first months or years of life as based on a cluster of genes, including APOE, whose function or dysfunction, directly predispose an individual to a higher risk of neurological and psychiatric risk later in life due to the very early impact of those gene-environmental interactions on specific brain structures and functions “already set up for” at birth or earlier. These early gene-environmental neurobiological phenomena could predispose to specific types of neurophenotypes later in life during the youth, middle-age or aging of that individual .
This necessarily succinct review focusing on the possible types of impact of APOE polymorphism on human brain structures, cerebral functions, and brain illnesses across different ages in normal and pathological conditions of the brain and possible modulatory effects of specific personality traits (e.g. conscientiousness, neuroticism) suggests that future larger longitudinal investigations would need to consider numerous genetic and environmental variables to fully identify the molecular mechanisms of APOE as well as the interactions between the APOE with other genes and other aspects such as environmental imprinting (nutritional, educational, behavioral, etc.) during the early phase of life [257,258].
Although this review aimed to describe the findings about different functional brain outcomes, in normal and pathological conditions of the brain, associated or influenced by the APOE allelic polymorphism in humans, we also briefly describe some of the possible APOE-molecular and non-molecular traits that could be associated with the proposed AP features of APOE. There is a plethora of animal studies (experiments employing transgenic animals, mainly rodents) that define various genetic (APOE), metabolic (ApoE proteins), and ApoE receptors (intracellular functional consequences) molecular aspects that would be impossible to describe here in an exhaustive way. For this reason, we preferred to focus on those possible APOE-traits that seem to have some antagonistic pleiotropic (AP) features across the lifespan in mammalians.