Impact of Apolipoprotein E gene polymorphism during normal and pathological conditions of the brain across the lifespan

Abstract

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.We reviewed some of the findings supporting the hypothesis that APOE polymorphism is an early modifier of various neurobiological aspects across the entire human lifespan - from the in-utero to the centenarian life - during both normal and pathological conditions of the brain.

Keywords: APOE-polymorphism; brain development and aging; environmental modifiers; in-utero and centenarian life; neural cells ratios.

Figure 1

The figure shows the theoretical antagonistic pleotropic (AP) effect of APOE gene across the entire human lifespan. The increased probability of early survival and normal cognition later in life are alternatively correlated with the presence of APOE4 and APOE2 allele. However, other genes and environmental factors through their mutual interactions from the in-utero life until centenarian age can probably potentiate the beneficial or detrimental effects on the onset and manifestations of brain diseases and, respectively, reduce or potentiate the genetic predisposition toward more negative or positive clinical outcomes during different periods of life.