Putative Survival Advantages in Young Apolipoprotein ɛ4 Carriers are Associated with Increased Neural Stress

Abstract

Inheritance of a single copy of the apolipoprotein E (APOE) 4 allele increases risk of Alzheimer's disease (AD) by 3-4-fold, with homozygosity associated with a 12-16-fold increase in risk, relative to 3 allele homozygosity. There is a decreased risk associated with the APOE 2 allele. The pathological consequence of APOE genotype has led to intense efforts to understand the mechanistic basis of the interplay between APOE status and loss of synapses. Numerous 4 allele-related associations have been reported with the potential relevance of these associations to the pathogenesis of AD unknown at this time. In primarily young subjects, we have reviewed a representative body of literature on 4 allele-associations related to the following: cardiovascular responses; impacts on reproduction and fetal development; co-morbidities; resistance to infectious disease; responses to head injury; biochemical differences possibly related to neural stress; and brain structure-function differences. In addition, the literature on the association between the 4 allele and cognitive performance has been reviewed comprehensively. The weight-of-the-evidence supports the hypothesis that possession of the ancestral 4 allele in youth is associated with improved fitness during fetal development, infancy, and youth relative to the more recently appearing 3 allele, at the expense of decreased fitness in old age, which is substantially improved by the 3 allele. However, possession of the 4 allele is also associated with higher levels of synaptic macromolecular turnover, which likely stresses basic cellular neuroplasticity mechanisms. Clinical trials of potential AD therapeutics should consider APOE status as an enrollment criterion. conceptualization of AD pathology dates from 1968 when Blessed et al. showed in elderly individuals that the NFTs correlated with the severity of the dementia, though the neuritic plaques, which contain cerebral amyloid-␤ (A␤), did not [2]. A major advance in understanding AD pathology was the demonstration that AD pathology predominantly affects the posterior-temporal, inferior parietal, posterior cingulate, and medial temporal region [3], with a characteristic pattern of progression beginning in the entorhinal cortex involving neurofibrillary (NF)

Differential Associations of Apolipoprotein E ε4 Genotype With Attentional Abilities Across the Life Span of Individuals With Down Syndrome

“…21 With respect to plasticity, in particular, it has been suggested that possession of the ε4 allele is associated with higher levels of synaptic macromolecular turnover, which may facilitate early development but also may stress basic cellular neuroplasticity mechanisms. 8 This would explain the improved early performance at the expense of a decreased performance during aging. 22…”

“…7,8 However, it is unclear what role APOE plays across the life span of an individual with DS, given that DS is associated with both intellectual disability in early life and an ultra-high risk for AD in later life. 1 The APOE gene plays a central role in the metabolism of lipids, 8 the principal components of myelin, and myelination is a crucial process in white matter development. 5,9 The early development of white matter pathways has been associated with faster reaction times in an attentional eye-tracking task, the gap-overlap task.…”

Seizures and early onset dementia: D2HGA1 inborn error of metabolism in adults

“…In addition, there are reports showing that APOE4 genotype may improve neuronal performance and survival during fetal development, infancy, and youth at the expense of decreased capacity in old age. 9 Dementia has not been described as a symptom of D2HGA1, perhaps because the patients described so far have not lived long enough, no formal natural history studies have been carried out for D2HGA1 or because the diagnosis of dementia is difficult in patients with ID. This report serves to shed light on the importance of a multidisciplinary approach to patients with unclear diagnosis, the importance of updated family histories, genetic investigations, and expanding the differential diagnosis to include inborn errors of metabolism in adults.…”

A multi-level developmental approach to exploring individual differences in Down syndrome: genes, brain, behaviour, and environment

“…This is because it has been identified as a genetic risk factor for AD in the general population ( Kim et al, 2009 ; Ritchie et al, 2019 ). The ε4 allele is an AD risk factor, the ε3 allele neutral, and the ε2 allele is protective; one copy of the ε4 allele increases risk of AD by 3-4-fold, two copies of ε4 by 12-16-fold, relative to possessing two copies of the ε3 allele, while there is a decreased risk associated with the ε2 allele ( Smith et al, 2019 ). The risk factor potentially operates via the effect of APOE on amyloid-β metabolism.…”

“… Dean et al (2014) compared magnetic resonance imaging measurements of white matter myelin water fraction and grey matter volume in healthy infant carriers and non-carriers of the ε4 allele between 2 and 25 months, and found decreased rate of growth in myelin in mid and posterior brain regions, in areas preferentially affected by AD in adulthood. Smith, Ashford and Perfetti (2019) suggest that possession of the ε4 allele is associated with higher levels of synaptic macromolecular turnover, which may produce greater early plasticity but also stress basic cellular neuroplasticity mechanisms. For both APP and APOE , then, there are links between development and pathological ageing.…”