APOE ε4 Allele-associated Alzheimer's disease risk is consistent with increased lifetime exposure to a neurotoxic process

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

“…Given the ancestral primacy of the 4 allele, and the evolutionary trade-off of superior performance in youth versus additional years beyond historical lifespans, the abnormality of the 4 allele is somewhat a matter of perspective. If part of the APOE 4-associated neurotoxic susceptibility is based on pharmacokinetic rather than toxicant receptor interactions on a per mole basis [20], future therapies that slow down synaptic pruning might carefully consider differential effects based on APOE allele subtype. Current knowledge of potential sources of AD patient heterogeneity is lacking.…”

“…Previously, we hypothesized that apolipoprotein E (APOE) 4 allele-associated AD risk is consistent with increased lifetime exposure to a neurotoxic process [20]. Specifically, if the hippocampal neurons of two individuals possess the same susceptibility to an endogenous or exogenous stress factor, the neurons with the highest turnover of proteins, lipids, and other macromolecules might experience a larger integrated dose of detriment.…”

“…Specifically, if the hippocampal neurons of two individuals possess the same susceptibility to an endogenous or exogenous stress factor, the neurons with the highest turnover of proteins, lipids, and other macromolecules might experience a larger integrated dose of detriment. Small differences in pharmacokinetic effects might be amplified by the extremely long pre-symptomatic phase of AD, i.e., average age of presentation for a homozygous 4 is about 68 years of age [20]. Studies conducted across the age spectrum from infancy through senescence have suggested that APOE 4-positive status is associated with increased brain activity and macromolecule turnover in young healthy individuals, with the reverse extant in elderly subjects.…”

“…Studies conducted across the age spectrum from infancy through senescence have suggested that APOE 4-positive status is associated with increased brain activity and macromolecule turnover in young healthy individuals, with the reverse extant in elderly subjects. In the current study, we extend our analysis from the limited number of studies examined in Smith and Ashford [20] and attempt herein to comprehensively examine the literature on reported associations between clinical conditions, cognitive performance, and presence or absence of the 4 allele in otherwise healthy young subjects.…”

Treatment of Alzheimer’s Disease: Trazodone, Sleep, Serotonin, Norepinephrine, and Future Directions

“…Neuroplasticity, the basic function of the brain, requires a tremendous amount of energy, including the management of the energy for maneuvering the lipids associated with synapse creation and removal, which may be related to the actions of APOE. APOE appears to have an important role in neuroplasticity and the life-long susceptibility to AD, which may be related to the generation of toxic substances [66], and such toxic substances may be cleared during SWS. The question for the consideration of trazodone is whether this medication may be remedying the demise of serotonin and/or norepinephrine neurons or whether it is modulating the role of serotonin and/or norepinephrine in energy management and sleep modulation beneficially against the specific adverse effect of APOE genotype which predisposes to AD.…”