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Early Life Stress ELS rodent models have successfully demonstrated sequelae of maternal separation resulting in LOAD-analogous pathology, thereby supporting a role of insulin receptor signalling pertaining to GSK-3beta facilitated tau hyper-phosphorylation and amyloidogenic processing.
Further considered were the roles of autophagy impairment, neuroinflammation, and brain insulin resistance. For the meta-analytic evaluation, candidate gene loci were extracted from reviews of animal studies of LOAD pathophysiological mechanisms, of which 60 had no positive results in human LOAD association studies. Of the risk gene loci evaluated, there were 35 human reports on epigenomic modifications in terms of methylation or histone acetylation. Genomic association studies support close relations of both noradrenergic and glucocorticoid systems with LOAD.
Regarding epigenetic modifications, both methylation variability and de-acetylation were reported for LOAD. Unclear in epigenomic studies remains the role of noradrenergic signalling, previously demonstrated by neuropathological findings of childhood nucleus caeruleus degeneration for LOAD tauopathy. The last decade has brought about a profound reorganisation of knowledge on the age-related senile dementia of the Alzheimer type LOAD.
It has nowadays become broadly accepted that life stresses must play a mediatory role [ 1 ] in the complex genotype-environmental interaction which precedes clinical manifestation of the fatal Alzheimer endo-phenotype [ 2 ].
