How can early stress influence later Alzheimer risk? Possible mediators and underlying mechanisms.

Alzheimer's Disease is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that also environmental and lifestyle-related factors, like exercise, nutrition, education, and also exposure to (early life) stress modify the onset, incidence and progression of Alzheimer's Disease. We here discuss recent preclinical findings on putative substrates that can explain or contribute to effects of stress early in life on the risk to develop Alzheimer's Disease. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles and neuroinflammation. We discuss that stress-exposure early in life can alter these processes, either combined or in isolation, thereby reducing the capacity of the brain to resist deleterious consequences of for example β-amyloid accumulation thereby accelerating cognitive decline and progression of Alzheimer-related changes, in model systems of the disease. A better understanding of whether experiences early in human life also modify trajectories of cognitive decline and pathology in Alzheimer's Disease, and how the substrates discussed translate to the human situation may help to develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life, and increase resilience to develop dementia.