Alzheimer's disease (AD) is a progressive, age-related neurodegenerative disorder to which genetic mutations and risk factors contribute. Evidence is increasing that environmental and lifestyle-related factors, such as exercise, nutrition, education, and exposure to (early-life) stress modify the onset, incidence, and progression of AD. Here, we discuss recent preclinical findings on putative substrates that can explain or contribute to the effects of stress early in life on the risk of developing AD. We focus in particular on stress hormones, neural networks, synapses, mitochondria, nutrient and lipid metabolism, adult neurogenesis, engram cell ensembles, and neuroinflammation. We discuss the idea 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, amyloid-β 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 life also modify trajectories of cognitive decline and pathology in AD and how the substrates discussed translate to humans may help develop novel preventive and/or therapeutic strategies to mitigate the consequences of stressors early in life and increase resilience to developing dementia.