A preclinical perspective on the enhanced vulnerability to Alzheimer's disease after early-life stress

Abstract

Stress experienced early in life (ES), in the form of childhood maltreatment, maternal neglect or trauma, enhances the risk for cognitive decline in later life. Several epidemiological studies have now shown that environmental and adult life style factors influence AD incidence or age-of-onset and early-life environmental conditions have attracted attention in this respect. There is now emerging interest in understanding whether ES impacts the risk to develop age-related neurodegenerative disorders, and their severity, such as in Alzheimer's disease (AD), which is characterized by cognitive decline and extensive (hippocampal) neuropathology. While this might be relevant for the identification of individuals at risk and preventive strategies, this topic and its possible underlying mechanisms have been poorly studied to date. In this review, we discuss the role of ES in modulating AD risk and progression, primarily from a preclinical perspective. We focus on the possible involvement of stress-related, neuro-inflammatory and metabolic factors in mediating ES-induced effects on later neuropathology and the associated impairments in neuroplasticity. The available studies suggest that the age of onset and progression of AD-related neuropathology and cognitive decline can be affected by ES, and may aggravate the progression of AD neuropathology. These relevant changes in AD pathology after ES exposure in animal models call for future clinical studies to elucidate whether stress exposure during the early-life period in humans modulates later vulnerability for AD.

Fig. 1

Proposed model of how exposure to early-life stress could modify Alzheimer's disease vulnerability. Early-life stress (ES) alters, either directly or through an enhanced sensitivity to later-life stress effects, neuroinflammatory, stress and metabolic regulation. Several potential candidate factors involved in such regulation have this far been identified to alter AD-related amyloid and tau pathological hallmarks and may therewith reduce neuroplasticity. These 3 systems can additionally impact neuroplasticity, irrespective of the development of AD neuropathology. Ultimately, the reduced neuroplasticity during this period may result in a lower cognitive reserve and finally in an earlier and possible more aggressive cognitive decline. These closely interrelated events may altogether determine AD vulnerability after exposure to stress in early-life.