The Effects of Stressful Life Events on Alzheimer’s Disease Biomarkers, Neuroinflammation and Brain Integrity in Later Life: A Life Course Perspective

Abstract

AbstractBackgroundStress is associated with adverse health outcomes, but the pathways through which stressful life events affect brain health, and the age periods most vulnerable to these effects, are unknown. We investigated these questions in relation to Alzheimer’s disease (AD) pathophysiology and brain integrity in cognitively unimpaired participants at risk for AD.MethodIn this cross‐sectional cohort study, 1168 participants completed the 18‐item Elder’s Life Stress Inventory measuring the occurrence (and age at occurrence) of stressful life events. Of these, 393 participants had data available on AD biomarkers (cerebrospinal fluid [CSF] phosphorylated‐tau and amyloid‐beta1−42/amyloid‐beta1−40 ratio measured with Elecsys® assays and NeuroToolKit panel of robust prototype assays [Roche Diagnostics International Ltd, Rotkreuz, Switzerland], respectively) and neuroinflammation markers (CSF interleukin 6 [IL‐6], soluble TREM‐2 and glial fibrillary acidic protein measured with NeuroToolKit). In total, 830 had structural magnetic resonance imaging data available for amygdala and hippocampal volume, and grey matter volume/thickness for areas of the prefrontal cortex. The association of stressful events with AD biomarkers, neuroinflammation and brain integrity (adjusting for total intracranial volume) was examined using multiple regression analyses adjusting for sex, age and education. Associations of stressful events during early life (ages 0−25), early adulthood (26−40), middle adulthood (41−55) and late adulthood (≥56) were also examined. Analyses were stratified by sex and Apolipoprotein ε4 (APOE ε4)‐status.ResultParticipants’ age ranged between 47−76 and 62.5% were women. A higher number of stressful events during life‐course was associated with an increase in IL‐6 levels among APOE ε4‐carriers; with a decreased amyloid‐beta ratio among APOE ε4‐noncarriers; and with a reduction in caudal anterior cingulate cortex volume among women. A higher number of events during early adulthood was associated with higher phosphorylated‐tau levels and prefrontal brain integrity, and during middle adulthood was associated with decreased prefrontal brain integrity (Table 1. & 2.).ConclusionStress may affect later‐life brain health through multiple pathways, including neuroinflammation, amyloid‐beta and brain integrity, depending on APOE ε4‐carrier status and sex. Stressful events during early adulthood may promote phosphorylated‐tau in later‐life, while events during early/middle adulthood may have differential effects on brain integrity, suggesting potential windows for stress‐prevention strategies.