Early parental death and late-life dementia risk: findings from the Cache County Study

Abstract

SIR—Dementia is a major public health problem. Alzheimer's disease (AD) comprises the majority of dementia cases, and while the causes are still largely unknown, epidemiological studies are investigating a broad array of both genetic and environmental risk factors. Plausible aetiological mechanisms include lipid metabolism, inflammation and glucose regulation. Emerging biological evidence suggests that another potential mechanism for increased AD risk is neuronal death through the lifelong cumulative effect of stress reactivity and recovery [1]. Repeated stress causes damage to the CA3 region of the hippocampus via glucocorticoids and excitatory amino acid neurotransmitters released during and immediately after stress. Long-term, chronic stress over many years appears to continue the process and result in neuronal death in the hippocampus [2]. Physiological stress responses may also affect health by modulating the rate of cellular ageing via higher oxidative stress, lower telomerase activity and shorter telomere length, all indicators of cell longevity [3] with evidence that neurodegenerative changes may begin decades before clinical manifestation [4, 5]. These potential biological mechanisms, viewed from a lifecourse perspective, are consistent with observations that poor growth and development and adverse environmental conditions in early childhood are associated with increased disease risk in late life [6]. Socioeconomic adversity in the early years of life, specifically father's occupation of unskilled manual labourer, has been associated with a 2-fold increase in offspring AD risk [7] and faster rate of late-life cognitive decline in offspring [8]. Early-life parental death is an unexpected and traumatic event which usually poses the greatest adaptive challenges [9] thus introducing a host of potential stressors. These are not only economic but also psychosocial and may have a lifelong impact, especially for individuals with inadequate access to social and emotional resources. Though few studies directly address this question, in a sample of elderly Swedes, a 6-fold increase in dementia risk was demonstrated among participants experiencing a parental death before age 16 [10]. Although early-life adversity is not easily modifiable, establishing a clear link between psychosocial adversity and increased vulnerability to AD and other dementias will aid in the identification of at-risk individuals for more targeted interventions. Effective interventions may reduce the intensity of the body's physiological stress response and vulnerability to neurodegenerative diseases such as AD and other dementias. We report here analyses of the relationship between early parental death and dementia risk, in a large population-based epidemiological study. The relative effect of parental death at different stages in the lifecourse was examined. We hypothesised that experiencing early parental death would significantly increase dementia risk, with stronger effects posited for parental deaths occurring earlier in the course of development. Analyses were conducted before and after controlling for gender, age, education and apolipoprotein E (APOE) genotype.