Research on Alzheimer’s disease has taught us that the disease is complex. There is little overall understanding of how Alzheimer’s disease starts and then develops. Despite this lack of understanding, once we observe the decline in cognitive capacity there seems to be a fast and unrelenting pattern of diminished capacity in the patient. The symptoms are real regardless of our lack of knowledge of its causes and development. Very slowly we are moving away from the shock and awe of the disease to looking at patterns and associations.
Although there is closer correlation of Alzheimer’s disease among twins that share the same genetic makeup—monozygotic/identical in contrast to dizygotic twins—there is nevertheless still a difference among identical twins. This variance indicates that non-genetic factors are playing a role in the expression of Alzheimer’s disease. Aging by itself is associated with epigenetic influences, with younger twins being more epigenetically similar than older twins. Such non-genetic factors might also explain why women are more prone to Alzheimer’s disease then men suggesting an important role for external factors.
The interconnections that are being made today across diseases—e.g. amyloidosis—and the connection between genes and geography—e.g. epigenetics—all point towards the need for a unified theory of Alzheimer’s disease. There are emerging attempts to do this through a public health approach.[1] But this needs to be broadened further and some of the processes involved in promoting the disease need to be further elucidated. The main theme emerging from the periphery of research is a renewed interest in the importance of emotions in the maintenance of diseases. Although the main reason for this interest might be the observation that emotions have biological repercussions, nevertheless this points to a pivotal change in perception of how we view diseases. We are looking at diseases as involving broader facets—e.g. emotions—as well as longer periods—e.g. development.
The “Barker Hypothesis” complements this view, that early childhood trauma--initial focusing on low birth weight—starts a cascade of negative events that are only expressed in adulthood or late adulthood. [2] The realization that chronic diseases, including Alzheimer’s disease, have developmental origins, has started to attract a life-course approach. Diane Miller and James O'Callaghan with the CDC-National Institute for Occupational Safety and Health explored this hypothesis for Alzheimer’s disease identifying certain childhood conditions that can contribute to Alzheimer’s disease. [3] Some researchers are also examining specific mechanisms for this chronic disease process. Debomoy K. Lahiri with Indiana University School of Medicine and his colleagues have proposed an epigenetic model of chronic disease. In this model, environmental agents (e.g., heavy metals), intrinsic factors (e.g., inflammatory cytokines), and dietary factors (e.g., folate and cholesterol) could alter gene expression through epigenetic influences. These changes that occur during childhood will not be expressed until significantly later in life.[4]
There are other factors that change epigenetics. Adverse childhood experiences—economic hardship, sexual and physical abuse, divorce, homelessness, hunger—initiate a cascade of risk behaviors that are associated with enduring changes in the body and brain—nervous, endocrine, and immune systems. [5] And adverse childhood experiences are common, with rates between 5–35% for physical abuse, 4–9% for severe emotional abuse,15–30% for sexual abuse in girls and 5–15% in boys, and 6–12% for neglect. In a 1997 study of over a thousand Californian elderly community residents the Australian epidemiologist John Lynch with Adelaide University and his colleagues found that self-reported cognitive function was lower than expected for those who had experienced sustained economic hardship, even after adjusting for age, sex, and co-morbidity. [6] Poverty, larger family size and urban residence are also associated with increased Alzheimer’s disease risk. [7]
Developmental considerations are important since the brain is an evolving structure and is more vulnerable at certain times than others. In brain development for example, we start to see grey matter loss at age seven which continues throughout older age. In contrast, glial cells in the white matter increase until approximately the mid-40 and peaking at around age 50. [8] Emotional trauma at these vulnerable stages have been shown to have long term effects on the developing brain. There is some support for this view from studies that report that people who engage in mentally stimulating activities at both younger and older ages are less likely to develop Alzheimer's disease.
These epigenetic changes can also be transmitted to the next generation. Some adverse childhood events continue to have a negative effect on later-life cognitive performance on some people. In contrast there are others who seem resilient to this negative effect. Such variance underlie the necessity to consider events individually and not as global test scores.[8] We are still a long way from undertaking experiments that exposes the true nature of Alzheimer’s disease, but at least we are starting to define the horizon. A horizon outside of the research cul de sac that has been defined by the federal government’s Alzheimer’s disease research guidelines.
References.
[1] Garrett MD, Valle R (2015) A New Public Health Paradigm for Alzheimer’s Disease Research. SOJ Neurol 2(1), 1-9.
http://www.symbiosisonlinepublishing.com/neurology/neurology17.pdf
[2] Barker DJP. The origins of the developmental origins theory. J Intern Med 2007;261:412-7. [3] Hall S. Small and thi
[3] Miller, D. B., & O'Callaghan, J. P. (2008). Do early-life insults contribute to the late-life development of Parkinson and Alzheimer diseases? Metabolism, 57, S44-S49.
[4] Maloney, B., Sambamurti, K., Zawia, N., & K Lahiri, D. (2012). Applying Epigenetics to Alzheimer's Disease via the Latent Early–life Associated Regulation (LEARn) Model. Current Alzheimer research, 9(5), 589-599.
[5] Danese A, McEwen BS. Adverse childhood experiences, allostasis, allostatic load, and age-related disease. Physiology & Behavior. 2012;106(1): 29-39. doi: 10.1016/j.physbeh.2011.08.019.
[6] Lynch JW, Kaplan GA, Shema SJ. Cumulative impact of sustained economic hardship on physical, cognitive, psychological, and social functioning. N Engl J Med. 1997;337(26):1889–1895.
[7] Moceri VM, Kukull WA, Emanuel I, et al. Early-life risk factors and the development of Alzheimer’s disease. Neurology. 2000;54(2):415–420.
[8] Sowell ER, Thompson PM, Toga AW. Mapping changes in the human cortex
throughout the span of life. Neuroscientist 2004; 10:372–392.
throughout the span of life. Neuroscientist 2004; 10:372–392.
[9] Ritchie K, Jaussent I, Stewart R, Dupuy AM, Courtet P, Malafosse A, et al. Adverse childhood environment and late-life cognitive functioning. International journal of geriatric psychiatry. 2011;26(5):503- 510. doi: 10.1002/gps.2553.
© USA Copyrighted 2016 Mario D. Garrett
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