Volume 61, Number 1 - Winter 2010

 

By Sue Stephenson, MD

Dementia is the seventh leading cause of death in the United States. One in six women and one in 10 men who reach age 55 can expect to develop dementia in their lifetime. As other causes of mortality decrease, deaths attributed to dementia will increase without effective prevention or treatment. Yet if dementia onset can be delayed by even a few years, expected prevalence would decrease significantly. 

It is now commonly accepted that most dementia is mixed (vascular and Alzheimer’s),[1] and I will address this type here, though some of the information applies to other types as well. Alzheimer pathology and cerebrovascular disease often occur together, and they appear to potentiate each other.

Some dementia risks are genetic. The ApoE4 allele is the most well-known, and probably the most common gene associated with late-onset Alzheimer/mixed dementia. The mechanism could include vascular effects, as people with one or two ApoE4 alleles generally have increased serum total and LDL cholesterol, along with increased atherosclerosis and coronary heart disease risk. ApoE4 is also linked to beta-amyloid generation and clearance, neurofibrillary tangle formation, oxidative stress, apoptosis, dysfunction in lipid transport and homeostasis, modulation of intracellular signaling, and synaptic plasticity.[2] The ApoE4 allele plays a key role in maintaining and repairing neurons, and ApoE4 carriers show poor compensation of neuronal loss in stroke.[3]

Observational evidence suggests that ApoE4 carriers are more vulnerable to physical inactivity, saturated fat and alcohol intake, diabetes, hypertension, and B12 and folate deficiencies.[3] ApoE testing is available, though costly, and a study looking at lifestyle changes and cognitive impairment onset after being informed of ApoE genotype would be helpful.

Prevention or delay of dementia has the most promise at this time. Current medical treatment does not alter the course of the disease and may not be cost-effective.[4,5] A second-generation vaccine in stage III clinical trials offers some hope, although an initial vaccine trial ended after complications of autoimmune meningoencephalitis and death.[6]

Most studies of dementia risks are observational, making it difficult to separate cause and effect. Dementia pathology often appears many years before symptoms, and may actually begin as early as the third decade of life, making meaningful controlled trials especially difficult. See the “Dementia prevention” article by Coley et al for further discussion.[7]

Before discussing individual risk factors for dementia, I would like to introduce the allostatic load model. This model provides a useful framework for studying dementia because it includes the effects of various known risks and takes into account the complexity of physiologic functions. In other words, the model shows an appreciation of multiple factors affecting each other and the organism over time. In contrast, individual studies generally look at only one variable at a time, thereby failing to reflect the natural state of the organism or the actual process of the disease.[3] 

The term allostasis is defined as “activation of stress management systems in the brain result[ing] in a highly integrated repertoire of responses involving secretion of stress hormones, increases in heart rate and blood pressure, protective mobilization of nutrients, redirection of blood perfusion to the brain, and induction of vigilance and fear.”[8] Allostasis can be protective in the acute setting, but it can become pathogenic if chronically altered. 

The term allostatic load is defined as “the wear and tear on the body and brain caused by the use of allostasis, particularly when the mediators are dysregulated, i.e., not turned off when stress is over or not turned on adequately when they are needed.”[9] Perhaps dementia is the result of extreme and/or permanent allostatic load damage.

A recent article by Middleton and Yaffe summarizes the observational and controlled-trial evidence for dementia risk factors.[10] Unless otherwise specified, the evidence for the risk factors discussed below appears in that article. 

Vascular risk factors are probably additive. Mid- and late-life hypertension, diabetes, metabolic syndrome, and dyslipidemia increase dementia risk in observational studies. Insulin and cholesterol levels may have an effect on beta-amyloid deposition in the brain, though vascular risk factors could simply increase cerebrovascular disease.[11] Some studies have shown decreased risk of dementia with statin or antihypertensive treatment for dyslipidemia and hypertension respectively, but results have not been consistent. Increased risk of dementia has been associated with both high systolic and low diastolic blood pressure in late life, though studies are complicated by the trend for dementia patients to have lower blood pressure and to lose weight as long as 10 years before diagnosis.[12] A few studies have shown decreased dementia risk with antihypertensive pharmacologic treatment.

Obesity in mid-life (and possibly later in life) is associated with increased risk of dementia. This may simply be a marker for vascular risks, though there are other theoretical links, such as increased sympathetic activity and increased secretion of adipocyte hormones, bioactive metabolites, cytokines and growth factors.[12]

Smokers at mid-life have increased dementia risk, possibly through vascular mechanisms. Interestingly, one study of cognitively normal 55+ year olds showed ApoE4 carriers statistically unlikely to be affected by smoking over a seven-year period compared to non-ApoE4 smokers, who showed increased risk of cognitive impairment.[13]

Education and cognitive activities are associated with decreased dementia risk. Everyone’s cognitive function declines somewhat with age, but some trials show improved function or less rapid decline with cognitive intervention. Nonetheless, effects of cognitive training at older ages seem to be domain-specific and tend to decrease with time. People with higher levels of education or who are more cognitively active may have more cognitive reserve, which may explain why they tend to have fewer signs and symptoms of dementia with more severe neuropathologic findings. Education tends to lessen an individual’s decline on a test of general cognitive function when there is incident brain infarct.[14]

Higher levels of physical activity or cardiovascular fitness in mid or late life are associated with better cognitive function. Aerobic fitness interventions, many of them walking only, have been found to improve cognitive function in previously inactive individuals after as little as four months. Such interventions have also been found to reverse decay in prefrontal, lateral temporal and hippocampal regions, and to increase brain-derived neurotrophic factor.[9] 

Major depression has been associated with increased risk of dementia, and risk increases with increased cumulative length of depression. Depression in late life may be an early clinical sign of dementia, however, so separating it out as a risk factor in late life is difficult. Depression increases cortisol levels, which may directly damage the hippocampus and increase risk of dementia. In addition, beta-amyloid plaques may be deposited more readily in depressed individuals. Antidepressant treatment increases neurogenesis in the dentate gyrus portion of the hippocampus and improves cognition in older adults.[9]

Many observational studies associate better social support and social engagement with decreased risk of dementia, though decreased social engagement could be a prodromal sign of dementia, even as early as midlife.

Mediterranean diet and diets high in fatty fish have been associated with lower risk of dementia, and dietary and supplement fish oil may be somewhat effective for slowing cognitive decline.[15] Oxidative stress may contribute to Alzheimer pathology. Higher intake of vitamins E and C is associated with decreased risk of dementia, but not in clinical trials. A vegan, fat-free diet proposed by Esselstyn has dramatic positive effects on coronary arteries, and may affect the brain similarly.[16]

Stress involves two-way communication between the brain and other systems via the autonomic nervous system and endocrine mechanisms in a non-linear manner.[17] The brain undergoes structural and functional changes in relation to acute and chronic stresses and stressors, mostly in the hippocampus, amygdala, and prefrontal cortex. Stress also brings changes in the autonomic, neuroendocrine and immune systems. These changes “alter behavioral and physiologic responses including anxiety, aggression, mental flexibility, memory and cognitive processes.”[8]

Though no human prospective trials link chronic stress to dementia, supportive evidence does exist. Decreased hippocampal size has been reported in humans with chronic stress, PTSD, borderline personality disorder, poor glucose regulation, and depression.[17] In addition, decreased temporal lobe size and lower performance on some cognitive tests were found in airline attendants who regularly changed time zones.[18] Treatments including exercise, some medications, social support and behavioral therapy have been shown to change structure and functional activity in regions such as the hippocampus and prefrontal cortex.[9]

Adverse childhood experiences are strongly associated with many adult health problems, including coronary artery disease, chronic pulmonary disease, cancer, alcoholism, depression, drug abuse, physical inactivity and smoking. In animal models, prenatal and neonatal environmental factors alter allostatic mechanisms. These factors facilitate epigenetic changes of DNA methylation and histone modification of chromatin in response to environmental cues. DNA methylation similar to changes in animals was seen in brain autopsy material from people who had experienced childhood abuse, supporting the application of this model to humans.[8]

Cardiac surgery has been associated with cognitive impairment. Other factors that may be associated with cognitive impairment or dementia include traumatic brain injury in professional football players, vitamin D deficiency, non-cardiac major surgery, atrial fibrillation, obstructive sleep apnea, chronic sleep deprivation, chronic stress and anxiety, and possibly carotid stenosis.[9,19-24]

Evidence at this time points to a human brain that is vulnerable to stressors in early life. These stressors can change the way a person responds to stress throughout his or her lifetime, with potential increased risks for several major adult diseases, many of which are risk factors for dementia. The allostatic load model helps us see external stressors and physiologic consequences of some diseases in a larger perspective. I strongly suspect dementia is among diseases caused directly or indirectly by chronic heavy allostatic load.

Healthy lifestyle is paramount for dementia prevention, and people with personal resources may be able to increase activity, change nutritional habits and decrease personal stress upon receiving relevant information. We physicians must model healthy lifestyles ourselves, even as we inform patients about their risk factors and help to control them. 

In the larger picture, there is an urgent need for further study and an increase in dementia awareness. Our society needs to fund public programs that decrease risks for dementia by helping elders engage socially and by providing social support to vulnerable young families, enabling personal resiliency starting at the beginning of life.

1. Langa K, et al, “Mixed dementia,” JAMA, 292:2901-08 (2004).
2. Cedazo-Minguez A, et al, “Apolipoprotein E,” J Cell Mol Med, 5:254-266 (2001).
3. Kivipelto M, et al “Alzheimer’s disease,” J Nutrition, Health & Aging, 12:S89-S94 (2008).
4. Raina P, et al, “Effectiveness of cholinesterase inhibitors and memantine for treating dementia,” Ann Int Med, 148:379-397 (2008).
5. Qaseem A, et al, “Current pharmacologic treatment of dementia,” Ann Int Med, 148:370-378 (2008).
6. Schneeberger M, et al, “Development of affitope vaccines for Alzheimer’s disease,” J Nutrition, Health & Aging, 13:264-267 (2009).
7. Coley N, et al, “Dementia prevention,” Epid Rev, 30:35-66 (2008).
8. Schonkoff JP, et al, “Neuroscience, molecular biology, and the childhood roots of health disparities,” JAMA, 301:2252-59 (2009).
9. McEwen BS, “Physiology and neurobiology of stress and adaptation,” Physiol Rev, 87:873-904 (2007).
10. Middleton L, Yaffe K, “Promising strategies for the prevention of dementia,” Arch Neurol, 66:1212-15 (2009).
11. Pregelj P, “Involvement of cholesterol in the pathogenesis of Alzheimer’s disease,” Psychiatria Danubina, 20:162-167 (2008).
12. Gustafson D, “Adiposity indices and dementia,” Lancet Neurol, 5:713-720 (2002).
13. Reitz C, et al, “Relation between smoking and risk of dementia and Alzheimer disease,” Neurology, 69:998-1005 (2007).
14. Elkas JS, et al, “Education and the cognitive decline associated with MRI-defined brain infarct,” Neurology, 67:435-440 (2006).
15. Fotuhi M, et al, “Fish consumption, long chain omega-3 fatty acids and risk of cognitive decline for Alzheimer’s disease,” Nature & Clin Prac Neur, 5:140-152 (2009).
16. Esselstyn CB, Prevent and Reverse Heart Disease, Penguin (2008).
17. McEwen BS, “Brain is the central organ of stress and adaptation,” NeuroImage, 47:911-913 (2009).
18. Cho K, “Chronic jet lag produces temporal lobe atrophy and spatial cognitive deficits,” Nature Neuroscience, 4:567-568 (2001).
19. Guskiewicz KM, “Association between recurrent concussion and late-life cognitive impairment in retired professional football players,” Neurosurgery, 57:719-726 (2005).
20. Wilkins CH, “Vitamin D deficiency is associated with low mood and worse cognitive performance in older adults,” Am J Ger Psych, 14:1032-40 (2006).
21. Caza N, et al, “Effects of surgery and anesthesia on memory and cognition,” Progress in Brain Research, 169:409-422 (2008).
22. Puccio D, “Atrial fibrillation and mild cognitive impairment,” Minerva Cardioangiologica, 57:143-150 (2009).
23. Auger RR, et al, “Sleep and neurodegenerative disorders,” Continuum Lifelong Learning Neurol, 13:201-224 (2007).
24. Zoler ML, “Revascularization improves cognitive function,” Fam Prac News, 39;19:42 (2009).

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