There is a dramatic increase in the prevalence of dementia among veterans. Because of the aging of the veteran population and a high prevalence of dementia risk factors among veterans, it is estimated that there will be 423,000 new cases of Alzheimer’s disease and other dementias among military veterans in the decade ending in 2020 (Veitch et al., 2013). Over 25% of these new cases of dementia will be associated with specific military factors, especially traumatic brain (TBI) and post-traumatic stress disorder (PTSD). This paper reviews what is currently known about dementia risk factors in military veterans as compared to civilian populations.

Traumatic Brain Injury

Estimated prevalence of TBI
As a result of the high frequency of blast injuries and improved acute medical and surgical care in the field, veterans of recent wars have survived serious head injuries in greater numbers than ever before. In a survey of Operation Iraqi Freedom veterans from two brigades (Hoge et al. 2008), 15% had sustained a traumatic brain injury (TBI) either with loss of consciousness (LOS) or change in mental status. Using direct clinical evaluation of U.S. veterans of Iraq, Terrio et al. found 22.8% had suffered TBI, although most were mild (Terrio et al., 2009).

Persistence of Symptoms after Mild or Repetitive TBI
There are few data to inform us of how frequent persistent cognitive problems are after mild TBI (Chapman, et al., 2014). Data from a large Swedish data base of both military personnel and civilians of people sustaining TBI confirm that most head injuries are mild, but many people sustain multiple mild TBI over time, which may be far worse in terms of long term outcomes than single injuries (Nordstrom, et al., 2014). There is naturally less objective evidence of injury in mild TBI; no or only brief loss of consciousness, no edema or bleeding visible on neuroimaging, vague symptoms and varying levels of mood and cognitive symptoms. Yet, Lange et al. found that 20-48% of people with mild TBI experienced neuropsychiatric symptoms at least three months after the injury (Lange, et al., 2012). The symptoms included headache, dizziness, fatigue, irritability, insomnia, decreased concentration, memory impairment, and depressed mood.

Mechanism of Injury in TBI
Direct forces may cause tissue laceration, hemorrhage, and contusion. The opposite pole of the brain may also be damaged through impact with the bony skull as the brain moves within the cranium. Indirect damage occurs through acceleration and de-acceleration. G-forces may also injure the brain diffusely through shearing forces that stretch neurons and fragile blood vessels. Improvements in military and emergency medicine in the field saved the lives of thousands of soldiers who would have likely died in previous wars, leaving them to live with the persistent sequelae of severe head injuries. Tragically, these immediate effects of TBI are only the beginning for many individuals. There can be secondary effects of the initial injury that initiate processes of inflammation and cascading processes that lead to progressive neurodegeneration and dementia.

Progressive Dementia after TBI
Chronic Traumatic Encephalopathy (CTE) is the term often applied to the condition of progressive cognitive decline (dementia) seen in some individuals after both single and repetitive head injury. Three stages of CTE symptoms were initially described in boxers: Stage 1 with mood and perception disturbances; Stage 2 with more pronounced emotional lability, impulsivity, poor judgment, memory impairment, slowed thinking, and early neuromuscular symptoms (Parkinsonism); and Stage 3, with cognitive impairment severe enough to be called dementia, along with more pronounced Parkinsonism (tremor, muscle rigidity and slowing of gait and movement) (Corsellis et al., 1973).

In more recent work, investigators have described four stages with more detailed neuropathological findings: Stage 1 with initial disruption of delicate blood vessel networks in frontal cortex and early white matter (myelin) abnormalities in deep brain (subcortical) regions. Stage 1 damage may be accompanied by vague symptoms of headache and disturbances in attention and focus. Stage 2 shows more pronounced abnormalities in neuronal axons in temporal lobes, accompanied by more pronounced psychological changes. In Stage 3, there are “macroscopic” changes visible with normal neuroimaging studies (brain CT or MRI), such as global cortical atrophy and more obvious white matter disruption. Increasing and measurable neuropsychological deficits in memory, executive function, and visuospatial function are present along with increasing impulsivity and emotional lability. Finally, in Stage 4, progressive atrophy is seen on brain imaging along with more extreme cognitive and psychiatric disorders (McKee, et al., 2013). Not all the psychiatric symptoms are due to structural brain damage; PTSD is likely an important factor in the mood and anxiety symptoms of CTE (Chapman & Diaz-Arrastia, 2014).  TBI may also increase risk for stroke later in life, yet another risk factor for dementia (Burke, et al., 2013). Finally, TBI increases risk for depression, PTSD and brain deposition of beta-amyloid protein, all three of which are associated with increased risk of dementia, including dementia from Alzheimer’s disease (Byers & Yaffe, 2014).

Post-Traumatic Stress Disorder (PTSD)

PTSD and Dementia Risk
Post Traumatic Stress Disorder is a chronic and severe anxiety disorder that can occur in people exposed to serious injury, violence, or threat of death or violence (DSM 5, 2013). It is diagnosable in 22% of Iraq and Afghanistan veterans entering the VA health care system (Seal, et al., 2009). It is known that PTSD increases vascular risk factors, such as hypertension, hyperlipidemia, and diabetes in veterans (Cohen, et al., 2009). Dysregulated stress response with chronically activated sympathetic nervous system tone also increases cardiovascular risk, especially of hypertension, and therefore may accelerate cognitive aging (Levine, et al., 2014). Having been a prisoner of war (POW) appears to increase risk of developing dementia, but also increases risk of developing PTSD. Veterans with PTSD who were POWs may have an especially high risk of dementia in late life (Meziab et al., 2014).

Like depression, PTSD is associated with smaller volumes of the hippocampus, a brain structure that is key to processing memory and emotions. Also like depression, PTSD increases production of cortisol, a stress hormone that impairs normal repair and regeneration of the hippocampus. That may be the reason combat veterans with PTSD have smaller hippocampal volumes and memory deficits compared to age-matched controls (Bremmer, et al., 1995). However, in a classic cause versus effect debate, it is not yet clear whether people with PTSD, on average had smaller hippocampal volumes to begin with. That is, reduced hippocampal size occurring as part of normal childhood brain development may predispose one to PTSD, rather than the smaller hippocampal volumes being the result of damage and atrophy from chronic stress (Weiner, et al., 2013). There are also genetic risk factors for PTSD that also increase risk for dementia (Weiner, et al., 2013). Thus, although we know that PTSD is associated with increased risk factors for dementia, we don’t yet know for certain that PTSD increases risk for late life dementia, or whether PTSD and dementia just share common risk factors. Current research is aimed at answering these and other questions regarding the degree to which PTSD accelerates cognitive aging and specifically, whether it increases risk of developing AD (Weiner, et al., 2013).

Depression

Depression and Dementia
There is considerable evidence showing that depression increases the risk of dementia in older adults (Byers & Yaffe,2014). An increased risk of dementia in old age from both minor and major depression has been shown to be true for veterans, as well (Byers, et al., 2012). The relationship between depression and dementia is complex and understanding associated risks can be challenging, since depression can cause cognitive problems and dementia can cause depression (Byers& Yaffe,2014). Depression is common in people with dementia, occurring in about 20% of persons with Alzheimer’s disease and 50% of people with vascular dementia (Byers & Yaffe, 2014). However, depression itself increases risk for dementia. Major depression and Alzheimer’s disease have several underlying mechanisms in common. Depression, for example, increases risk for cardiovascular disease. Vascular disease, such as atherosclerosis and small strokes can cause cognitive impairment and dementia. Vascular disease can also affect mood, motivation, and behavior to create a syndrome of “vascular depression” that is one form of   mood disorder in older adults. Older veterans tend to have high rates of vascular disease and likely have higher rates of vascular depression. Depression itself increases risk for stroke and hence, dementia (Liebetrau, et al., 2008). Impaired blood flow to the frontal lobes and their connections to deeper (subcortical) brain regions are thought to contribute to some of the symptoms depression and dementia have in common: impaired executive function, cognitive slowing, motor slowing, and resistance to antidepressant treatment (Alexopoulos, 2006).

The Syndrome of “Pseudodementia”
The term “pseudodementia” has been used to refer to the syndrome of depression-caused cognitive impairment. The term is commonly used by clinicians when cognitive impairment is attributed to depression but appears much like the dementia of Alzheimer’s disease (AD). Some may argue that there is nothing at all “pseudo” about the cognitive impairment of depression, since it can be as debilitating as neurodegenerative dementia and may better be referred to as “dementia of depression”. In fact, dementia of depression may represent an early phase of a degenerative process such as AD, even though the cognitive impairment does improve as the depression lifts. But while depressed, older adults may experience many of the same symptoms seen in persons with AD, vascular dementia and other old age dementias: impaired attention, working memory, processing speed, and dysfunction in activities of daily living. (Steffens DC and Potter GG 2008) Whether or not the depression simply “unmasks” the incipient dementia or accelerates its development through shared mechanisms is uncertain. (Byers AM et al. 2012)

Potential Mechanisms Linking Depression and Dementia in Veterans
Depression increases the output of the stress-related hormone, cortisol, which impairs the regenerative capacity of the hippocampus. This is thought to be one factor in the hippocampal atrophy seen in people with histories of severe depression. (O’Brien et al. 2004; Videbach & Ravnkilde, 2004) The hippocampus is essential for new learning and memory and hippocampal atrophy is associated with impaired memory and ultimately with developing dementia. (Byers & Yaffe, 2014) A history of depression has been found to increase density of the microscopic elements in the brain that define the presence of Alzheimer’s disease (neurofibuliatory tangles and amyloid plaques). (Rapp MA et al. 2006) Increased inflammation in the brain of depressed people has been documented and is thought to contribute to the neuronal damage that accelerates cognitive decline. (Maes et al., 2009) Finally, depression appears to decrease the production of brain chemicals (“neurotrophic factors”) that are necessary to maintain brain health, memory and learning (“neuroplasticity”) (Byers & Yaffe, 2014).

We’ve already discussed the relationship of TBI and dementia, but TBI also increases risk for depression, thereby increasing dementia risk by another factor. Depression appears to increase the cognitive impairment of veterans who have suffered TBI (Vasterling et al., 2012).

Health-Related Risk Factors
In a study of veterans receiving care in the VA system, 16% of patients had diabetes and 37% had high blood pressure. (Yu et al., 2003). Between 25 and 36% veterans have high cholesterol or triglycerides (Richlie et al., 1991). These chronic health conditions increase risk for both vascular dementia and Alzheimer’s disease later in life (Yaffe et al., 2014). High blood pressure through the middle age years may be particularly risky for more rapid cognitive decline in later years (Sharp et al., 2011; Power et al., 2011). High cholesterol levels increase risk for heart disease and stroke, but may also accelerate the development of dementia from Alzheimer’s disease (Shepardson et al., 2011).

Adult onset diabetes (Type II), which is increasing in prevalence, has long been known to increase dementia risk, including dementia from both stroke and Alzheimer’s disease (Ott et al., 1996; Profenno et al., 2010). The risk may even be greater in those treated with insulin: poor diabetes control is typically associated with elevated blood sugars, but episodes of low blood sugar (hypoglycemia) from excessive insulin dosing may also lead to cognitive decline (Yaffe et al., 2012; Fox & Kilvert, 2014).

Diabetes risk is increased in obese individuals, and fat tissue itself may increase risk of dementia because of the secretion of pro-inflammatory proteins that accelerate brain aging (Zeki & Hazzouri, 2012). Similar to the general population in the US, more than half of veterans are overweight and one-quarter meet criteria for obesity (body mass index ≥ 30) (Almond et al., 2008).

A significant minority of veterans (25%) have several of these cardiovascular and dementia risk factors, a combined disorder called “metabolic syndrome” (Keane et al., 2009), which is also thought to accelerate cognitive decline (Misiak et al., 2012). The prevalence of cardiovascular risk factors and metabolic syndrome may be especially high in veterans with mental health disorders, such as depression and PTSD (Yaffe et al., 2014).

Health-Promoting Lifestyle
Several health-promoting habits have been associated with reduced dementia risk. Physical activity, a healthy diet, social contact, adequate sleep, minimal or moderate alcohol intake, and minimal tobacco use have all been shown to reduce risk of dementia later in life (Yaffe et al., 2014).Veterans without mental health problems generally do as well (or as poorly) as the general civilian population with regard to lifestyle habits that promote healthy brain aging, but that still means that large numbers of veterans lead sedentary lives, eat diets rich in animal fats and high glycemic foods and deficient in antioxidants and anti-inflammatory nutrients (e.g. omega-3 fatty acids), are socially isolated, suffer sleep disorders, and drink and smoke too much.

Providing Services for Veterans at Risk for Dementia
Veterans with histories of TBI, depression and PTSD, especially those over 60, should be routinely screened for cognitive impairment and declines in activities of daily living. They should receive counseling and support in lifestyle changes that may reduce their risk of developing dementia. Theoretical projections of the effects of increased physical activity and reductions in other cardiovascular and cognitive risk factors on dementia incidence suggest that such efforts may prevent many cases (25%) of dementia in the future (Barnes & Yaffe, 2011). These theoretical estimates are being tested in programs that promote healthy lifestyles in both veteran and non-veteran populations to determine impact on cardiac and dementia risk (Yaffe, 2014). Once cognitive impairment develops, veterans need expert assessment for accurate diagnosis and multidisciplinary interventions to keep them safe and reduce excessive disability from medications and co-morbid health conditions. Active case management has been found to reduce caregiver stress and patient readmission to hospital (Robert Woods Johnson Foundation Report, 2012). Treating symptoms related to dementia in veterans with co-morbid TBI, PTSD and depression can be especially challenging and requires rapid response and coordination among discipline within the medical and social service communities.

Written by: Clifford M. Singer, MD

Leave a Comment