Assessing Risk Factors for Cognitive Decline and Dementia

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Age and genetics are the best-known risk factors for Alzheimer’s disease. While these factors are beyond our control, we may be able to influence other risk factors involved in age-related cognitive decline and dementia. Scientists are exploring whether or not exercise and diet or other lifestyle choices, and certain medical conditions, including mental health conditions, can influence risk for cognitive decline or dementia.

For instance, recent research has examined the possible role of depression in the risk for age-related cognitive decline. Scientists are also continuing to study the possibility that engagement in intellectually stimulating activities throughout the lifespan can help stave off age-related cognitive decline. Finally, researchers are finding that in some people, the brain can compensate for the toxic buildup of amyloid.

Cognitive Activity

Late-Life Mental Stimulation and Cognitive Health

two older men playing chess in a parkA study at Rush University Medical Center, Chicago, showed that older people may benefit cognitively from continued engagement in intellectually stimulating activities. The researchers followed more than 1,000 older people—all of whom were free of dementia at the start of the study—with annual cognitive evaluations for an average of 5 years (Wilson et al., 2012). The scientists evaluated each participant’s cognitive performance and level of engagement in mentally stimulating activities, such as reading the newspaper, writing letters, visiting a library, or playing games like chess or checkers. Those who reported higher levels of cognitive activity in any given year also showed better cognitive performance in subsequent years.

Cognitive Activity and Plaque Formation

A study led by researchers at the University of California, Berkeley, assessed how lifelong cognitive activity impacts beta-amyloid accumulation in the brain in late life (Landau et al., 2012). Using Pittsburgh Compound B, a chemical that binds to amyloid in the brain, during positron emission tomography scans, the researchers measured beta-amyloid levels in the brains of 65 cognitively normal volunteers (average age, 76). The participants also rated how often they engaged in intellectually stimulating activities currently and at age 6, 12, 18, and 40.

Higher levels of cognitive stimulation in early and midlife were associated with lower beta-amyloid levels in late life. Indeed, beta-amyloid levels in the older subjects who reported the highest past levels of cognitive activity resembled those of control subjects in their mid-20s. Previously, researchers had believed that cognitive activity might help protect older people from the detrimental effects of beta-amyloid. This study suggests further exploration of the idea that cognitive activity might actually help prevent beta-amyloid deposition in the first place.

Physical Activity

Activity Versus Exercise

older women dancingPast studies of the cognitive benefits of physical activity have typically relied on self-report by volunteers to assess how much they exercise. Rush University Medical Center, Chicago, researchers used a more objective approach to measure physical activity in a study of more than 700 older people (average age, 82), all of whom were free of dementia at the start of the study (Buchman et al., 2012). The researchers fitted each subject with an actigraph, a device worn on the wrist for up to 10 days, to record all movements, from exercise like bike riding to physical activities such as gardening, housework, or even fidgeting.

The researchers tracked participants’ cognitive health for the next 4 years. Those with the highest levels of total daily activity had the slowest rates of cognitive decline. Compared to the least active participants, they also had about half the risk of developing Alzheimer’s.

Exercise-Diet Interactions

In a study at the University of Washington, Seattle, physical activity interacted with diet to influence Alzheimer’s-like changes in beta-amyloid 42 levels in cerebrospinal fluid (CSF) (Baker et al., 2012). The study involved 41 participants (average age, 68) with normal cognition or mild cognitive impairment (MCI). Based on self-reports of their typical exercise levels, volunteers were categorized in “high intensity” or “low intensity” physical activity groups. (High-intensity activities included jogging, biking, or participating in a structured aerobic exercise class; low-intensity activities included leisurely walking, stretching, and light gardening.) The volunteers then consumed either a “healthy” diet (one low in saturated fat and refined sugars) or an “unhealthy” diet (one high in saturated fat and sugar) for 4 weeks, while maintaining their usual exercise routines.

At the beginning and end of the study, the researchers measured levels of several CSF Alzheimer’s biomarkers. One of these, beta-amyloid 42, was impacted by diet. Beta-amyloid 42 levels decreased (moved in the direction seen in people with Alzheimer’s disease) in participants who ate the unhealthy diet and increased (moved towards normal levels) in those who ate the healthy diet. This effect of diet on CSF beta-amyloid 42 levels was influenced by exercise.

Among participants with MCI, those who engaged in regular high-intensity exercise showed greater benefits of the healthy diet on CSF beta-amyloid 42 levels. In addition, in volunteers with normal cognition, those who engaged in high-intensity exercise showed less negative impact of the unhealthy diet on their CSF beta-amyloid 42 levels. These findings, while preliminary, suggest that potential protective effects of a healthy diet are likely to be greatest when combined with regular vigorous physical exercise.

Exercise, Neuronal Growth Factors, and Brain Plasticity

A number of studies have shown that aerobic exercise benefits brain function in older adults, but by what biological mechanisms remains unclear. A study led by University of Iowa researchers and others suggests that exercise works in part by increasing the levels of certain protein growth factors that support neuronal health (Voss et al., 2013). The study involved 65 older adults (average age, 66) who were assigned to either an aerobic walking program or a control program of flexibility, toning, and balance exercises.

After 1 year, people in the aerobic walking group showed increased functional connectivity on MRI scans in certain brain networks that typically degenerate with age, compared to the non-walking group. Among the aerobic walkers, improved functional connectivity was associated with increased blood levels of three growth factors known to promote neuronal function, growth, and plasticity: brain-derived neurotrophic factor, insulin-like growth factor type 1, and vascular endothelial growth factor.

Cardiovascular Risk Factors

Cardiovascular disease risk factors, such as high blood pressure, may increase the risk of Alzheimer’s disease. A team led by researchers at Banner Alzheimer’s Institute, Phoenix, used positron emission tomography imaging to show that higher blood pressure was associated with increased brain beta-amyloid levels in 32 cognitively normal adults, age 47 to 68 (Langbaum et al., 2012). Brain scans of participants with higher blood pressure also showed reduced brain glucose metabolism, a change often seen in people with Alzheimer’s. This study provides additional evidence that high blood pressure is associated with increased risk of preclinical Alzheimer’s.


Many scientists suspect that depression increases the risk of age-related cognitive decline in older people. Two new studies in very large populations lend further support to this idea.

A retrospective study led by researchers at the University of California, San Francisco, analyzed 45 years of medical records from more than 13,500 people enrolled in the Kaiser Permanente Medical Care Program in Northern California (Barnes et al., 2012). People who had reported on Kaiser health surveys that they felt depressed or were hospitalized for depression in midlife (40s to early 50s) and/or late life (70s) were at greater risk of developing dementia in their 80s than people who had never been depressed.

The age at which people became depressed also influenced their likelihood of developing Alzheimer’s or vascular dementia (dementia associated with stroke or other vascular disease). The risk of developing vascular dementia was increased threefold in people who experienced depression both in midlife and late life, but only by 50 percent in those who first became depressed in late life. In contrast, the risk of developing Alzheimer’s was increased twofold in both groups.

Similarly, researchers at Emory University, Atlanta, looked at the possible link between depression and cognitive decline in a group of more than 8,000 volunteers (Steenland et al., 2012). They used data stored at the NIA-supported National Alzheimer’s Coordinating Center database that had been collected at 30 Alzheimer’s Disease Centers between 2005 and 2011. About one third of the participants (average age, 73) had MCI, and the rest were cognitively normal when first evaluated. Twenty-two percent of the participants had recent (within the past 2 years) depression, as defined by clinician judgment.

The Emory researchers found that volunteers who were recently or currently depressed at the first evaluation performed significantly worse on cognitive tests than did their nondepressed peers. In addition, cognitively normal people with recent or current depression were at significantly greater risk of developing MCI within the next 3 years; the risk was highest for those who continued to experience depression during that time. Significantly, treatment with antidepressant medications did not alter the risk of progression from normal cognition to MCI among depressed volunteers. The relationship between late-life depression and cognitive decline warrants further study.

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