Alzheimer’s disease (AD) currently impacts over 5 million individuals in the United States and that number is expected to increase to nearly 14 million by 2050. Studies have shown that African Americans have an increased risk for AD compared to their White counterparts. African Americans are also more likely to develop vascular risk factors (e.g., diabetes and hypertension) associated with increased risk for Alzheimer’s disease. While the relationship between certain vascular risk factors and risk for Alzheimer’s disease has been tested, little is known about how these vascular risk factors relate to cognitive activity, which studies have shown to significantly change with increased risk for AD. The aim of the proposed study is to examine how vascular risk factors (e.g., diabetes, hypertension and high cholesterol) associate with brain activation during different stages of the memory process and how this relationship may differ in African Americans versus non-Hispanic Whites. Older adults age 50 to 75 from the southeastern United States with at least one risk factor for AD (e.g., family history and lifestyle factors) will be selected as participants for the proposed study. Participants will voluntarily complete clinical and cognitive assessments, which measure health factors and cognitive abilities (e.g. memory and attention), and take part in an fMRI session that allows cognitive activity to be assessed while participants perform facial recognition/association tasks. Results from this study may provide additional insight on how vascular risk factors may contribute to ethnic minorities’ heightened risk for AD and further support the initiative to address this racial health disparity.
Keywords: health disparity, Alzheimer’s disease, vascular risk factors, brain activation
How Race Moderates the Relationship Between Vascular Risk Factors and Brain Activation
In the United States, someone develops Alzheimer’s disease (AD) approximately every 66 seconds (Alzheimer’s Association, 2017). Alzheimer’s disease is the most prevalent form of dementia characterized by a decline in cognitive abilities (e.g. episodic memory and language abilities) and the collection of degenerative neuropathology (e.g., neurofibrillary tangles and beta-amyloid plaques.) Research has shown that vascular risk factors such as diabetes and hypertension have been consistently associated with an increased risk for AD (Kloppenborg, Van den Berg, Kappelle, & Biessels, 2008; Luchsinger et al., 2005; Skoog et al., 1996; Van den Berg, Kloppenborg, Kessels, Kappelle, & Biessels, 2009; Whitmer, Sidney, Selby, Johnston, & Yaffe, 2005). African Americans have been found to be at a higher risk for certain vascular risk factors (Brancati, Kao, Folsom, Watson, & Szklo, 2000; Ford, 2011; Fryar, Hirsch, Eberhardt, Yoon, & Wright, 2010; Van Itallie, 1985), and evidence in the field suggests that AD disproportionately impacts ethnic minorities groups (i.e., Hispanics and African Americans) in the United States as well (Demirovic et al., 1993; Dilworth-Anderson, Hendrie, Manly, Khachaturian, & Fazio, 2008; Harwood & Ownby, 2000; Mehta & Yeo, 2017; Perkins et al., 1997; Steenland, Goldstein, Levey, & Wharton, 2016). As the United States population ages and diversifies, it is estimated that the number of adults over 65 will more than double by 2050 (Ortman, Velkoff, & Hogan, 2014) and over one-third of the older population will be part of an ethnic minority group (The Federal Interagency Forum on Aging-Related Statistics, 2016; Yeo, 2009). Not only are people in the United States living longer, but also individuals who have an increased risk for AD will compose a larger proportion of the population. This change in demographics raises a public health concern on how to address prevention methods for this disease and how individuals can receive proper care without overextending community healthcare resources and placing additional stress on caregivers. While substantial evidence exist in the field examining the relationship between these risk factors and Alzheimer’s disease, few studies have considered how these vascular risk factors may relate to brain activity in at-risk populations. To address some of these gaps in the literature, the objective of this study is to compare how vascular risk factors (e.g. hypertension, diabetes) associated with Alzheimer’s disease relate to brain activation during different stages of memory processing (i.e., encoding and retrieval) in African Americans compared to non-Hispanic Whites.
Background
Vascular Risk Factors
Evidence from the literature suggests that these vascular risk factors are related to an increased risk for AD: diabetes, hypertension, high cholesterol, obesity, and smoking (Anstey, von Sanden, Salim, & O'kearney, 2007; Kloppenborg et al., 2008; Luchsinger et al., 2005; Profenno, Porsteinsson, & Faraone, 2010; Skoog et al., 1996; Van den Berg et al., 2009). Other studies have suggested these vascular conditions may have more of an influence on the risk for AD during different developmental periods (i.e., middle adulthood vs. later adulthood); hypertension, high cholesterol, diabetes, obesity, and smoking during mid-life were more associated with an elevated risk for AD in the future compared to encountering these health complications in later years (Anstey, Cherbuin, Budge, & Young, 2011; Kivipelto et al., 2001; Kivipelto, et al., 2005; Meng et al., 2014; Qiu et al., 2005; Rusanen, Kivipelto, Quesenberry, Zhou, & Whitmer, 2011; Whitmer et al., 2005). By comparison, hypotension (Kennelly, Lawlor, & Kenny, 2009a; Kennelly, Lawlor, & Kenny, 2009b; Kloppenborg et al., 2008) and low body mass index (BMI) later in life (Barnes et al., 2009; Dahl, Löppönen, Isoaho, Berg, & Kivelä, 2008) have been related to an increased risk for AD. Also, having two or more vascular risk factors (i.e., obesity, current smoking, high blood pressure, diabetes, and total cholesterol) during middle adulthood, in comparison to older adulthood, was found to be associated with the development of AD pathology (i.e., amyloid build-up; Gottesman et al., 2017). Results from these studies show that these vascular risk factors, especially during mid-life, are significant factors to consider when analyzing risk for Alzheimer’s disease.
Vascular Risk Factors in African Americans
Studies have examined how vascular risk factors may impact diverse populations. African Americans have shown an increased risk for vascular risk factors such as hypertension (Ford, 2011; Fryar, Hirsch, Eberhardt, Woon, & Wright, 2010) and diabetes (Brancati, Kao, Folsom, Watson, & Szklo, 2000; Fryar et al, 2010). Specifically, African American women are at a higher risk for developing obesity compared to their non-Hispanic White counterparts and conditions such as high blood pressure, high cholesterol levels, and diabetes have been found more commonly in overweight individuals during young and mid–adulthood years (Van Italie, 1985). According to the National Heart, Lung, and Blood Institute, many of these vascular risk factors (e.g., high blood pressure, diabetes, current smoker) may increase an individual’s risk for having a stroke (Stroke, n.d.). These vascular risk factors combined with sociocultural factors (Bravata et al., 2005; Sacco et al., 2001) may explain why members of the African American community have an increased vulnerability for experiencing a stroke (Cruz-Flores et al., 2011; Trimble & Morgenstern, 2008), earlier encounters with strokes, and possibly more severe strokes compared to non-Hispanic Whites (Trimble & Morgenstern, 2008). In addition, experiencing a stroke has been associated with increased risk for AD (Honig et al., 2003; de la Torra, 2006), possibly contributing to African Americans’ risk for AD. Overall, these results suggest that health conditions related to an increased risk for Alzheimer’s disease impact African Americans differently compared to other ethnic groups, which may contribute to the racial health disparity associated with this disease.
Research has considered why minorities may experience these adverse health conditions more frequently compared to their non-Hispanic White counterparts. Proposed models suggest that not only biological (e.g., gene expression), but also sociocultural factors (e.g., hazardous environments, racial discrimination, financial stress, and lack of quality healthcare) impact health outcomes, which may apply to health disparities in neurological disorders like Alzheimer’s disease (Chiao & Blizinsky, 2013; Glymour & Manly, 2008; Hill, Pérez-Stable, Anderson, & Bernard, 2015). Studies focusing on these social influences have provided support for these models and have found that factors such as lower education attainment, poverty, and adverse childhood experiences might contribute to the increased risk for AD in African Americans and Hispanics (Yaffe et al., 2013; Zhang, Hayward, & Yu, 2016).
Compensatory Hypothesis
Several studies focusing on patients in the early stages of AD proposed the compensatory hypothesis based on indications of over activation in brain regions associated with memory (Becker et al., 1996; Grady et al., 1993). Researchers predicted that this excessive activation represented patients overcompensating due to loss of cognitive abilities. In a study conducted by Bookheimer et al. (2000), this idea of compensation was suggested in a cognitively healthy sample of older adults with genetic risks for AD. Based on results, Bookheimer et al. (2000) hypothesized that people with increased risk for developing AD may use additional cognitive resources to maintain normal functioning and to reach performance levels comparable to those without risk for Alzheimer’s disease. Later studies have found support for this hypothesis when analyzing brain activation associated with vascular risk factors and have indicated specific regions where this hyperactivation may occur. Vascular risk factors, such as a high systolic blood pressure and body mass index, were associated with hyperactivation in the posterior cingulate cortex and frontal, temporal, and parietal regions during a verbal memory task in cognitively healthy older adults (Braskie, Small, & Bookheimer, 2010). Having multiple vascular risk factors based on the Framingham cardiovascular disease risk profile was associated with excessive activation in parietal regions during memory tasks requiring high cognitive demand in a predominately older, African American sample (Chuang et al., 2014). These results provide support in favor of the compensatory hypothesis, but more research should be conducted to further understand how vascular risk factors associate with brain activity for further insight into the changes in brain functioning that occur before the development of AD.
CRUNCH Hypothesis
Building upon the compensatory hypothesis, Reuter-Lorenz and Cappell (2008) proposed the Compensation-Related Utilization of Neural Circuits Hypothesis (CRUNCH). After conducting studies focused on cognition in older adults, Reuter-Lorenz and Cappell (2008) theorized that as cognitive functioning abilities begin to decline, older adults use more cognitive resources in tasks requiring lower cognitive demand to perform at comparable levels to younger adults. So compensation appears in the form of hyperactivation in neural circuits in the utilized brain regions during these tasks. As the task becomes more demanding, a ceiling effect may occur, leading to a decline in brain activation and quality of cognitive performance in older adults. Using event-related fMRI, Cappell, Gmeindl and Reuter-Lorenz (2010) found an inverse relationship between brain activation and task demand in the dorsolateral prefrontal cortex in older adults compared to younger adults, providing support in favor of the CRUNCH hypothesis. The proposed study will incorporate both of these hypotheses for how vascular risk factors associated with AD may relate to brain activation in brain regions associated with the encoding and recall during memory tasks.
Despite the evidence that certain ethnic minority groups may have increased risk for developing AD, there has been limited research focusing on African American samples, especially when examining how vascular risk factors associate with brain activation. In one of the few studies focused on this relationship in an African American sample, there was a lack of comparison groups (i.e. non-Hispanic Whites) and a more narrow focus on predominately older adults predominately female and over the age of 60 (Chuang et al., 2014). Through the proposed study, I would like address these issues within the literature by analyzing both non-Hispanic Whites and African Americans that have vascular risk factors and examine how the potential risks associate with brain activity during different stages of memory processing.
Proposed Study
In my proposed study, I will be utilizing data currently being collected in a memory, aging, and cognition laboratory at a large, southeastern university. Participants will include middle-aged (50-62 years of age) and older adults (63 to 75 years of age) from both non-Hispanic White and African-American racial backgrounds. To be included in the study, participants are screened to make sure they have at least one risk factor for AD (i.e. family history, lifestyle or vascular risk factor) and to be sure they are physically eligible for the fMRI session later in the study. Then, participants complete a clinical assessment, which is a self-report questionnaire that assesses overall health (physical, cognitive, and emotional) and sociocultural factors. Participants must undergo a cognitive assessment to provide additional screening for dementia, but also to measure performance in memory and attention functioning. The final stage of study requires individuals to perform a facial recognition/association task within an fMRI machine. Vascular risk factors are primarily accessed through the clinical assessment, and in this study, I would like to focus on hypertension, diabetes, obesity, high cholesterol, and smoking history, which have been found to be risk factors in the AD literature.
Hypotheses
The proposed study will test the compensatory and CRUNCH hypothesis in relation to how vascular risk factors individually and aggregated relate to brain activation in regions associated with memory in cognitively intact African American and non-Hispanic White middle-aged and older adults. The first hypothesis is that as the number of vascular risk factors increase, activation in regions like the mediotemporal lobe, visual cortex, and prefrontal cortex will be at elevated levels during the encoding process compared to activation during resting state. Based on the proposed CRUNCH hypothesis, accumulating multiple vascular risk factors will place additional stress on cognitive functioning abilities. After accumulating numerous vascular risk factors, individuals will reach a ceiling threshold and display a decline in activation after accumulating a certain number of risk factors. The second hypothesis is similar pattern of behavior will be found in the relationship between aggregation of vascular risk factors and activation in regions, such as the mediotemporal lobe and posterior cingulate cortex during the retrieval process. In these two hypotheses, it is believed that race will moderate the relationship between the number of vascular risk factors and brain activation. African Americans will reach the vascular risk factor threshold sooner than non-Hispanic Whites and will require a lower number of vascular risk factors to display the inverse relationship in activation and cognitive strain.