Cardiovascular contributions to dementia: beyond individual risk factors

Abstract

Dementia poses a serious public health threat worldwide. The number of people living with dementia more than doubled between 1990 and 2016, from 20.2 million to 43.8 million individuals, primarily due to an increasingly older population (Nichols et al., 2019). Dementia is the fifth leading cause of death globally and causes substantial disability (Nichols et al., 2019). With no cure, these trends are projected to continue for the foreseeable future. Thus, we desperately need a better understanding of dementia risk mechanisms to advance prevention strategies for this devastating disease.

Several risk factors are associated with an increased risk of dementia, including but not limited to diabetes, physical inactivity, smoking, midlife hypertension and obesity, depression and low educational attainment (Norton et al., 2014). Poor cerebrovascular health has been established as the primary cause of vascular dementia, the second leading type of dementia. However, the pathogenesis of Alzheimer’s Disease (AD), the leading cause of dementia, remains controversial (Pase et al., 2017). Historically, much of AD research has focused on the amyloid hypothesis, which posits that beta-amyloid plaque deposition in the brain is the primary cause of AD (Hardy and Higgins, 1992). However, recent clinical trials targeting beta-amyloid have failed to deliver significant benefits, and the field has begun to shift toward a multi-modal approach to understanding dementia pathophysiology that considers metabolic, inflammatory and vascular influences, particularly in early stages of disease (Makin, 2018). For example, one recent study using data from the Alzheimer’s Disease Neuroimaging Initiative study found cerebrovascular dysregulation is the earliest pathological event during AD development, followed by changes in beta-amyloid deposition, metabolic dysfunction, functional impairment and structural atrophy; these findings suggest a central contribution of poor vascular health to early stages of dementia development (Iturria-Medina et al., 2016). Indeed, the idea of vascular health playing a primary role in dementia risk has gained traction over the last two decades, and the American Stroke Association and American Heart Association released a joint scientific statement highlighting the importance of cardiovascular contributions to dementia (Gorelick et al., 2011).

While early studies of cardiovascular contributions to dementia focused on individual risk factors (Kalaria, 2003), the growing literature is starting to answer more complex questions about the role of these risk factors. For example, studies show that mid-life obesity may increase the risk of dementia but late-life obesity may be protective (Pase et al., 2017). Cardiovascular risk factors often co-occur, and recent studies show that cardiovascular factors may have a cumulative impact on the development of dementia (Perales et al., 2018, Perales-Puchalt et al., 2019). However, there remains a gap in the literature regarding whether the cumulative impact of specific cardiovascular risk factors on the development of dementia acts additively or synergistically.

In the current issue of International Psychogeriatrics, Shaaban and colleagues (2019) address this gap by further exploring the connection between cardiovascular health and dementia with their study entitled “Independent and joint effects of vascular and cardiometabolic risk factor pairs for risk of all-cause dementia: a prospective population-based study.” This longitudinal cohort study included up to 10 annual study visits for the 1,701 participants from an economically depressed small-town population in the USA. The authors selected pairs of vascular and cardiometabolic risk factors (VCMRFs) to test joint effects on cognitive impairment in these individuals. They found ApoE4 carrier status paired with hypertension (HTN), congestive heart failure (CHF), and low physical activity contributed additively to dementia risk, while ApoE4 paired with stroke and stroke paired with CHF acted synergistically to increase dementia risk. Specifically, if ApoE4 and stroke were to contribute additively to dementia risk, this pair would have had a hazard ratio (HR) of 9.31 (compared to participants with neither risk factor); strikingly, the actual HR for this pair was 28.33, suggesting synergistic contributions. Likewise, if the CHF and stroke joint effect were additive, the expected HR would have been 5.36; however, the HR for all-cause dementia was 50.30. Considering two of the three of these risk factors are modifiable (stroke and CHF), these findings have implications for clinical and lifestyle interventions. Overall, they suggest a potential benefit to more aggressively targeting cardiovascular health to prevent dementia, particularly in those with the highest genetic risk.

With this study, Shaaban et al. (2019) addressed a crucial need to better understand the interactions among risk factors in promoting the development of dementia. ApoE4 is the greatest known genetic risk factor for AD and is associated with an increased incidence of vascular and all-cause dementia (Rasmussen et al., 2018). However, there remains a striking lack of insight into why certain ApoE4 carriers develop dementia while others do not. For example, while an estimated 91% of homozygotes (ApoE4/ApoE4) will develop AD, only 47% of people heterozygous for the allele will be diagnosed with AD on average; this can be compared to the 20% estimated lifetime risk for ApoE4 non-carriers (Liu et al., 2013). Considering not all ApoE4 carriers will develop dementia, other factors beyond the inheritance of an ApoE4 allele must modulate its impact on cognitive decline, determining which carriers will be diagnosed with the disease. Importantly, this study by Shaaban et al. (2019) provides novel evidence that cerebrovascular health may be particularly important for ApoE4 carriers because stroke – an indication of poor cerebrovascular health - and ApoE4 were found to act synergistically to increase dementia risk. That is, while each of these factors independently increased dementia risk, their combined effects were stronger than would be expected by simply adding each individual effect. This suggests that maintaining cerebrovascular health may be even more important for ApoE4 carriers than for the general population in order to prevent dementia. Additionally, the ability or inability to prevent decline in cerebrovascular health may determine (at least partially) which ApoE4 carriers do or do not develop dementia. Future studies are needed to examine the role of changes in cerebrovascular health on dementia development over time in people with high genetic risk.

Although there is currently no cure for dementia, more than one-third of cases may be preventable by eliminating common risk factors, such as lack of exercise, reduced social engagement, cigarette use, and hypertension (Livingston et al., 2017). Physical inactivity in particular has been established as a significant modifiable risk factor for dementia. Rabin et al. (2019) presented data at the 2019 Alzheimer’s Association International Conference showing greater baseline physical activity attenuated gray matter loss and beta-amyloid related cognitive decline in 182 older adults. The study provided evidence that physical activity may play an important role in preventing dementia in those at risk due to beta-amyloid deposition but did not probe the association within ApoE4 carriers. In contrast, this issue’s article (Shaaban et al., 2019) considers the importance of physical activity in preventing cognitive decline in ApoE4 carriers specifically. Although the joint effect of low physical activity and ApoE4 was determined to be additive and not synergistic, these findings further support the role of exercise in preventing cognitive decline in all older adults, and, considering one in two ApoE4 carriers will develop dementia, clinicians may wish to implement exercise interventions for this particularly vulnerable population.

Evidence increasingly points to a heart-brain connection in dementia development. Poor cardiac health has been associated with a range of brain pathologies. For example, one study found that the Framingham Stroke Risk Profile score - which incorporates measures of heart health including atrial fibrillation, left ventricular hypertrophy, and prior cardiovascular disease - was associated with impairment of white-matter integrity in older adults with depression (Allan et al., 2012). Likewise, maintaining cardiac health may prevent brain aging, as evidenced by the Framingham Heart Study that found cardiac function was associated with increased brain volume and information processing speed (Jefferson et al., 2010). However, the connection between cardiovascular health and cognitive function may vary across populations. For example, Martin et al. (2019) reported that heart problems were associated with lower Mini-Mental State Examination scores among U.S. but not Japanese centenarians. In the current issue, Shaaban et al. (2019) extend upon these studies by providing evidence that, at least in their predominantly-white USA sample, CHF is one of the most important risk factors for the development of all-cause dementia. Strikingly, the joint effect of CHF and stroke increased risk of dementia almost 50 times compared to participants who had neither risk factor, which was significantly higher than the predicted additive effect of these two factors. CHF may lower cerebral blood flow (Roy et al., 2017), while ischemic stroke has been shown to impair cerebral autoregulation (Salinet et al., 2018). As alluded to by Shaaban and colleagues (2019), the synergistic effect of these two factors on dementia risk may therefore result from an inability of the cerebral vasculature to effectively compensate (due to stroke) for the reduced cerebral blood flow (due to CHF), leading to inadequate delivery of oxygen and nutrients to the brain and an increased rate of cognitive decline. These findings are important because they show evidence of the relevance of heart health in addition to cerebrovascular health in the prevention of dementia.

This longitudinal study had a number of strengths, including but not limited to the large sample size and 10-year follow-up period. One potential weakness was the assessment of dementia. Shaaban and colleagues (2019) utilized the Clinical Dementia Rating scale but noted that informants were not always present. This may have resulted in inaccurate classification at times because participants may not have been able to correctly assess their own changes in memory, orientation, personal care, etc. The authors acknowledged this weakness. Additionally, the health conditions (stroke, TIA, diabetes, etc.) were self-reported which could have led to information bias, and this may have been particularly troublesome for participants with cognitive impairment. Physical activity was defined based on time spent walking but did not account for exercise performed in other activities, work-related or otherwise, which could have caused inaccurate classification for individuals with labor-intensive jobs or active hobbies like cycling or swimming. Finally, one noteworthy finding reported but not addressed by the authors was that ever smoking was significantly associated with a decreased risk of dementia, which contradicts established longitudinal research literature [14].

Overall, in this issue of International Psychogeriatrics, Shabaan and colleagues (2019) present novel findings from a well-designed longitudinal study of almost 2,000 participants that has important clinical and research implications. Their study suggests that interventions to improve cardiovascular health could be particularly useful to delay or prevent dementia development, considering the observed additive and synergistic interactions of risk factors such as stroke, CHF, HTN, physical activity and ApoE4 status. Future studies should focus on implementing interventions to improve cardiovascular health and measure dementia incidence over time, particularly for those at highest genetic risk.