In this population-based prospective cohort study, we found that hypertension, diabetes, and smoking measured in midlife were strongly associated with an increased risk of being hospitalized with dementia later in life. The associations were similar in whites and African-Americans, and persisted after adjustment for dementia risk factors including APOE
genotype and cognitive function at baseline. Associations were stronger when risk factors were measured at a younger age. Results from previous observational studies conducted in Caucasian and Asian populations have shown that cardiovascular risk factors, including hypertension, diabetes, obesity/overweight and smoking, are associated with a higher risk of developing dementia.[8
] The present study extends the results to African-Americans.
Cardiovascular risk factors can lead to vascular disease in the brain by causing multi-infarcts, manifested as classic vascular dementia, as well as small vessel disease (lacunes and smaller infarcts, white matter lesions, and arteriolar changes).[29
] The burden of cerebral small vessel disease, in turn, is a major contributor to cognitive decline and dementia.[31
] Diabetes, hypertension, and smoking were the factors more strongly associated with the risk of dementia hospitalization in this sample, probably as a consequence of their potential role on microvascular disease and occurrence of white matter lesions.[30
In the present study, cardiovascular risk factors measured in midlife were stronger predictors of dementia hospitalization than factors measured in older age. This observation, which confirms our a priori hypothesis, has several possible explanations. First, cardiovascular risk factors could have a cumulative effect, with increased risk of dementia if an individual has suffered hypertension or diabetes, or has smoked for a longer period of time. Second, midlife measures could better predict future risk of dementia if individuals susceptible to develop dementia caused by vascular risk factors did so before reaching older age. As a result, older samples would be somewhat depleted of individuals vulnerable to cardiovascular risk factors.[14
] Third, a diagnosis of dementia could be more easily overlooked in older individuals, with a greater number of co-morbidities, than in younger individuals. Finally, cardiovascular risk factors may lead to secondary changes including illness (e.g. heart failure, weight loss) and behavioral modification (e.g. smoking cessation before or after the onset of a vascular event). Such changes and better control of risk factors in older than younger individuals would diminish associations of cardiovascular risk factors measured at older age with subsequent risk. Although control rates of diabetes are higher among individuals older than 60 in the US,[34
] the opposite pattern has been observed for hypertension.[35
] Additionally, our knowledge of the effect of medications for hypertension and diabetes in older individuals is sparse. Independently of the underlying mechanism, our results suggest that, for prevention of dementia, control of cardiovascular risk factors starting in midlife is likely to be more important in the prevention of dementia than control starting later on. Our results may also help explain the lack of cognitive benefit found in most [36
] but not all [40
] antihypertensive clinical trials whose follow-up was only 3-5 years.
The study has a number of limitations including the endpoint ascertainment. Cases were individuals with dementia who were hospitalized and dementia was included among their discharge diagnoses. Dementia hospitalizations likely underestimate disease. In fact, the observed age-specific rates are lower than those reported in the Cardiovascular Health Study or the Northern Manhattan study.[2
] This could be problematic if the probability of hospitalization with dementia depended on the presence of cardiovascular risk factors. Smokers, hypertensives or diabetics have a higher risk of hospitalization due to cardiovascular, renal or lung diseases, creating a positive association between these risk factors and dementia hospitalization. Conversely, the presence of multiple diagnoses in smokers, hypertensives or diabetics may decrease the probability of the dementia diagnosis being recorded among the discharge codes and, thereby, creating a downward bias in the association. Several reasons, however, support the validity of dementia hospitalization as an adequate proxy for dementia incidence. First, different studies have found a high positive predictive value for dementia ICD discharge code.[42
] Second, the strong association of poor cognitive scores with dementia hospitalization, a factor unlikely to lead by itself to hospitalization, suggests that our study is identifying true cases of dementia. Finally, an overall higher risk of hospitalization in individuals with cardiovascular risk factors could not easily explain the interaction between these factors and age.
Our study has several strengths. Cardiovascular risk factors were assessed before the age of higher risk of dementia, reducing the risk of reverse causation. Also, measurements of cognitive function allowed the exclusion at baseline of individuals with possible early dementia. Other covariates that could act as confounders were determined in the different study visits, including sociodemographic variables, lifestyles and APOE genotype. Finally, the ARIC cohort comprises a large, representative, and racially diverse sample, facilitating the generalizability of the results.
In conclusion, we have observed that hypertension, diabetes and smoking in midlife are associated with a higher risk of dementia hospitalization. We present one of the only studies demonstrating this association in African-Americans, showing that they have a higher risk of dementia hospitalization as well as higher level of cardiovascular risk factors. Our results directly demonstrate that cardiovascular risk factors in midlife play an important role in the development of dementia at older age despite a weaker association when the risk factors are measured at older age. These results suggest that smoking cessation and prevention or control of hypertension and diabetes starting in midlife may have the added benefit of decreasing dementia hospitalization risk. Physiologic pathways and intermediate cerebral changes detectable by non-invasive imaging involved in the vascular pathophysiology of dementia should be studied, since clinical trials might require a decade or more of treatment to fully realize a benefit on dementia prevention.