The current social expenditure of dementia is US$ 604 billion/ year worldwide, and it is projected that the number of dementia patients will triple by 2050. Therefore, it is possible to estimate the global socio-economic impact of dementia.[6, 9] For treatment of dementia, a variety of pharmacologic and non-pharmacologic approaches has been attempted, but their efficacy has not been confirmed. Rather, treatment is focused on symptom control, and prevention is considered the top priority.[1, 2, 6, 10] A recent review by Livingston and coworkers suggests that approximately 35% of dementias is attributable to nine modifiable risk factors.[2] To prevent dementia, it is necessary to manage these risk factors including diabetes, hypertension, smoking, and obesity.
Each risk factor affects dementia through a variety of mechanisms. A precise mechanism between diabetes and dementia has not been reported in human research but has been suggested through animal models. Such mechanisms include cerebral insulin resistance, accumulation of glycation end products, and inflammation.[11, 12] Several mechanisms are suggested between hypertension and dementia. Hypertension causes vessel wall remodeling and endothelial dysfunction, which result in an autoregulatory deficit. Due to these neurological changes, the brain is vulnerable to hypoperfusion resulting from decrease in systemic blood pressure.[13] This decrease in cerebral blood flow affects dementia through direct damage to the brain, such as a decrease in hippocampal volume. However, further research is needed to elucidate the mechanisms that directly act on cognitive decline.[14] In cases of obesity, dementia is affected by both distinct and overlapping physiological changes, such as increased central inflammation, oxidative stress, sleep apnea, decreased neurogenesis, and silent infarcts. These can directly impact brain function.[15] Smoking can contribute secondarily by causing diseases considered risk factors for AD such as DM, CVD, hypertension and dyslipidemia. Also, smoking generates oxidative stress, leading to pathological β-amyloid (Aβ) processing, tau protein hyperphosphorylation, and mild cerebrovascular dysfunction.[16]
Unlike in dementia, DM shows a protective effect in AAA, and the mechanisms are the activity of glycation and cross-linking on ECM remodeling and the anti-inflammatory properties of the TGF-β signaling pathway, as well as the impact of intraluminal thrombus (ILT) formation, neoangiogenesis, and vascular smooth muscle cell (VSMC) apoptosis. Also, antidiabetic drugs such as metformin, sulfonylurea, and thiazolidinedione interfere with the pathophysiological mechanisms of AAA.[17] In hypertension, a meta-analysis demonstrated an association with dementia. However, DBP is more highly correlated with dementia than is SBP, and further studies are needed to identify the precise mechanism.[4, 18] The mechanism of the relationship between obesity and dementia can be explained by the following mechanism. Interleukin-18 (IL18) uses both the IL18 receptor (IL18r) and the Na-Cl co-transporter (NCC) to promote AAA formation. Lesion adipocyte and perivascular adipose tissues contribute to AAA pathogenesis by releasing leptin and FABP4 to induce IL18, IL18r, and NCC expression and promote IL18 activity.[19] To date, no causative link has been proven between smoking and AAA formation [4]; however, some studies suggest that the effect of tobacco smoke on AAA development is related to altered inflammatory cell function acting to enhance matrix damage through MMP-independent pathways.[20]
While AAA and dementia share risk factors, there are both commonalities and differences in the mechanisms by which the factors act on the disease. In addition, there is a lack of research on the mechanisms of risk factors related to AAA. As the association between dementia and AAA was verified through this study, the mechanisms by which risk factors act on AAA in dementia must be studied.
In this study, even when the effects of the common risk factors of the two diseases were excluded, there was a relationship between AAA and dementia. These associations can be estimated by examining the pathophysiology of AAA.
The first such association is related to atherosclerosis. Traditionally, it was thought that AAA develops as a pathological response to aortic atherosclerosis. Until half a century ago, the term “atherosclerotic aneurysm” was used. This view still is favored by some researchers.[21, 22] Atherosclerotic plaque growth leads to a compensatory arterial response. In other words, due to arterial narrowing, hemodynamic changes such as those in shear stress occur. The endothelium detects this and changes the phenotype of vascular smooth muscle cells, allowing remodeling through secretion of proteolytic enzymes such as metalloproteinase (MMP).[21–23] Atherosclerosis typically is widespread throughout the vasculature, and the carotid artery is not exempt.[24] Carotid atherosclerosis and stiffness consequently cause brain microcirculation transformation and increase blood-brain barrier (BBB) permeability, leading to cognitive impairment.[25] Similarly, associations between descending thoracic aortic plaque and acceleration of brain aging have been demonstrated, and trends in accelerated progression of brain atrophy and progression of cerebrovascular lesions have been reported.[26, 27]
The second association is inflammation and matrix degradation. Aortic inflammation is believed to lead to destruction of aortic media and vascular smooth muscle cell apoptosis and dysfunction. Release of a range of proteolytic enzymes, such as MMP and cysteine proteases, produces reactive oxygen, cytokines, and related products.[21] The tissue inhibitors of MMP (TIMP) are increased in the wall of the aneurysm[28]; however, the balance between TIMP and MMP seems to favor proteolysis,[29] and elastin and collagen fibers are degraded. Also, due to the paracrine effect of VSMC, a protective effect is needed to maintain homeostasis from proteolysis and inflammatory reactions.[30] However, VSMC apoptosis prevents this protective effect. These MMPs (MMP-2) induce breakdown of the BBB, disrupt oxidative homeostasis in AD,[31] and play a role in the impaired Aβ peptide metabolism responsible for progression of dementia.[32] Reactive oxygen species (ROS) affect AD by inducing oxidation of lipids, proteins, and nucleic acids and impairing Aβ clearance by the low density lipoprotein receptor-related protein (LPR1) through its oxidation.[33]
The hazard ratio of AAA for dementia in this study was 1.422, and the reason for this was deduced based on the mechanisms of AAA occurrence. However, since this deduction is only a possibility, further research is needed. Also, as documented in Supplemental Ttable 3, there were interactions of age, hypertension, and history of cardiovascular disease with AAA. The HR of dementia was high according to the presence or absence of AAA in the presence of hypertension, in the younger age group, and in the group with no history of cardiovascular disease. In this study, all of these factors were related to dementia, but there were differences in the directions of the interactions. Synergy was present with hypertension because it uniquely influenced dementia with AAA. However, other factors influenced the occurrence of dementia in various ways, indicating a common denominator with AAA. As a result, the HR of AAA for dementia was decreased statistically. This, too, will require further research.
The present study has several limitations. First, this study was a retrospective analysis. To overcome this, the influence of each variable was adjusted through a multivariate logistic regression model. However, control of the confounders among variables was not achieved. Second, diagnosis of AAA and dementia and identification of other risk factors solely were based on diagnostic codes, possibly introducing bias. Third, considering the time of onset, a rough causal relationship might be inaccurately inferred because of the it is a retrospective nature of the study. Also, the degree of cognitive impairment and issues such as AAA diameter are not known, so the correlation between these could not be demonstrated clearly.
However, our study also has a number of strengths. First, we believe that this is the first study to not only demonstrate the relationship between AAA and dementia, but also to illustrate the effect of AAA on dementia in relation to each risk factor. Second, this study used a large, national sample with a relatively long follow-up period.