Vascular disease, cardiovascular disease, and Alzheimer’s disease

Several risk factors are associated with AD and cardiovascular disease (CVD).¹ From a genetic standpoint, understanding the risk for AD is complex.¹ The apolipoprotein (APOE) e4 allele has been identified as a risk factor for both AD and cardiovascular disease.¹ Additionally, two polymorphisms in the methylenetetra-hydrofolate reductase (MTHFR) gene have been found to be associated with AD and vascular contributions to cognitive impairment and dementia (VCID).^6,7 In a study of AD in an Asian population, mutations in the MTHFR gene were found to increase the risk of AD by 2.5 fold and VCID by 3.7 fold.⁷ Beyond APOE and MTHFR, there are few other genes that have been found to significantly increase the risk of both AD and CVD.¹

Aside from genetics, there are several cardiometabolic and lifestyle risk factors that occur during middle- to late-life.¹ AD and CVD are associated with increasing age, and both are among the leading causes of death.¹

CVD is primarily caused by coronary heart disease, hypertension, stroke, and heart failure; all of which share an underlying pathology of atherosclerosis.¹ All known risk factors for atherosclerosis have been investigated in studies to identify modifiable risk factors for AD.¹ Hypertension results in reduced cerebral blood flow, which contributes to the pathophysiology of both AD and CVD.¹ Interventions that lower blood pressure in mid-life (i.e., lifestyle changes, medications), may help retain or improve cognitive function by reducing the risk of AD and/or VCID.¹ Diabetes and other risk factors are associated with accelerated cognitive decline and dementia.¹ While there is some overlap between the underlying molecular mechanisms of diabetes and AD, the exact mechanism of how insulin insufficiency increases the risk of AD is unclear, yet there is evidence that treatment for diabetes reduces the risk of AD.¹

Inactive lifestyles and high-fat diets have been associated with obesity, dyslipidaemia, high blood pressure, and metabolic syndromes.¹ These conditions are often precursors for, or develop along with, atherosclerosis, diabetes, and CVD, and can increase risk of AD.¹ Unlike metabolic syndromes, observational studies have found that aerobic exercise and a healthy lifestyle reduce the incidence of both AD and CVD.¹ Particularly, aerobic exercise promotes and improves brain vascularization and cognitive function, and may reduce vascular risk factors.¹

Other risk factors for AD and CVD include smoking, major depressive disorder (MDD), and environmental exposures, such as pollution.¹ There is evidence to suggest that long-term smoking is an independent risk factor for AD, CVD, and cerebrovascular disease.¹ Smoking accelerates atherosclerosis,¹ and increases homocysteine, an independent risk factor for stroke and cognitive impairment, AD and other dementias.¹ There are shared common aetiological substrates between MDD and AD, with evidence that chronic, untreated MDD is associated with selective loss of noradrenergic cells in the locus coeruleus and the loss of dorsal raphe serotonergic nuclei;¹ both of which are associated with AD.¹ Another study suggested that amyloid pathology (hallmark protein in AD) co-exists in the brain and heart of patients with AD.⁸

Another environmental risk factor associated with both AD and CVD includes air pollution.¹ Long-term exposure to high ozone and high particulate matter within the air increases the risk for a range of physiological disorders and diseases.¹

References:
1.Santos CY, Snyder PJ, Wu WC, et al. Pathophysiologic relationship between Alzheimer’s disease, cerebrovascular disease, and cardiovascular risk: a review and synthesis. Alzheimers Dement (Amst) 2017; 7: 69–87.

2.Lanctôt KL, Hahn-Pedersen JH, Eichinger CS, et al. Burden of illness in people with Alzheimer’s disease: a systematic review of epidemiology, comorbidities and mortality. J Prev Alzheimers Dis 2023; 1–11.

3.Pinho J, Quintas-Neves M, Dogan I, et al. Incident stroke in patients with Alzheimer’s disease: systematic review and meta-analysis. Sci Rep 2021; 11 (1): 16385.

4.Zupanic E, von Euler M, Winblad B, et al. Mortality after ischemic stroke in patients with Alzheimer’s disease dementia and other dementia disorders. J Alzheimers Dis 2021; 81 (3): 1253–1261.

5.Gottesman RF, Schneider AL, Zhou Y, et al. Association between midlife vascular risk factors and estimated brain amyloid deposition. JAMA 2017; 317 (14): 1443–1450.

6.McIlroy SP, Dynan KB, Lawson JT, et al. Moderately elevated plasma homocysteine, methylenetetrahydrofolate reductase genotype, and risk for stroke, vascular dementia, and Alzheimer disease in Northern Ireland. Stroke 2002; 33 (10): 2351–2356.

7.Mansoori N, Tripathi M, Luthra K, et al. MTHFR (677 and 1298) and IL-6-174 G/C genes in pathogenesis of Alzheimer’s and vascular dementia and their epistatic interaction. Neurobiol Aging 2012; 33 (5): 1003.e1–8.

8.Troncone L, Luciani M, Coggins M, et al. Aβ amyloid pathology affects the hearts of patients with Alzheimer’s disease: mind the heart. J Am Coll Cardiol 2016; 68 (22): 2395–2407.