Some scientific evidence suggests that hypertension has a negative impact on cognitive function, including psychomotor function. Long-term fluctuating blood pressure has also been reported to cause an increase in white matter intensity, affect the thickness of the intima-media tunica, and cause atherosclerosis of the carotid arteries.

Antihypertensive Drugs Reduce Risk of Dementia

Hypertension has also been reported as a major risk factor for vascular cognitive impairment (VCI). VCI is a term that describes the spectrum of neurological deficits resulting from vascular disorders. One of the severe manifestations of VCI is vascular dementia. Hypertension has also been reported as a risk factor for Alzheimer's dementia. So, can antihypertensive drugs reduce the risk of dementia?

Alleged Effects of Antihypertensive Drugs on Dementia

The renin-angiotensin system (ARS) is thought to have a role in the progression of Alzheimer's dementia by:
  • increase vasoconstriction and decrease cerebral blood flow,
  • increases the degradation of â-amyloid,
  • inhibits the release of acetylcholine,
  • and increase the production of proinflammatory cytokines.

The prolonged fluctuation of blood pressure due to hypertension will cause microvascular dysfunction, such as microinfarction or microhemorrhages. This microvascular dysfunction reduces cerebral perfusion and causes ischemic injury in the brain, leading to cognitive dysfunction. These things form the basis of the hypothesis that antihypertensive drugs have a protective effect against dementia.

Calcium channel blockers work by inhibiting signal transduction processes in neurons (i.e., those associated with hyperphosphorylation and apoptosis). So, this type of antihypertensive drug is thought to play a protective effect against dementia. Calcium channel blocking drugs are also thought to inhibit the onset of Alzheimer's disease by blocking an unnecessary increase in transmembrane transport.

Through a passive mechanism (increasing uric acid concentration), loop diuretics reduce cognitive impairment and dementia risk and a systemic vasodilating effect. Torasemide, a loop diuretic, has also been shown to reduce cerebral edema in experimental animal models.

Correlation of Antihypertensive and Dementia 

Until now, several previous studies have reported a correlation between the administration of antihypertensive drugs with dementia, cognitive impairment, and Alzheimer's disease. However, the limited number and the varying results of studies makes the correlation between the two is inconclusive.

a. Supportive Studies

Tully et al. conducted a prospective cohort study in 6537 populations aged ≥65 years. They found that the risk of dementia was lower in the group taking non-dihydropyridine calcium blockers and loop diuretics. Examples of non-dihydropyridine calcium-blocking antihypertensive drugs are verapamil and diltiazem. An example of a loop diuretic antihypertensive drug is furosemide.

A meta-analysis of the prospective cohort also showed similar results. This study, which evaluated ten prospective cohorts with a total sample of 30,895 subjects, found that antihypertensive drugs' administration reduced the incidence of dementia (RR 0.86), but did not reduce the incidence of Alzheimer's dementia and cognitive impairment.

In another study involving 2,248 subjects, Yasar et al. reported that diuretics, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) were associated with a reduced risk of Alzheimer's disease. However, Yasar et al. also stated that the interpretation of these studies' results must be carried out with caution considering that most of the study subjects already had various metabolic comorbid, such as a history of diabetes and coronary heart disease.

b. Unsupportive Study

Not all studies have reported a good correlation between antihypertensive drugs and dementia. Peters et al. conducted a randomized controlled trial involving 3336 participants to evaluate the benefits and risks of antihypertensive therapy on cognitive function. Patients received 1.5 mg slow-release indapamide, 2–4 mg perindopril, or placebo, at random. Researchers reported that administering antihypertensive therapy to the elderly population did not reduce the risk of developing dementia.

The results of Peters et al. 's clinical trial support a previous clinical trial, the study of systolic hypertension in the elderly program (SHEP). In the SHEP study, the effect of antihypertensive drugs on dementia was investigated as a secondary outcome. In this study, there was no significant difference in the dementia incidence in patients receiving antihypertensive drugs (12.5–25 mg/day chlorthalidone or 25–50 mg/day atenolol) with the placebo group.

The administration of antihypertensive drugs is thought to reduce the dementia risk by regulating calcium homeostasis, passively increasing uric acid, preventing blood pressure fluctuations, and preventing perfusion disorders in the brain. There have been many previous studies showing that antihypertensive drugs have a protective effect against dementia. However, there are clinical trials that do not support this. Randomized controlled clinical trials with large sample sizes are needed before concluding more definitively.

1. Al-Khateeb E, Althaher A, Al-Khateeb M, Al-Musawi H, Azzouqah O, Al-Shweiki S, et al. Relation between uric acid and Alzheimer's disease in elderly Jordanians. Journal of Alzheimers Disease. 2015; 44(3):859-65.
2. Brickman AM, Reitz C, Luchsinger JA, Manly JJ, Schupf N, Muraskin J, et al. Long-term blood pressure fluctuation and cerebrovascular disease in an elderly cohort. Archives of Neurology. 2010; 67(5):564-9.
3. Elias M, Goodell A, Dore G. Hypertension and cognitive functioning: a perspective in historical context. Hypertension. 2012; 2012(60):260-8.
4. Gorelick PB, Scuteri A, Black SE, DeCarli C, Greenberg SM, Iadecola C, et al. Vascular Contributions to Cognitive Impairment and Dementia. Stroke. 2011; 42(9):2672-713.
5. Iadecola C. Hypertension and Dementia. Hypertension. 2014; 64(1):3-5.
6. Kehoe P, Passmore P. The renin-angiotensin system and antihypertensive drugs in Alzheimer's disease: current standing of the angiotensin hypothesis? Journal of Alzheimers Disease. 2012; 2012(30):S251-68.
7. Masereel B, Renard P, Schynts M, Pirotte B, de Tullio P, Delarge J. Synthesis and pharmacology of pyrid-3-yl sulfonylureas and sulfonylthioureas as inhibitors of the astrocytic Na+ 2Cl- K+ co-transporter. European Journal of Medical Chemistry. 1994; 1994(29):527-35.
8. Paris D, Cahmeier C, Patel N, Quadros A, Volmar C-H, Laporte V, et al. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Molecular Medicine. 2011; 17(3-4):149-62.
9. Peters R, Beckett N, Forette F, Toumilehto J, Clarke R, Ritchie C, et al. Incident dementia and blood pressure lowering in hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo-controlled trial. The Lancet Neurology. 2008; 7(8):P683-9.
10. Probstfield JL, Applegate WB, Borhani NO, et al. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). SHEP Cooperative Research Group. JAMA. 1991;265(24):3255-3264.
11. Tully PJ, Dartigues J-F, Debette S, Helmer C, Artero S, Tzourio C. Dementia risk with antihypertensive use and blood pressure variability: A cohort study. Neurology. 2016; 87(6):601-8.
12. Xu G, Bai F, Lin X, Wang Q, Wu Q, Sun S, et al. Association between Antihypertensive Drug Use and the Incidence of Cognitive Decline and Dementia: A Meta-Analysis of Prospective Cohort Studies. BioMed Research International. 2017; 2017(11):4368474.
13. Yasar S, Xia J, Yao W, Furberg CD, Xue Q-L, Mercado CI, et al. Antihypertensive drugs decrease risk of Alzheimer disease. Neurology. 2013; 81(10):896-903.