No Pressure, But Could Hypertension Medication Prevent AD?

They have been used for decades to lower blood pressure, but evidence now suggests that some specific forms of diuretic drugs may help stave off Alzheimer disease (AD). In the March 13 Archive of Neurology online, John Breitner, University of Washington School of Medicine, Seattle, and researchers of the Cache County Study Group report that potassium-sparing diuretics reduce the risk of developing AD by around 70 percent. The finding helps explain conflicting data on the potential benefit of hypertension medicines for incipient AD and suggests that this particular subtype of blood pressure medication should be more thoroughly explored as a prophylactic.

Previous epidemiological studies have examined the effect of hypertension medications on dementia but, as is often the case in AD epidemiology, the results have been confusing. The Kungsholmen Project found that antihypertension medication reduced the incidence of AD in the elderly (see Guo et al., 1999), but while the Rotterdam study found that blood pressure medication reduced rates of vascular dementia, it also found that the same meds did not alter the chances of getting AD (see in’t Veld et al., 2001). The reasons for these discrepancies are unclear. Because other studies reported that cognitive performance in the elderly improved only on specific types of hypertension drugs, Breitner and colleagues decided to examine if the incidence of AD is altered among those taking different classes of hypertension agents.

First author Ara Khachaturian of Khachaturian and Associates, Potomac, Maryland, and colleagues followed up with more than 3,000 elderly people who had taken part in Utah’s Cache County Study in the late 1990s. Nearly 1,500 of the volunteers were using hypertension medication at that time. The drugs used fall into four main classes: angiotensin converting enzyme (ACE) inhibitors; β-adrenergic blockers; calcium channel blockers; and diuretics.

When Khachaturian and colleagues parsed the data according to drug type, they found that only diuretics and β-blockers decreased the odds of getting Alzheimer’s. After correcting for age, education, sex, number of ApoE4 alleles, and other potential confounding factors, they found that hazard ratios (HRs) for AD were 0.53 and 0.61 for those patients on β-blockers and diuretics, respectively. But when the authors delved a little deeper, they found that hazard ratios were even lower for some specific types of drugs, namely potassium-sparing diuretics (HR, 0.26), and the calcium channel blocker dihydropyridine (HR, 0.53). The findings suggest that potassium-sparing diuretics, which help the body lose water without also losing potassium, and possibly the β-blockers and dihydropyridine may protect against AD.

These findings corroborate results from some previous trials. SHEP (Systolic Hypertension in the Elderly Project), the Medical Research Council trial, and SCOPE (the Study on Cognition and Prognosis in the Elderly) all found that β-blockers, thiazide diuretics (which are not potassium-sparing), and angiotensin II type I receptor blockers have no effect on cognition in the elderly. But the Syst-Eur (Systolic Hypertension in Europe) trial found that the dihydropyridine calcium channel antagonist nitrendipine reduced the incidence of dementia by 50 percent. No other trial has examined the effects of potassium-sparing drugs on cognition, and the authors suggest that further studies should be carried out to evaluate the epidemiology and also the potential mechanism whereby these drugs may protect against AD.—Tom Fagan

Comments

  1. In this study, Khachaturian and colleagues compared a group of elderly, nondemented subjects who used antihypertensive medication (AH) with non-users for their risk of developing Alzheimer disease (AD) 3 years after they were first examined and declared dementia-free. The study found that the use of antihypertensive medication (AH) was associated with a lower risk of developing AD. These findings add to the literature supporting the benefits of AH medication in the prevention of dementia. However, as for all observational studies, there could be potential biases influencing the results.

    The authors compared subjects based on their treatment status, not on their hypertensive status. The reference group of non-treated subjects could include people with a worse health profile (untreated hypertensives and subjects who have low blood pressure resulting from pathological conditions such as heart failure or incipient dementia). In this case, the observed protective effect of AH medication could be due in part to the comparison with a group that is at high risk for cognitive impairment resulting from other reasons than not being treated. More information on the comparison group would help to clarify this.

    The study was sufficiently powered to test the main hypothesis about the overall protection of AH against AD. The power was reduced when the different subclasses of AH were tested separately. Additional analyses reported by the authors seem to provide support that, among the drugs tested, the potassium-sparing diuretics are the most effective against AD, but the numbers of AD cases in these sub-analyses is very small. The reduced power could explain the lack of significance for the β-blockers and the calcium channel blockers.

    The question remains whether the observed protective effect is the result of a better control of blood pressure among the potassium-sparing AH users or if this drug category has a specific effect on AD, as the authors suggest. Although this hypothesis should not be excluded, at present the sample sizes are not sufficient to test it. Previous clinical trials found that other categories of AH drugs, such as ACE inhibitors and the calcium channel blockers, were protective against cognitive decline, dementia and AD (1-3). Some of the benefits from these drugs may reflect protection against vascular damage rather than AD pathology per se. Vascular damage is often present in cases diagnosed with AD, and the presence of vascular damage worsens the clinical presentation of dementia (4-6).

    References:

    Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J, . Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003 May 12;163(9):1069-75. PubMed.

    Forette F, Seux ML, Staessen JA, Thijs L, Birkenhäger WH, Babarskiene MR, Babeanu S, Bossini A, Gil-Extremera B, Girerd X, Laks T, Lilov E, Moisseyev V, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Fagard R. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998 Oct 24;352(9137):1347-51. PubMed.

    Forette F, Seux ML, Staessen JA, Thijs L, Babarskiene MR, Babeanu S, Bossini A, Fagard R, Gil-Extremera B, Laks T, Kobalava Z, Sarti C, Tuomilehto J, Vanhanen H, Webster J, Yodfat Y, Birkenhäger WH, . The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002 Oct 14;162(18):2046-52. PubMed.

    Jellinger KA. Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm. 2002 May;109(5-6):813-36. PubMed.

    Launer LJ. Demonstrating the case that AD is a vascular disease: epidemiologic evidence. Ageing Res Rev. 2002 Feb;1(1):61-77. PubMed.

    Snowdon DA, Greiner LH, Mortimer JA, Riley KP, Greiner PA, Markesbery WR. Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA. 1997 Mar 12;277(10):813-7. PubMed.

    View all comments by Rita Peila

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References

Paper Citations

  1. Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75 years and older: relationship of antihypertensive medication use. Arch Neurol. 1999 Aug;56(8):991-6. PubMed.
  2. in't Veld BA, Ruitenberg A, Hofman A, Stricker BH, Breteler MM. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiol Aging. 2001 May-Jun;22(3):407-12. PubMed.
  3. Prince M, Lewis G, Bird A, Blizard R, Mann A. A longitudinal study of factors predicting change in cognitive test scores over time, in an older hypertensive population. Psychol Med. 1996 May;26(3):555-68. PubMed.
  4. Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A, . The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003 May;21(5):875-86. PubMed.

External Citations

  1. Systolic Hypertension in the Elderly Project

Further Reading

No Available Further Reading

Primary Papers

  1. Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, Tschanz JT, Mayer LS, Welsh-Bohmer KA, Breitner JC. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006 May;63(5):686-92. PubMed.

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