Is exposure to angiotensin converting enzyme inhibitors related to Alzheimer’s disease?

(first published on Nature Network May 11th)  

One of the questions I have been investigating is whether a type of anti-hypertensive drug, angiotensin converting enzyme inhibitors, may inadvertently cause some people to develop Alzheimer’s disease.

There is currently no cure for Alzheimer’s disease.  Patients diagnosed with dementia on average survive for 4 years.  Alzheimer’s disease was first described in 1906, but scientists do not know exactly what causes the biological changes characteristic of the disease.  We do know Alzheimer’s disease gets more common as people get older:

Data from MRC CFAS study.¹

This hypothesis around angiotensin converting enzyme inhibitors was motivated by research suggesting that angiotensin converting enzymes may have a role in clearing amyloid-β plaques from the brain.  So angiotensin converting enzyme inhibitors which, as their name suggests, inhibit angiotensin converting enzyme, may increase the build up of amyloid-β, increasing the likelihood of Alzheimer’s disease.²

The ideal way to answer this question would be to do an experiment, which randomly allocates some people to angiotensin converting enzyme inhibitors and others to another anti-antihypertensive, and then see whether there were differences in the number of diagnosed with Alzheimer’s.  However, the effects of angiotensin converting enzyme inhibitors are only thought to build up after long periods of exposure.  So participants would need to be followed in the experiment for a very long time.  Mercifully, Alzheimer’s disease is relatively rare in younger people, so we would either need to run the experiment in older people, or in a very large number of people to detect any difference in diagnosis rates.  This could be hugely expensive.

Some epidemiologists, Anderson and colleagues, did the next best thing.³  They followed-up an experiment that had already been run, the ONTARGET study.  In which the outcomes of people given angiotensin converting enzyme inhibitors were compared to those given another anti-hypertensive drug, angiotensin receptor blockers. 

They investigated whether the participants experienced differences in cognitive impairments, defined as a diagnosis of dementia, or had a low score in a cognitive test, the mini-mental state examination depending on the treatment they were allocated.  They found that people allocated to angiotensin converting enzyme inhibitors were around 10% more likely to develop cognitive impairments over the four years of the experiment,(odds-ratio 1.11 95%CI (0.99,1.25) p-value =0.06).  However, they found little difference in another outcome, cognitive decline (a fall in the mini-mental state exam score).

These findings are certainly not conclusive.  This might be because the participants of the ONTARGET experiment were relatively young, average age of 66, so few participants would be expected to develop Alzheimer’s disease.  Also the ONTARGET trial’s primary outcome was death from cardiovascular causes, myocardial infarction, stroke, or hospitalization for heart failure.  This means it did not necessarily have enough data to detect an effect of the drugs on cognitive impairments or cognitive decline.

Another way to investigate whether angiotensin converting enzyme inhibitors cause Alzheimer’s disease, is to compare the outcomes of patients prescribed ACE-Is and other anti-hypertensive drugs as part of their normal medical care.  Some more epidemiologists, Li and colleagues, did this using data from the United States.⁴

They found that patients prescribed lisinopril (an angiotensin converting enzyme inhibitor) were 23% more likely to develop Alzheimer’s disease than those prescribed angiotensin receptor antagonists, (odds-ratio 1.23 (95%CI:1.04,1.47), p<0.001).  Patients prescribed lisinopril were slightly more likely to develop Alzheimer’s disease than patients given other cardiovascular drugs (such as statins) odds-ratio 1.04 (95%CI: 0.99,1.11, p=0.15).  But this association was relatively small weak and could be due to chance.  Whist Li and colleagues adjusted their findings for their patients’ characteristics; it is possible that these differences are due to underlying differences between patients prescribed lisinopril and angiotensin receptor antagonists in their sample.  For instance patients prescribed angiotensin receptor antagonists might be richer or younger.

I looked into this using data from the General Practice Research Database.⁵  This is contains administrative data on diagnoses and prescriptions from over 600 general practices in the UK.  We found evidence that fewer patient prescribed angiotensin converting enzymes were diagnosed with Alzheimer’s than those prescribed other anti-hypertensives.  However, when we looked at historical exposure to angiotensin converting enzymes we found little evidence of an association. Again this is frustratingly inconclusive.

The only way to conclusively prove whether long term exposure to angiotensin converting enzyme inhibitors is related to Alzheimer’s disease is with a randomised controlled trial of sufficient size in older people with higher risks for the disease.

Oh also Louis Theroux’s most recent show on dementia is really interesting, catch it on iplayer.

And here’s podcast from Professor June Andrews on care services for people with dementia.

I'd hear your thoughts on this and our other posts, and do pass on any papers or links.

 

1. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study(MRC CFAS). Pathological correlates of late-onset dementia in a multicentre, community-based population in England and Wales. Neuropathology Group of the Medical Research Council Cognitive Function and Ageing Study (MRC CFAS). Lancet. 2001;357(9251):169–175.

2. Kehoe P, Miners S, Love S. Angiotensins in Alzheimer’s disease-friend or foe? Trends Neurosci. 2009;32(12):619–628.

3. Anderson C, Teo K, Gao P, et al. Renin-angiotensin system blockade and cognitive function in patients at high risk of cardiovascular disease: analysis of data from the ONTARGET and TRANSCEND studies. The Lancet Neurology. 2011;10(1):43–53.

4. Li N, Lee A, Whitmer R, et al. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340(jan12 1):b5465.

5. Davies NM, Kehoe PG, Ben-Shlomo Y, Martin RM. Associations of anti-hypertensive treatments with Alzheimer’s disease, vascular dementia, and other dementias. J. Alzheimers Dis. 2011;26(4):699–708.

Images from: http://www.nlm.nih.gov/medlineplus/magazine/issues/fall10/articles/fall10pg20-21.html