. Angiotensin-converting enzyme inhibitors and amyotrophic lateral sclerosis risk: a total population-based case-control study. JAMA Neurol. 2015 Jan;72(1):40-8. PubMed.


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  1. Overall effect size reported here is modest. Historically, epidemiological studies showing modest effects have not panned out prospectively.

    Captopril and enalapril exhibited the statistically significant effects—the sample size for the other medications was generally too small to be informative. Captopril is brain-penetrant; enalapril is not brain-penetrant. If one is to interpret the results, then brain penetration must be factored into the equation with the resulting conclusion that brain penetration is not relevant to the putative mechanism of action.

    Much of the discussion focuses on scavenging of free radicals. This focus is disappointing because it ignores the major mechanism of action of ACEIs and instead focuses on a secondary hypothesis (free-radical scavenging) which is known to have no therapeutic value in ALS. A hypothesis based on free-radical scavenging is also unlikely to be relevant because enalapril does not get into the brain, which means that it would have to be putatively therapeutic without getting to the neurons and astrocytes to scavenge free radicals.

    A more likely putative mechanism of action would relate to the interaction between angiotensin II and its receptors. Many studies suggest that angiotensin receptors modulate neuroprotection, and it is easy to imagine that modulating such receptors could elicit neuroprotection in ALS. In AD, studies originally focused on ACEI, but then my studies focused attention on angiotensin receptor blockers, which directly act on the type I angiotensin receptor. This receptor inhibits neuroprotection, while the type II angiotensin receptor promotes neuroprotection. Studies examining angiotensin receptor blockers (ARBs) proved to be more significant than the ACEI results. In our studies, the brain-penetrant ARBs were associated with a reduction in the incidence of dementia, while the brain-non-penetrant ARBs were not associated with risk reduction. I am pleased to say that subsequent studies have supported these results. Pathologists (Dave Bennett) showed reduced AD pathology with ARBs, and some prospective trials for ARBs in the cardiovascular/stroke domain showed a reduced incidence of AD. What has definitely been shown in prospective clinical trials is that ARBs are associated with a reduced risk of diabetes, prospectively.

    In summary, the results are thought-provoking, although the discussion in the manuscript misses many key details.

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