Cuddy LK, Prokopenko D, Cunningham EP, Brimberry R, Song P, Kirchner R, Chapman BA, Hofmann O, Hide W, Procissi D, Hanania T, Leiser SC, Tanzi RE, Vassar R. Aβ-accelerated neurodegeneration caused by Alzheimer's-associated ACE variant R1279Q is rescued by angiotensin system inhibition in mice. Sci Transl Med. 2020 Sep 30;12(563) PubMed.

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  1. This is an important study that contributes to the understanding of the complex relationship between blood pressure, antihypertensive drug use, and the risk of dementia. This study partly fills a knowledge gap between genetics and epidemiology. Previous GWAS had linked variants in the angiotensin-converting enzyme (ACE) gene to an increased risk of AD. Although not conclusive, we have linked the use of specific antihypertensive medications, including non-dihydropiridine calcium-channel blockers (CCBs) and angiotensin 1 receptor blockers, to a lower risk of dementia in observational studies (van Middelaar et al., 2017). Recent meta-analyses of such studies could not confirm these class effects, but primarily compared each antihypertensive drug to all other antihypertensive drugs together, potentially masking class effects if more than one class is associated with a lower dementia risk. (Peters et al., 2020; Ding et al., 2020). The underlying mechanisms of specific class effects are speculative, and the current study of Cuddy et al. helps elucidate these mechanisms.

    The authors used CRISPR-Cas9-mediated gene editing to create a knock-in mouse with a rare variant of the ACE gene, which in human studies was highly associated with Alzheimer’s disease. These knock-in mice had more neurodegeneration, particularly in the hippocampus, and more signs of neuroinflammation with increasing age. In addition, they had more impaired memory. All of this in the absence of a difference in blood pressure over the life course of the mice.

    Treatment of these mice, with antihypertensive medications that cross the blood-brain barrier and can inhibit ACE 1 and angiotensin II receptor signaling, prevented these changes from occurring. Interestingly enough, the effects all seemed to be independent of blood pressure, which strongly suggests a class effect of these drugs, and may suggest that this could, in theory, also be a treatment for persons without hypertension—of course limited by the potential side effects of blood pressure-lowering drugs in persons without elevated blood pressure.

    Crossing the ACE knock-in mouse with a mouse model of cerebral amyloidosis did not impact amyloid-β pathology, but did seem to accelerate the effect of ACE1 on neurodegeneration. This may provide an important lead for future research aiming to bridge the knowledge gaps spanning links among blood pressure, antihypertensive medication, neurodegeneration, and dementia. How exactly hypertension contributes to neurodegeneration is still not properly understood.

    The reasons for the sex-specific effects found in this study, with female KI mice having more severe neurodegeneration and neuroinflammation, remain speculative, I think. The authors suggest several possible underlying mechanisms. In human observational studies there is no consistent sex-specific antihypertensive class-effect, but this may not have been addressed in detail before. There is, however, accumulating data that sex differences may play a role in the effects of ACE on metabolic processes and cardiovascular disease.

    In an upcoming paper in Neurology, we suggest a potential explanation for why AT1 receptor blockers but not ACE inhibitors are associated with a decreased risk of dementia in epidemiological studies, whereas this animal model suggests both should do the job. It may be that ACE inhibitors and AT1 receptor blockers have different effects in the renin-angiotensin system, where the former decreases angiotensin-II activity, and the latter, together with dihydropyridine calcium channel blockers, increase angiotensin-II activity. Also, in human studies, confounding by indication bias is an important factor obscuring analyses of antihypertensive class effects.

    These results, together with the results from epidemiological studies, do suggest that repurposing of cheap, out-of-patent, antihypertensive drugs to slow down or prevent cognitive decline and dementia should be explored further. Most researchers will by now agree that there will not be a silver bullet for AD and that pursuing AD treatment or prevention by solely following the amyloid-path will most likely not lead to spectacular results. In a combined approach, using specific antihypertensive drugs in selected populations may thus contribute to the prevention of cognitive decline and dementia. Future clinical studies should provide further evidence on whether such an approach is viable, leads to clinical benefits, and does not lead to unacceptable risks.

    Further delineation of the target population for such interventions is warranted. After all, a knock-in mouse with a rare variant of the ACE1 gene, is not a human being.

    References:

    van Middelaar T, van Vught LA, van Charante EP, Eurelings LS, Ligthart SA, van Dalen JW, van den Born BJ, Richard E, van Gool PW. Lower dementia risk with different classes of antihypertensive medication in older patients. J Hypertens. 2017 May 13; PubMed.

    Peters R, Yasar S, Anderson CS, Andrews S, Antikainen R, Arima H, Beckett N, Beer JC, Bertens AS, Booth A, van Boxtel M, Brayne C, Brodaty H, Carlson MC, Chalmers J, Corrada M, DeKosky S, Derby C, Dixon RA, Forette F, Ganguli M, van Gool WA, Guaita A, Hever AM, Hogan DB, Jagger C, Katz M, Kawas C, Kehoe PG, Keinanen-Kiukaanniemi S, Kenny RA, Köhler S, Kunutsor SK, Laukkanen J, Maxwell C, McFall GP, van Middelaar T, Moll van Charante EP, Ng TP, Peters J, Rawtaer I, Richard E, Rockwood K, Rydén L, Sachdev PS, Skoog I, Skoog J, Staessen JA, Stephan BC, Sebert S, Thijs L, Trompet S, Tully PJ, Tzourio C, Vaccaro R, Vaaramo E, Walsh E, Warwick J, Anstey KJ. Investigation of antihypertensive class, dementia, and cognitive decline: A meta-analysis. Neurology. 2020 Jan 21;94(3):e267-e281. Epub 2019 Dec 11 PubMed.

    Ding J, Davis-Plourde KL, Sedaghat S, Tully PJ, Wang W, Phillips C, Pase MP, Himali JJ, Gwen Windham B, Griswold M, Gottesman R, Mosley TH, White L, Guðnason V, Debette S, Beiser AS, Seshadri S, Ikram MA, Meirelles O, Tzourio C, Launer LJ. Antihypertensive medications and risk for incident dementia and Alzheimer's disease: a meta-analysis of individual participant data from prospective cohort studies. Lancet Neurol. 2020 Jan;19(1):61-70. Epub 2019 Nov 6 PubMed.

    View all comments by Edo Richard

  2. This is an excellent paper by Cuddy et al., showing a potentially pathogenic mechanism by which ACE might increase the odds of developing AD. This pathogenic mechanism targeted the hippocampus in the brain, but not the cortex or cerebellum, thus one wonders what the mechanism(s) of selective neuronal vulnerability might be. Nevertheless, the findings in this article provide critical insight into the role of the ACE1 in AD pathogenesis. More importantly, the evidence presented provides a rationale for repurposing ACE inhibitors in the protection against AD.

    This article corroborates previous findings showing ACE inhibition could be exploited to develop AD therapeutics. For example, we showed convincingly that ARBs, including Valsartan, lowered Aβ accumulation, and also attenuated the development of Aβ-mediated cognitive deterioration, even when delivered at a dose much lower than that used for hypertension treatment in humans, suggesting a mechanism independent of vascular effects. Taken together, it’s reasonable to suggest that brain-penetrant ACE1 inhibitors and ARBs may still hold potential for the prevention of AD.

    References:

    Wang J, Ho L, Chen L, Zhao Z, Zhao W, Qian X, Humala N, Seror I, Bartholomew S, Rosendorff C, Pasinetti GM. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007 Nov;117(11):3393-402. PubMed.

    View all comments by Giulio Pasinetti

  3. Epidemiologists have known for more than a decade that blood-pressure-lowering medicines, such as ACE inhibitors and angiotensin receptor blockers, are associated with reduced incidence and prevalence of Alzheimer’s disease. The recent discovery of an SNP in the ACE1 gene that is significantly associated with AD by GWAS drives home the relevance of the renin-angiotensin system for AD. However, the mechanism through which dysfunction of the ACE1 gene might contribute to AD has been unclear.

    This paper enables a mechanistic deep dive into this field. The initial findings are both surprising and striking. The renin-angiotensin system is best known for its role in controlling vascular function, and has given rise to multiple frontline medications used in treatment of cardiovascular disease. However, the angiotensin receptors I and II are not restricted to the vasculature and are distributed broadly throughout the body.

    In the current manuscript, Cuddy et al. generate a transgenic knock-in mouse harboring the ACE1 R1279Q gene, which is a polymorphism associated with elevated risk of AD. These mice exhibit a strong phenotype with enhanced neurodegeneration, memory impairment, and abnormal EEGs. Surprisingly, the mice do not exhibit blood pressure abnormalities, and crosses with 5XFAD mice show no changes in amyloid deposition. Rather, the major change appears to be increased expression in neurons.

    The group goes on to examine the effects of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs). They show significant neuroprotection by both. These results raise the possibility that the benefits of ACEIs and ARBs observed in studies of AD subjects might derive from direct actions of these compounds on neurons.

    Indeed, in a study my group published in 2010, we observed that brain-penetrant ARBs were associated with improved outcomes compared to ARBs that did not distribute into the brain (Li et al., 2010). These results suggested that the ARBs were acting on a target in the brain beyond the vasculature. The current work by Cuddy et al. complement these results nicely, although the exact cell type most relevant in AD to ACEIs and ARBs remains to be determined.

    The new ACE1 R1279Q knock-ins provide an outstanding mouse model to explore the role of the renin-angiotensin system in the pathophysiology of AD. I expect many additional insights to come from this valuable mouse model.

    References:

    Li NC, Lee A, Whitmer RA, Kivipelto M, Lawler E, Kazis LE, Wolozin B. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis. BMJ. 2010;340:b5465. PubMed.

    View all comments by Benjamin Wolozin

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