Antihypertensive agents in Alzheimer’s disease: beyond vascular protection

References

• Wimo A, Guerchet M, Ali G-C, et al. The worldwide costs of dementia 2015 and comparisons with 2010. Alzheimers Dement. 2017;13:1–7.
   PubMed Web of Science ®Google Scholar
• Reitz C, Brayne C, Mayeux R. Epidemiology of Alzheimer disease. Nat Rev Neurol. 2011;7:137–152.
   PubMed Web of Science ®Google Scholar
• O’Brien JT, Markus HS. Vascular risk factors and Alzheimer’s disease. BMC Med. 2014;12:218.
   PubMed Web of Science ®Google Scholar
• Norton S, Matthews FE, Barnes DE, et al. Potential for primary prevention of Alzheimer’s disease: an analysis of population-based data. Lancet Neurol. 2014;13:788–794.
   PubMed Web of Science ®Google Scholar
• Kivipelto M, Ngandu T, Laatikainen T, et al. Risk score for the prediction of dementia risk in 20 years among middle aged people: a longitudinal, population-based study. Lancet Neurol. 2006;5:735–741.
   PubMed Web of Science ®Google Scholar
• Valenzuela M, Esler M, Ritchie K, et al. Antihypertensives for combating dementia? A perspective on candidate molecular mechanisms and population-based prevention. Transl Psychiatry. 2012;2:e107.
   PubMed Web of Science ®Google Scholar
• Safouris A, Psaltopoulou T, Sergentanis TN, et al. Vascular risk factors and Alzheimer’s disease pathogenesis: are conventional pharmacological approaches protective for cognitive decline progression? CNS Neurol Disord Drug Targets. 2015;14:257–269.
   PubMed Web of Science ®Google Scholar
• Meschia JF, Bushnell C, Boden-Albala B, et al. Guidelines for the primary prevention of stroke: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:3754–3832.
   PubMed Web of Science ®Google Scholar
• Lane CA, Barnes J, Nicholas JM, et al. Associations between blood pressure across adulthood and late-life brain structure and pathology in the neuroscience substudy of the 1946 British birth cohort (Insight 46): an epidemiological study. Lancet Neurol. 2019;18:942–952.
   PubMed Web of Science ®Google Scholar
• Tzourio C, Dufouil C, Ducimetière P, et al. Cognitive decline in individuals with high blood pressure: a longitudinal study in the elderly. EVA study group. Epidemiology of vascular aging. Neurology. 1999;53:1948–1952.
   PubMed Web of Science ®Google Scholar
• Richards SS, Emsley CL, Roberts J, et al. The association between vascular risk factor-mediating medications and cognition and dementia diagnosis in a community-based sample of African-Americans. J Am Geriatr Soc. 2000;48:1035–1041.
   PubMed Web of Science ®Google Scholar
• Ruitenberg A, Hofman A, Stricker BH, et al.; in’t Veld BA. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. NBA. 2001;22:407–412.
   Google Scholar
• Qiu C, Winblad B, Fastbom J, et al. Combined effects of APOE genotype, blood pressure, and antihypertensive drug use on incident AD. Neurology. 2003;61:655–660.
   PubMed Web of Science ®Google Scholar
• Peila R, White LR, Masaki K, et al. Reducing the risk of dementia: efficacy of long-term treatment of hypertension. Stroke. 2006;37:1165–1170.
   PubMed Web of Science ®Google Scholar
• Hanon O, Pequignot R, Seux M-L, et al. Relationship between antihypertensive drug therapy and cognitive function in elderly hypertensive patients with memory complaints. J Hypertens. 2006;24:2101.
   PubMed Web of Science ®Google Scholar
• Haag MDM, Hofman A, Koudstaal PJ, et al. Duration of antihypertensive drug use and risk of dementia: A prospective cohort study. Neurology. 2009;72:1727–1734.
   PubMed Web of Science ®Google Scholar
• Khachaturian AS, Zandi PP, Lyketsos CG, et al. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006;63:686–692.
   PubMed Web of Science ®Google Scholar
• Forette F, Seux ML, Staessen JA, et al. Prevention of dementia in randomised double-blind placebo-controlled Systolic Hypertension in Europe (Syst-Eur) trial. Lancet. 1998;352:1347–1351.
   PubMed Web of Science ®Google Scholar
• Tzourio C, Anderson C, Chapman N, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003;163:1069–1075.
   PubMed Web of Science ®Google Scholar
• Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet Neurol. 2008;7:683–689.
   PubMed Web of Science ®Google Scholar
• Forette F, Seux M-L, Staessen JA, et al. The prevention of dementia with antihypertensive treatment: new evidence from the Systolic Hypertension in Europe (Syst-Eur) study. Arch Intern Med. 2002;162:2046–2052.
   PubMed Web of Science ®Google Scholar
• SPRINT MIND Investigators for the SPRINT Research Group, Williamson JD, Pajewski NM, Auchus AP, et al., Effect of intensive vs standard blood pressure control on probable dementia: a randomized clinical trial. JAMA. 2019;321:553–561.
   PubMed Web of Science ®Google Scholar
• SPRINT MIND Investigators for the SPRINT Research Group, Nasrallah IM, Pajewski NM, Auchus AP et al., Association of intensive vs standard blood pressure control with cerebral white matter lesions. JAMA. 2019;322:524–534.
   PubMed Web of Science ®Google Scholar
• Rozzini L, Vicini Chilovi B, Bellelli G, et al. Effects of cholinesterase inhibitors appear greater in patients on established antihypertensive therapy. Int J Geriat Psychiatry. 2005;20:547–551.
   PubMed Web of Science ®Google Scholar
• Duron E, Rigaud A-S, Dubail D, et al. Effects of antihypertensive therapy on cognitive decline in Alzheimer’s disease. Am J Hypertens. 2009;22:1020–1024.
   PubMed Web of Science ®Google Scholar
• Bellew KM, Pigeon JG, Stang PE, et al. Hypertension and the rate of cognitive decline in patients with dementia of the Alzheimer type. Alzheimer Dis Assoc Disord. 2004;18:208–213.
   PubMed Web of Science ®Google Scholar
• Iadecola C, Yaffe K, Biller J, et al. Impact of Hypertension on cognitive function: a scientific statement from the American heart association. Hypertension. 2016;68:1–56.
   Web of Science ®Google Scholar
• Gorelick PB, Scuteri A, Black SE, et al. Vascular contributions to cognitive impairment and dementia: a statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2011;42:2672–2713.
   PubMed Web of Science ®Google Scholar
• Sweeney MD, Montagne A, Sagare AP, et al. Vascular dysfunction-The disregarded partner of Alzheimer’s disease. Alzheimer’s Dementia. 2019;15:158–167.
   PubMed Web of Science ®Google Scholar
• Petrovitch H, White LR, Izmirilian G, et al. Midlife blood pressure and neuritic plaques, neurofibrillary tangles, and brain weight at death: the HAAS. Honolulu-Asia aging study. NBA. 2000;21:57–62.
   Google Scholar
• Cifuentes D, Poittevin M, Dere E, et al. Hypertension accelerates the progression of Alzheimer-like pathology in a mouse model of the disease. Hypertension. 2015;65:218–224.
   PubMed Web of Science ®Google Scholar
• Ashby EL, Miners JS, Kehoe PG, et al. Effects of hypertension and anti-hypertensive treatment on Amyloid-β (Aβ) plaque load and Aβ-synthesizing and Aβ-degrading enzymes in frontal cortex. J Alzheimers Dis. 2016;50:1191–1203.
   PubMed Web of Science ®Google Scholar
• Shih Y-H, Wu S-Y, Yu M, et al. Hypertension accelerates Alzheimer’s disease-related pathologies in Pigs and 3xTg Mice. Front Aging Neurosci. 2018;10:73.
   PubMed Web of Science ®Google Scholar
• Zaman MA, Oparil S, Calhoun DA. Drugs targeting the renin-angiotensin-aldosterone system. Nat Rev Drug Discovery. 2002;1:621–636.
   PubMed Web of Science ®Google Scholar
• Hemming ML, Selkoe DJ. Amyloid beta-protein is degraded by cellular angiotensin-converting enzyme (ACE) and elevated by an ACE inhibitor. J Biol Chem. 2005;280:37644–37650.
   PubMed Web of Science ®Google Scholar
• Jalkute CB, Barage SH, Dhanavade MJ, et al. Molecular dynamics simulation and molecular docking studies of Angiotensin converting enzyme with inhibitor lisinopril and amyloid Beta Peptide. Protein J. 2013;32:356–364.
   PubMed Web of Science ®Google Scholar
• Bernstein KE, Koronyo Y, Salumbides BC, et al. Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer’s-like cognitive decline. J Clin Invest. 2014;124:1000–1012.
   PubMed Web of Science ®Google Scholar
• Hemming ML, Selkoe DJ, Farris W. Effects of prolonged angiotensin-converting enzyme inhibitor treatment on amyloid beta-protein metabolism in mouse models of Alzheimer disease. Neurobiol Dis. 2007;26:273–281.
   PubMed Web of Science ®Google Scholar
• AbdAlla S, Langer A, Fu X, et al. ACE inhibition with captopril retards the development of signs of neurodegeneration in an animal model of Alzheimer’s disease. Int J Mol Sci. 2013;14:16917–16942.
   PubMed Web of Science ®Google Scholar
• Hou D-R, Wang Y, Zhou L, et al. Altered angiotensin-converting enzyme and its effects on the brain in a rat model of Alzheimer disease. Chin Med J. 2008;121:2320–2323.
   PubMed Web of Science ®Google Scholar
• Asraf K, Torika N, Apte RN, et al. Microglial activation is modulated by captopril: in vitro and in vivo studies. Front Cell Neurosci. 2018;12:116.
   PubMed Web of Science ®Google Scholar
• Kehoe PG, Davies NM, Martin RM, et al. Associations of angiotensin targeting antihypertensive drugs with mortality and hospitalization in primary care patients with dementia. J Alzheimers Dis. 2013;33:999–1008.
   PubMed Web of Science ®Google Scholar
• Rist PM, Chalmers J, Arima H, et al. Baseline cognitive function, recurrent stroke, and risk of dementia in patients with stroke. Stroke. 2013;44:1790–1795.
   PubMed Web of Science ®Google Scholar
• Sink KM, Leng X, Williamson J, et al. Angiotensin-converting enzyme inhibitors and cognitive decline in older adults with hypertension: results from the cardiovascular health study. Arch Intern Med. 2009;169:1195–1202.
   PubMed Web of Science ®Google Scholar
• Gao Y, O’Caoimh R, Healy L, et al. Effects of centrally acting ACE inhibitors on the rate of cognitive decline in dementia. BMJ Open. 2013;3:e002881.
   PubMed Web of Science ®Google Scholar
• Wharton W, Stein JH, Korcarz C, et al. The effects of ramipril in individuals at risk for Alzheimer’s disease: results of a pilot clinical trial. J Alzheimers Dis. 2012;32:147–156.
   PubMed Web of Science ®Google Scholar
• de Oliveira FF, Chen ES, Smith MC, et al. Pharmacogenetics of angiotensin-converting enzyme inhibitors in patients with Alzheimer’s disease dementia. Curr Alzheimer Res. 2018;15:386–398.
   PubMed Web of Science ®Google Scholar
• Nalivaeva NN, Turner AJ. Targeting amyloid clearance in Alzheimer’s disease as a therapeutic strategy. Br J Pharmacol. 2019;4:190.
   Google Scholar
• Liu J, Liu S, Tanabe C, et al. Differential effects of angiotensin II receptor blockers on Aβ generation. Neurosci Lett. 2014;567:51–56.
   PubMed Web of Science ®Google Scholar
• Liu X, Wang Z, Xia Y, et al. Losartan-induced hypotension leads to tau hyperphosphorylation and memory deficit. J Alzheimers Dis. 2014;40:419–427.
   PubMed Web of Science ®Google Scholar
• Zhao W, Wang J, Ho L, et al. Identification of antihypertensive drugs which inhibit amyloid-beta protein oligomerization. J Alzheimers Dis. 2009;16:49–57.
   PubMed Web of Science ®Google Scholar
• Wang J, Ho L, Chen L, et al. Valsartan lowers brain beta-amyloid protein levels and improves spatial learning in a mouse model of Alzheimer disease. J Clin Invest. 2007;117:3393–3402.
   PubMed Web of Science ®Google Scholar
• Mogi M, Li J-M, Tsukuda K, et al. Telmisartan prevented cognitive decline partly due to PPAR-gamma activation. Biochem Biophys Res Commun. 2008;375:446–449.
   PubMed Web of Science ®Google Scholar
• Tsukuda K, Mogi M, Iwanami J, et al. Cognitive deficit in amyloid-beta-injected mice was improved by pretreatment with a low dose of telmisartan partly because of peroxisome proliferator-activated receptor-gamma activation. Hypertension. 2009;54:782–787.
   PubMed Web of Science ®Google Scholar
• Zhai Y, Yamashita T, Kurata T, et al. Strong reduction of low-density lipoprotein receptor/apolipoprotein E expressions by telmisartan in cerebral cortex and hippocampus of stroke resistant spontaneously hypertensive rats. J Stroke Cerebrovasc Dis. 2014;23:2350–2361.
   PubMed Web of Science ®Google Scholar
• Apolipoprotein BG. E and its receptors in Alzheimer’s disease: pathways, pathogenesis and therapy. Nat Rev Neurosci. 2009;10:333–344.
   PubMed Web of Science ®Google Scholar
• Shindo T, Takasaki K, Uchida K, et al. Ameliorative effects of telmisartan on the inflammatory response and impaired spatial memory in a rat model of Alzheimer’s disease incorporating additional cerebrovascular disease factors. Biol Pharm Bull. 2012;35:2141–2147.
   PubMed Web of Science ®Google Scholar
• Torika N, Asraf K, Danon A, et al. Telmisartan modulates glial activation: in vitro and in vivo studies. PLoS One. 2016;11:e0155823.
   PubMed Web of Science ®Google Scholar
• Tian M, Zhu D, Xie W, et al. Central angiotensin II-induced Alzheimer-like tau phosphorylation in normal rat brains. FEBS Lett. 2012;586:3737–3745.
   PubMed Web of Science ®Google Scholar
• Takeda S, Sato N, Takeuchi D, et al. Angiotensin receptor blocker prevented beta-amyloid-induced cognitive impairment associated with recovery of neurovascular coupling. Hypertension. 2009;54:1345–1352.
   PubMed Web of Science ®Google Scholar
• Ongali B, Nicolakakis N, Tong X-K, et al. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer’s disease model. Neurobiol Dis. 2014;68:126–136.
   PubMed Web of Science ®Google Scholar
• Chiu W-C, Ho W-C, Lin M-H, et al. Angiotensin receptor blockers reduce the risk of dementia. J Hypertens. 2014;32:938–947.
   PubMed Web of Science ®Google Scholar
• Hsu C-Y, Huang -C-C, Chan W-L, et al. Angiotensin-receptor blockers and risk of Alzheimer’s disease in hypertension population–a nationwide cohort study. Circ J. 2013;77:405–410.
   PubMed Web of Science ®Google Scholar
• Skoog I, Lithell H, Hansson L, et al. Effect of baseline cognitive function and antihypertensive treatment on cognitive and cardiovascular outcomes: study on COgnition and Prognosis in the Elderly (SCOPE. Am J Hypertens. 2005;18:1052–1059.
   PubMed Web of Science ®Google Scholar
• Zanchetti A, Elmfeldt D. Findings and implications of the study on cognition and prognosis in the elderly (SCOPE) - a review. Blood Press. 2006;15:71–79.
   PubMed Web of Science ®Google Scholar
• Saxby BK, Harrington F, Wesnes KA, et al. Candesartan and cognitive decline in older patients with hypertension: a substudy of the SCOPE trial. Neurology. 2008;70:1858–1866.
   PubMed Web of Science ®Google Scholar
• Wharton W, Goldstein FC, Tansey MG, et al. Rationale and design of the mechanistic potential of antihypertensives in preclinical Alzheimer’s (HEART) trial. JAD. 2017;61:815–824.
   Google Scholar
• Szabo-Reed AN, Vidoni E, Binder EF, et al. Rationale and methods for a multicenter clinical trial assessing exercise and intensive vascular risk reduction in preventing dementia (rrAD Study). Contemp Clin Trials. 2019;79:44–54.
   PubMed Web of Science ®Google Scholar
• Heneka MT, Landreth GE, Hüll M. Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders. Nat Clin Pract Neurol. 2007;3:496–504.
   PubMedGoogle Scholar
• Michel MC, Foster C, Brunner HR, et al. A systematic comparison of the properties of clinically used angiotensin II type 1 receptor antagonists. Pharmacol Rev. 2013;65:809–848.
   PubMed Web of Science ®Google Scholar
• Kume K, Hanyu H, Sakurai H, et al. Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease. Geriatr Gerontol Int. 2012;12:207–214.
   PubMed Web of Science ®Google Scholar
• Ozawa Y, Hayashi K, Kobori H. New generation calcium channel blockers in hypertensive treatment. Curr Hypertens Rev. 2006;2:103–111.
   PubMedGoogle Scholar
• Zamponi GW. Targeting voltage-gated calcium channels in neurological and psychiatric diseases. Nat Rev Drug Discov. 2016;15:19–34.
   PubMed Web of Science ®Google Scholar
• Weiss JH, Pike CJ, Cotman CW. Ca2+ channel blockers attenuate beta-amyloid peptide toxicity to cortical neurons in culture. J Neurochem. 1994;62:372–375.
   PubMed Web of Science ®Google Scholar
• Freir DB, Costello DA, Herron CE. A beta 25-35-induced depression of long-term potentiation in area CA1 in vivo and in vitro is attenuated by verapamil. J Neurophysiol. 2003;89:3061–3069.
   PubMed Web of Science ®Google Scholar
• Iwasaki K, Egashira N, Takagaki Y, et al. Nilvadipine prevents the impairment of spatial memory induced by cerebral ischemia combined with beta-amyloid in rats. Biol Pharm Bull. 2007;30:698–701.
   Google Scholar
• Gholamipour-Badie H, Naderi N, Khodagholi F, et al. L-type calcium channel blockade alleviates molecular and reversal spatial learning and memory alterations induced by entorhinal amyloid pathology in rats. Behav Brain Res. 2013;237:190–199.
   PubMed Web of Science ®Google Scholar
• Paris D, Bachmeier C, Patel N, et al. Selective antihypertensive dihydropyridines lower Aβ accumulation by targeting both the production and the clearance of Aβ across the blood-brain barrier. Mol Med. 2011;17:149–162.
   PubMed Web of Science ®Google Scholar
• Ho R, Ortiz D, Shea TB. Amyloid-beta promotes calcium influx and neurodegeneration via stimulation of L voltage-sensitive calcium channels rather than NMDA channels in cultured neurons. J Alzheimers Dis. 2001;3:479–483.
   PubMed Web of Science ®Google Scholar
• Yagami T, Ueda K, Asakura K, et al. Effects of endothelin B receptor agonists on amyloid beta protein (25-35)-induced neuronal cell death. Brain Res. 2002;948:72–81.
   PubMed Web of Science ®Google Scholar
• Fu H, Li W, Lao Y, et al. Bis(7)-tacrine attenuates beta amyloid-induced neuronal apoptosis by regulating L-type calcium channels. J Neurochem. 2006;98:1400–1410.
   PubMed Web of Science ®Google Scholar
• Pierrot N, Ghisdal P, Caumont A-S, et al. Intraneuronal amyloid-beta1-42 production triggered by sustained increase of cytosolic calcium concentration induces neuronal death. J Neurochem. 2004;88:1140–1150.
   PubMed Web of Science ®Google Scholar
• Facchinetti F, Fasolato C, Del Giudice E, et al. Nimodipine selectively stimulates beta-amyloid 1-42 secretion by a mechanism independent of calcium influx blockage. NBA. 2006;27:218–227.
   Google Scholar
• Paris D, Ait-Ghezala G, Bachmeier C, et al. The spleen tyrosine kinase (Syk) regulates Alzheimer amyloid-β production and Tau hyperphosphorylation. J Biol Chem. 2014;289:33927–33944.
   PubMed Web of Science ®Google Scholar
• Bachmeier C, Beaulieu-Abdelahad D, Mullan M, et al. Selective dihydropyiridine compounds facilitate the clearance of β-amyloid across the blood-brain barrier. Eur J Pharmacol. 2011;659:124–129.
   PubMed Web of Science ®Google Scholar
• Paris D, Quadros A, Humphrey J, et al. Nilvadipine antagonizes both Abeta vasoactivity in isolated arteries, and the reduced cerebral blood flow in APPsw transgenic mice. Brain Res. 2004;999:53–61.
   PubMed Web of Science ®Google Scholar
• Ekinci FJ, Ortiz D, Shea TB. Okadaic acid mediates tau phosphorylation via sustained activation of the L-voltage-sensitive calcium channel. Brain Res Mol Brain Res. 2003;117:145–151.
   PubMedGoogle Scholar
• Sanz JM, Chiozzi P, Colaianna M, et al. Nimodipine inhibits IL-1β release stimulated by amyloid β from microglia. Br J Pharmacol. 2012;167:1702–1711.
   PubMed Web of Science ®Google Scholar
• Gaasch JA, Geldenhuys WJ, Lockman PR, et al. Voltage-gated calcium channels provide an alternate route for iron uptake in neuronal cell cultures. Neurochem Res. 2007;32:1686–1693.
   PubMed Web of Science ®Google Scholar
• Bostanci MÖ, Bagirici F. Blocking of L-type calcium channels protects hippocampal and nigral neurons against iron neurotoxicity. The role of L-type calcium channels in iron-induced neurotoxicity. Int J Neurosci. 2013;123:876–882.
   PubMed Web of Science ®Google Scholar
• López-Arrieta JM, Birks J. Nimodipine for primary degenerative, mixed and vascular dementia. Cochrane Database Syst Rev. 2002;14:CD000147.
   Google Scholar
• Caramelli P, Laks J, Palmini ALF, et al. Effects of galantamine and galantamine combined with nimodipine on cognitive speed and quality of life in mixed dementia: a 24-week, randomized, placebo-controlled exploratory trial (the REMIX study. Arq Neuropsiquiatr. 2014;72:411–417.
   PubMed Web of Science ®Google Scholar
• Matsuda H, Araki N, Kuji I, et al. Effect of nilvadipine on regional cerebral blood flow in a patient with early Alzheimer disease. Clin Nucl Med. 2008;33:34–35.
   PubMed Web of Science ®Google Scholar
• Kennelly SP, Abdullah L, Paris D, et al. Demonstration of safety in Alzheimer’s patients for intervention with an anti-hypertensive drug Nilvadipine: results from a 6-week open label study. Int J Geriat Psychiatry. 2011;26:1038–1045.
   PubMed Web of Science ®Google Scholar
• Kennelly S, Abdullah L, Kenny RA, et al. Apolipoprotein E genotype-specific short-term cognitive benefits of treatment with the antihypertensive nilvadipine in Alzheimer’s patients–an open-label trial. Int J Geriat Psychiatry. 2012;27:415–422.
   PubMed Web of Science ®Google Scholar
• Lawlor B, Kennelly S, O’Dwyer S, et al. NILVAD protocol: a European multicentre double-blind placebo-controlled trial of nilvadipine in mild-to-moderate Alzheimer’s disease. BMJ Open. 2014;4:e006364.
   PubMed Web of Science ®Google Scholar
• Lawlor B, Segurado R, Kennelly S, et al. Nilvadipine in mild to moderate Alzheimer disease: A randomised controlled trial. PLoS Med. 2018;15:e1002660.
   PubMed Web of Science ®Google Scholar
• de Jong DLK, de Heus RAA, Rijpma A, et al. Effects of nilvadipine on cerebral blood flow in patients with Alzheimer Disease. Hypertension. 2019;74:413–420.
   PubMed Web of Science ®Google Scholar
• Dobarro M, Gerenu G, Ramírez MJ. Propranolol reduces cognitive deficits, amyloid and tau pathology in Alzheimer’s transgenic mice. Int J Neuropsychopharmacol. 2013;16:2245–2257.
   PubMed Web of Science ®Google Scholar
• Dobarro M, Orejana L, Aguirre N, et al. Propranolol restores cognitive deficits and improves amyloid and Tau pathologies in a senescence-accelerated mouse model. Neuropharmacology. 2013;64:137–144.
   PubMed Web of Science ®Google Scholar
• Dobarro M, Orejana L, Aguirre N, et al. Propranolol reduces cognitive deficits, amyloid β levels, tau phosphorylation and insulin resistance in response to chronic corticosterone administration. Int J Neuropsychopharmacol. 2013;16:1351–1360.
   PubMed Web of Science ®Google Scholar
• Wang J, Wright HM, Vempati P, et al. Investigation of nebivolol as a novel therapeutic agent for the treatment of Alzheimer’s disease. J Alzheimers Dis. 2013;33:1147–1156.
   PubMed Web of Science ®Google Scholar
• Saber AJ, Cain DP. Combined beta-adrenergic and cholinergic antagonism produces behavioral and cognitive impairments in the water maze: implications for Alzheimer disease and pharmacotherapy with beta-adrenergic antagonists. Neuropsychopharmacology. 2003;28:1247–1256.
   PubMed Web of Science ®Google Scholar
• Kenton L, Boon F, Cain DP. Combined but not individual administration of beta-adrenergic and serotonergic antagonists impairs water maze acquisition in the rat. Neuropsychopharmacology. 2008;33:1298–1311.
   PubMed Web of Science ®Google Scholar
• Gelber RP, Ross GW, Petrovitch H, et al. Antihypertensive medication use and risk of cognitive impairment: the Honolulu-Asia Aging Study. Neurology. 2013;81:888–895.
   PubMed Web of Science ®Google Scholar
• Yasar S, Xia J, Yao W, et al. Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo evaluation of memory study. Neurology. 2013;81:896–903.
   PubMed Web of Science ®Google Scholar
• Ruilope LM, Dukat A, Böhm M, et al. Blood-pressure reduction with LCZ696, a novel dual-acting inhibitor of the angiotensin II receptor and neprilysin: a randomised, double-blind, placebo-controlled, active comparator study. Lancet. 2010;375:1255–1266.
   PubMed Web of Science ®Google Scholar
• McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med. 2014;371:993–1004.
   PubMed Web of Science ®Google Scholar
• Vodovar N, Paquet C, Mebazaa A, et al. Neprilysin, cardiovascular, and Alzheimer’s diseases: the therapeutic split? Eur Heart J. 2015;36:902–905.
   PubMed Web of Science ®Google Scholar
• Iwata N, Tsubuki S, Takaki Y, et al. Metabolic regulation of brain Abeta by neprilysin. Science. 2001;292:1550–1552.
   PubMed Web of Science ®Google Scholar
• Hüttenrauch M, Baches S, Gerth J, et al. Neprilysin deficiency alters the neuropathological and behavioral phenotype in the 5XFAD mouse model of Alzheimer’s disease. J Alzheimers Dis. 2015;44:1291–1302.
   PubMed Web of Science ®Google Scholar
• Campbell DJ. Long-term neprilysin inhibition - implications for ARNIs. Nat Rev Cardiol. 2017;14:171–186.
   PubMed Web of Science ®Google Scholar
• Schoenfeld HA, West T, Verghese PB, et al. The effect of angiotensin receptor neprilysin inhibitor, sacubitril/valsartan, on central nervous system amyloid-β concentrations and clearance in the cynomolgus monkey. Toxicol Appl Pharmacol. 2017;323:53–65.
   PubMed Web of Science ®Google Scholar
• Langenickel TH, Tsubouchi C, Ayalasomayajula S, et al. The effect of LCZ696 (sacubitril/valsartan) on amyloid-β concentrations in cerebrospinal fluid in healthy subjects. Br J Clin Pharmacol. 2016;81:878–890.
   PubMed Web of Science ®Google Scholar
• Katsouri L, Vizcaychipi MP, McArthur S, et al. Prazosin, an α(1)-adrenoceptor antagonist, prevents memory deterioration in the APP23 transgenic mouse model of Alzheimer’s disease. Neurobiol Aging. 2013;34:1105–1115.
   PubMed Web of Science ®Google Scholar
• Wang LY, Shofer JB, Rohde K, et al. Prazosin for the treatment of behavioral symptoms in patients with Alzheimer disease with agitation and aggression. Am J Geriatr Psychiatry. 2009;17:744–751.
   PubMed Web of Science ®Google Scholar
• Arya U, Dwivedi H, Subramaniam JR. Reserpine ameliorates Abeta toxicity in the Alzheimer’s disease model in Caenorhabditis elegans. Exp Gerontol. 2009;44:462–466.
   PubMed Web of Science ®Google Scholar
• Saharia K, Arya U, Kumar R, et al. Reserpine modulates neurotransmitter release to extend lifespan and alleviate age-dependent Aβ proteotoxicity in Caenorhabditis elegans. Exp Gerontol. 2012;47:188–197.
   PubMed Web of Science ®Google Scholar
• O’Donnell MJ, Xavier D, Liu L, et al. Risk factors for ischaemic and intracerebral haemorrhagic stroke in 22 countries (the INTERSTROKE study): a case-control study. Lancet. 2010;376:112–123.
   PubMed Web of Science ®Google Scholar
• Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril protection against recurrent stroke study) Magnetic resonance imaging substudy. Circulation. 2005;112:1644–1650.
   PubMed Web of Science ®Google Scholar
• Friedman JI, Tang CY, de Haas HJ, et al. Brain imaging changes associated with risk factors for cardiovascular and cerebrovascular disease in asymptomatic patients. JACC Cardiovasc Imaging. 2014;7:1039–1053.
   PubMed Web of Science ®Google Scholar
• Toledo J, Arnold S, Raible K, et al. Contribution of cerebrovascular disease in autopsy confirmed neurodegenerative disease cases in the National Alzheimer’s coordinating centre. Brain. 2013;136:2697–2706.
   PubMed Web of Science ®Google Scholar
• Jellinger KA. The enigma of mixed dementia. Alzheimer’s Dementia. 2007;3:40–53.
   PubMed Web of Science ®Google Scholar
• Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer’s disease and other disorders. Nat Rev Neurosci. 2011;12:723–738.
   PubMed Web of Science ®Google Scholar
• Regan C, Katona C, Walker Z, et al. Relationship of vascular risk to the progression of Alzheimer disease. Neurology. 2006;67:1357–1362.
   PubMed Web of Science ®Google Scholar
• Ezzati A, Wang C, Lipton RB, et al. Association between vascular pathology and rate of cognitive decline independent of Alzheimer’s disease pathology. J Am Geriatr Soc. 2017;65:1836–1841.
   PubMed Web of Science ®Google Scholar
• Korf ESC, White LR, Scheltens P, et al. Midlife blood pressure and the risk of hippocampal atrophy: the Honolulu Asia Aging Study. Hypertension. 2004;44:29–34.
   PubMed Web of Science ®Google Scholar
• Hoffman LB, Schmeidler J, Lesser GT, et al. Less Alzheimer disease neuropathology in medicated hypertensive than nonhypertensive persons. Neurology. 2009;72:1720–1726.
   PubMed Web of Science ®Google Scholar
• Thal DR, Griffin WST, Vos RAI, et al. Cerebral amyloid angiopathy and its relationship to Alzheimer’s disease. Acta Neuropathol. 2008;115:599–609.
   PubMed Web of Science ®Google Scholar
• Charidimou A, Gang Q, Werring DJ. Sporadic cerebral amyloid angiopathy revisited: recent insights into pathophysiology and clinical spectrum. J Neurol Neurosurg Psychiatry. 2012;83:124–137.
   PubMed Web of Science ®Google Scholar
• Hughes TM, Kuller LH, Barinas-Mitchell EJM, et al. Arterial stiffness and β-amyloid progression in nondemented elderly adults. JAMA Neurol. 2014;71:562–568.
   PubMed Web of Science ®Google Scholar
• Sweeney MD, Sagare AP, Zlokovic BV. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14:133–150.
   PubMed Web of Science ®Google Scholar
• Ozacmak VH, Sayan H, Cetin A, et al. AT1 receptor blocker candesartan-induced attenuation of brain injury of rats subjected to chronic cerebral hypoperfusion. Neurochem Res. 2007;32:1314–1321.
   PubMed Web of Science ®Google Scholar
• Fleegal-DeMotta MA, Doghu S, Banks WA. Angiotensin II modulates BBB permeability via activation of the AT(1) receptor in brain endothelial cells. J Cereb Blood Flow Metab. 2009;29:640–647.
   PubMed Web of Science ®Google Scholar
• Pelisch N, Hosomi N, Ueno M, et al. Blockade of AT1 receptors protects the blood-brain barrier and improves cognition in Dahl salt-sensitive hypertensive rats. Am J Hypertens. 2011;24:362–368.
   PubMed Web of Science ®Google Scholar
• Min L-J, Mogi M, Shudou M, et al. Peroxisome proliferator-activated receptor-γ activation with angiotensin II type 1 receptor blockade is pivotal for the prevention of blood-brain barrier impairment and cognitive decline in type 2 diabetic mice. Hypertension. 2012;59:1079–1088.
   PubMed Web of Science ®Google Scholar
• Appleby BS, Nacopoulos D, Milano N, et al. A review: treatment of Alzheimer’s disease discovered in repurposed agents. Dement Geriatr Cognit Disord. 2013;35:1–22.
   PubMed Web of Science ®Google Scholar
• Barone E, Di Domenico F, Butterfield DA. Statins more than cholesterol lowering agents in Alzheimer disease: their pleiotropic functions as potential therapeutic targets. Biochem Pharmacol. 2014;88:605–616.
   PubMed Web of Science ®Google Scholar
• Corbett A, Pickett J, Burns A, et al. Drug repositioning for Alzheimer’s disease. Nat Rev Drug Discovery. 2012;11:833–846.
   PubMed Web of Science ®Google Scholar
• Corbett A, Williams G, Ballard C. Drug repositioning: an opportunity to develop novel treatments for Alzheimer’s disease. Pharmaceuticals (Basel). 2013;6:1304–1321.
   PubMedGoogle Scholar
• Dubois B, Feldman HH, Jacova C, et al. Advancing research diagnostic criteria for Alzheimer’s disease: the IWG-2 criteria. Lancet Neurol. 2014;13:614–629.
   PubMed Web of Science ®Google Scholar
• Jack CR, Bennett DA, Blennow K, et al. NIA-AA Research Framework: toward a biological definition of Alzheimer’s disease. Alzheimers Dement. 2018;14:535–562.
   PubMed Web of Science ®Google Scholar
• Banerjee G, Wilson D, Jäger H, et al. Novel imaging techniques in cerebral small vessel diseases and vascular cognitive impairment. Biochim Biophys Acta. 2016;1862:926–938.
   PubMed Web of Science ®Google Scholar
• Villemagne VL, Doré V, Burnham SC, et al. Imaging tau and amyloid-β proteinopathies in Alzheimer disease and other conditions. Nat Rev Neurol. 2018;14:225–236.
   PubMed Web of Science ®Google Scholar
• Qiu C, Strauss von E, Winblad B, et al. Decline in blood pressure over time and risk of dementia: a longitudinal study from the Kungsholmen project. Stroke. 2004;35:1810–1815.
   PubMed Web of Science ®Google Scholar
• Qiu C, Winblad B, Fratiglioni L. Low diastolic pressure and risk of dementia in very old people: a longitudinal study. Dement Geriatr Cognit Disord. 2009;28:213–219.
   PubMed Web of Science ®Google Scholar
• De Heus R, Donders RSantoso A, et al. Blood pressure lowering with nilvadipine in patients with mild-to-moderate alzheimer disease does not increase the prevalence of orthostatic hypotension. J Am Heart Assoc. 2019;8:e011938.
   PubMed Web of Science ®Google Scholar
• Barthold D, Joyce G, Wharton W, et al. The association of multiple anti-hypertensive medication classes with Alzheimer’s disease incidence across sex, race, and ethnicity. PLoS One. 2018;13:e0206705.
   PubMed Web of Science ®Google Scholar
• Roshandel G, Khoshnia M, Poustchi H, et al. Effectiveness of polypill for primary and secondary prevention of cardiovascular diseases (PolyIran): a pragmatic, cluster-randomised trial. Lancet. 2019;394:672–683.
   PubMed Web of Science ®Google Scholar
• Valenti R, Pantoni L, Markus HS. Treatment of vascular risk factors in patients with a diagnosis of Alzheimer’s disease: a systematic review. BMC Med. 2014;12:160.
   PubMed Web of Science ®Google Scholar