Table IV.

Clinical studies documenting the effect of renin angiotensin system modulation on cognition

1. Comparison of losartan and hydrochlorothiazide on cognitive function and quality of life in hypertensive patients [133].
Study design:	Double-blind randomized, control study
Patient population:	69 hypertensive patients ages 30 – 73 yo (mean 55 yo)
Study duration/ Follow-up:	A period of ~2.2 years (26 months)
Treatments:	Losartan (ARB), HCTZ (thiazide diuretic)
Study end-points:	Long-term changes in cognitive function and health state QoL index
Results/Conclusions:	Both drugs significantly lowered BP. Losartan improved health state QoL index in all subjects while HCTZ only improved it in patients ≥ 60 years old. Losartan also led to significant improvements in cognitive function, particularly memory, attention/concentration and comprehension while no changes in memory, attention/concentration or comprehension were observed in the HCTZ group. The authors concluded that losartan can have a positive effect not only on BP but also on impaired cognitive function, reversing even minimal cognitive deficits induced by hypertension

2. Influence of losartan and atenolol on memory function in very elderly hypertensive patients [130].
Study design:	Randomized double-blind active comparator parallel arm design
Patient population:	120 hypertensive patients mean age 81.3 yo
Study duration/ Follow-up:	A 6 months active treatment period (after 4-weeks wash-out)
Treatments:	Atenolol (βB) vs Losartan (ARB)
Study end-points:	Cognitive function (immediate memory, delayed recall, verbal fluency)
Results/Conclusions:	Although both atenolol and losartan had similar antihypertensive efficacy (no differences in BP lowering), only losartan significantly improved both immediate and delayed memory function

3. Effects of valsartan compared with enalapril on blood pressure and cognitive function in elderly patients with essential hypertension [110].
Study design:	PROBE active comparator parallel arm design
Patient population:	144 hypertensive patients age 61– 80 yo
Study duration/ Follow-up:	A 4 months active treatment period (after 2-weeks wash-out)
Treatments:	Enalapril (ACEI) vs Valsartan (ARB)
Study end-points:	Cognitive function (immediate memory, recognition, delayed recall, verbal fluency)
Results/Conclusions:	Both valsartan and enalapril had a clear antihypertensive effect, but the former led to a greater reduction at 16 weeks. Valsartan significantly improved both immediate and delayed memory function compared to both baseline and enalapril. Enalapril didn’t result in significant changes in any of the cognitive function tests

4. Use of angiotensin receptor blockers is associated with a lower incidence and progression of alzheimer’s disease matter lesions are present [139].
Study design:	prospective cohort analysis
Patient population:	Veterans aged ≥65 yo
Study duration/ Follow-up:	A 6-month period
Treatments:	ARBs, lisinopril (ACEI), other AH medications
Study end-points:	Incidence and progression of AD/ dementia
Results/Conclusions:	Patients taking ARBs exhibited a reduced incidence of AD/dementia compared to those taking lisinopril or other AHs. The use of ARBs was also associated with lower progression of AD/dementia compared to lisinopril group and other AHs. Therefore, ARBs are associated with a significant reduction in the incidence and progression of AD/ dementia compared to both ACEIs and AH medications.

5. Effects of hypertension therapy based on eprosartan on systolic arterial blood pressure and cognitive function: Primary results of the Observational Study on Cognitive function and Systolic Blood Pressure Reduction open-label study [136].
Study design:	Large, multinational open-label observational study
Patient population:	25, 745 newly diagnosed hypertensive patients mean age 65 yo
Study duration/ Follow-up:	A period of 6-months
Treatments:	Eprosartan 600 mg/d (ARB)
Study end-points:	Mean absolute change in SBP and cognitive/ MMSE score from baseline (relation between AH therapy with ARB and cognitive status)
Results/Conclusions:	Eprosartan based therapy was associated with overall improvements in cognitive function (MMSE score), which were related to the magnitude of BP reduction and support the use of ARB based AH treatment to delay or prevent cognitive decline hypertensive individuals

6. Use of angiotensin receptor blockers and risk of dementia in a predominantly male population: prospective cohort analysis [140].
Study design:	Prospective cohort analysis
Patient population:	819, 491 participants (98% male) aged ≥65 yo with CV disease
Study duration/ Follow-up:	A period of 5 years
Treatments:	3 cohorts (ARBs, ACEI-lisinopril, other CV drugs-βB, CCBs),
Study end-points:	Time to incident AD/ dementia, Disease progression (admission to nursing homes and death) among participants with pre-existing AD/ dementia
Results/Conclusions:	ARBs were associated with significant reductions in incident dementia compared with lisinopril or CV comparators. In patients with pre-existing AD/ dementia, ARBs showed significantly lower rates of admissions to nursing homes and death compared with users of the CV comparators Participants who used ARBs throughout the study or who started using ACEIs and switched to ARBs showed significantly lower risk of dementia than the group that used ACEIs throughout the study and did not switch to ARBs. The authors concluded that ARBs are associated with a significant reduction in the incidence and progression of AD and dementia compared with other AH agents.

7. Impact of Angiotensin Receptor Blockers on Alzheimer Disease Neuropathology in a Large Brain Autopsy Series [149].
Study design:	Multiple logistic regression analysis of patient data from the National Alzheimer Coordinating Center
Patient population:	890 hypertensive patients, mean age 81 yo
Study duration/ Follow-up:	Median time between enrollment and death was 2 years
Treatments:	ARBs, other AH meds, untreated
Study end-points:	Cognitive function (scores) and neuropathologic data (neuritic plaque, neurofibrillary tangle measures and vascular injury markers)
Results/Conclusions:	When comparing all 3 groups, those who received ARBs had significantly higher cognitive function and memory scores relative to the other 2 groups. Participants treated with ARBs were also less likely to have a clinical and neuropathologic diagnosis of AD. They showed less amyloid deposition, compared with both untreated participants and those treated with other AH medications including ACEIs.

8. Candesartan and cognitive decline in older patients with hypertension - A substudy of the SCOPE trial [134].
ClinicalTrials.gov Identifier	Foreign (UK)
Study design	Randomized double-blind, placebo-controlled clinical trial
Patient population	257 older adults (70–89 years) with hypertension
Study duration/ Follow-up	A period of 44 months
Treatments	8–16 mg candesartan or placebo once daily
Study end-points	Cognitive function
Results/Conclusions	The candesartan group showed significantly less decline in the cognitive domains of attention and episodic memory with a slight benefit in speed compared to placebo and no significant differences in working memory or executive function. The authors concluded that the potential for ARB–based antihypertensive therapy to reduce cognitive decline associated with hypertension in older adults may need further study.

9. Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease [148].
ClinicalTrials.gov Identifier	Foreign (Japan)
Study design	prospective randomized, open-label parallel design
Patient population	20 patients with hypertension and probable AD
Study duration/ Follow-up	A period of 6 months
Treatments	Telmisartan (40–80 mg/ day) or Amlodipine (5–10 mg daily)
Study end-points	Cognitive function, CBF, BP
Results/Conclusions	The telmisartan group showed similar or improved cognitive performance after 6 months, but the amlodipine group had worse performance on all tests after 6 months, although both groups had similar reductions in BP with telmisartan increasing CBF in multiple regions but amlodipine group increasing CBF only in the right cingulate gyrus. The authors concluded that telmisartan may have additional benefits making it useful for the treatment of elderly hypertensive patients with AD

10. Antihypertensive classes, cognitive decline and incidence of dementia: a network meta-analysis. [142].
Study design:	Meta-analysis / systematic review of RCTs
Patient population:	850,189 hypertensive patients with no prior cerebrovascular disease, mean age range 64–75yo
Study duration/Follow-up:	Median duration of 6 months
Treatments:	Diuretics, ARB, ACE-I, CCB, βB
Study end-points:	Cognitive function andincidence of dementia
Results/Conclusions:	AH treatment had significant benefits on overall cognition and may be effective for slowing cognitive decline and prevention of dementia with ARBs being most effective. ARBs were more effective than βB, diuretics and± ACEIs). The mean change in BP didn’t differ significantly between different AH drug classes.

11. Antihypertensive drugs decrease risk of Alzheimer disease- Ginkgo Evaluation of Memory Study [137].
Study design:	Secondary, post hoc, longitudinal analysis of GEMS trial (double-blind RCT)
Patient population:	older adults aged 75–96 yo with normal cognition (n = 5 1,928) or MCI (n = 5,320)
Study duration/ Follow-up:	6 years
Treatments:	Diuretics, ARB, ACE-I, CCB, βB
Study end-points:	Incidence of AD/ dementia among different AH medication user groups
Results/Conclusions:	Incidence of AD/ dementia among those with normal cognition and MCI at baseline was significantly lower in those using RAS modulators or diuretics. Authors concluded that diuretic, ARB, and ACE-I use was, in addition to and/or independently of BP, associated with reduced risk of AD/ dementia in participants with normal cognition, with similar trends among participants with MCI.

12. Renin-angiotensin system blockers affect cognitive decline and serum adipocytokines in Alzheimer’s disease. [146].
Study design:	Retrospective study
Patient population:	184 AD patients, age 76.4 ±7.9 years (range 52–90 years)
Study duration/ Follow-up:	The average length of follow-up was 2.45 ± 0.95 years (range 1–4.33 years)
Treatments:	ARB, other AH drugs, no AH drugs (in the case of normotensive patients)
Study end-points:	Cognitive function, Neuro-radiological assessment
Results/Conclusions:	The modified Fazekas scale scores for deep subcortical WMH and periventricular hyperintensities did not differ significantly among the 3 groups. Although the cognitive scores at onset/first visit were almost the same among all 3 groups, the annual decline in cognitive score was significantly lower in the ARB group compared to all other groups. The authors concluded that treatment with ARBs might slow the rate of cognitive decline in patients with AD and is a good therapeutic option with well-established safety for the management of hypertension in patients with AD.

13. The Antihypertensives and Vascular, Endothelial and Cognitive Function Trial (AVEC) [132].
ClinicalTrials.gov Identifier	NCT 00605072
Study design	Randomized Double-blind clinical trial
Patient population	53 Participants, age ≥ 60 years with hypertension and executive dysfunction
Study duration/ Follow-up	A period of 1 year
Treatments	Candesartan, Lisinopril, HCTZ
Study end-points	Cognitive function and cerebrovascular hemodynamics
Results/Conclusions	The candesartan group had the greatest improvement in executive function and cerebrovascular hemodynamics compared with both the lisinopril and HCTZ treatment groups. The authors concluded that in older adults with hypertension and mild executive dysfunction, an ARB-based regimen may be associated with preserved executive function, improved blood flow and cerebrovascular reserve compared to ACEI- or diuretic- based regimens, especially in those with relatively lower pretreatment blood flow velocity.

14. Effects of Centrally Acting Angiotensin Converting Enzyme Inhibitors on Functional Decline in Patients with Alzheimer’s Disease [155].
Study design	observational study- secondary analysis of the DARAD trial, a multicenter, blinded, randomized controlled trial
Patient population	406 patients with mild to moderate AD, age ≥ 50 years
Study duration/ Follow-up	A period of 12-months
Treatments	Central ACEIs (Ramipril, perindopril, lisinopril, trandolapril and fosinopril) vs other BP meds
Study end-pts	Cognitive and memory function, psychiatric
Results/Conclusions	There 12-month rate of cognitive decline was a significantly lower, 25% difference in patients taking central ACE-Is, compared to the other BP meds. This remained significant after adjusting for age, gender, education, and BP. The authors concluded that central ACEIs are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior, suggesting that these agents may slow AD progression.

15. Associations of Anti-Hypertensive Treatments with Alzheimer’s Disease, Vascular Dementia, and Other Dementias [29].
Study design:	Prospectively recorded, nested case-control study
Patient population:	9,197 aged ≥ 60 yo diagnosed with dementia
Study duration/ Follow-up:	Duration ≥ 6 months
Treatments:	ARB, ACEI, other AH drugs
Study end-points:	Associations of ARBs and ACE-Is with VaD/AD/unspecified other dementia
Results/Conclusions:	Patients prescribed either ARBs or ACE-Is were less likely to develop VaD, AD and unspecified/other dementia (inverse associations) than patients prescribed other AH drugs. Inverse associations were strongest for ARBs compared with ACE-Is. There were inverse dose-response relationships between ARBs and ACE-Is with AD.

16. Antihypertensive drugs, prevention of cognitive decline and dementia: A systematic review of observational studies, randomized controlled trials and meta-analyses, with discussion of potential mechanisms [143].
Study design:	Systematic review of observational studies, RCTs and Meta-Analyses
Patient population:	Study populations consisted of 1,346,176 subjects, mean age 74 years
Study duration/ Follow-up:	Range 6 months-9 years
Treatments:	AH medications
Study end-points:	Incidence and progression of cognitive decline/dementia
Results/Conclusions:	AH therapy, especially ARBs, ACEIs and CCBs, could reduce the incidence and progression of cognitive impairment/dementia, not only by lowering BP but also through other inherent neuroprotective properties.

17. Antihypertensive drug use and risk of cognitive decline in the very old: an observational study-The Newcastle 85+ Study [135].
ClinicalTrials.gov Identifier	Foreign (U.K.)
Study design	population-based observational cohort study
Patient population	238 older adults aged 75–96 yo with normal cognition (n=5 1,928) or MCI (n = 5,320)
Study duration/ Follow-up	A period of 3 years
Treatments	Diuretics, ARB, ACE-I, CCB, βB
Study end-points	Rate of cognitive decline over a 3 yr period
Results/Conclusions	Unadjusted analysis for AH use and cognitive change over 3 years suggested less cognitive decline was associated with ARBs and CCBs only. These remained significant only for CCBs after adjustment for confounders. On the other hand, βBs were associated with a significantly higher rate of cognitive decline. No significant associations were found for ACE-I or diuretics

18. Renin-Angiotensin-System Modulation may slow the Convension from Mild Cognitive Impairment to Alzheimer’s Disease [150].
Study design	longitudinal
Patient population	2,520 participants with MCI, age ≥ 75 years
Study duration/ Follow-up	A maximum follow-up period of 5 years
Treatments	RAS medication group (ARB, ACE-I), non-RAS medication group (Diuretics, CCB, βB)
Study end-pts	Cognitive, functional decline and AD conversion rate
Results/Conclusions	Even though BP control was statistically better among non-RAS medication users compared to RAS medication users, RAS users were a lot less likely to convert to AD. RAS users also demonstrated slower declines in memory and attention than non-RAS users. This slowing of cognitive decline was even more pronounced with BBB-crossing RAS medications, which were also associated with better executive function, language and global cognition compared to all other groups. Atenolol didn’t induce changes in cognitive performance The comparison between losartan and atenolol was significant for both memory functions. The authors concluded that in very elderly hypertensive patients, chronic AT1 receptor blockade by losartan could improve cognitive function

19. Associations of centrally acting ACE inhibitors with cognitive decline and survival in Alzheimer’s disease [147].
ClinicalTrials.gov Identifier	Foreign (U.K.)
Study design	retrospective observational study
Patient population	5,260 patients receiving acetylcholinesterase inhibitors who use Centrally acting-ACEIs (C-ACEIs); Noncentrally acting ACEIs (NC-ACEIs) or neither, at the time of AD diagnosis.
Study duration/ Follow-up	A period of 9 months
Treatments	Centrally acting-ACEIs l; Noncentrally acting NC-ACEIs
Study end-pts	Change in cognitive function as measured by MMSE
Results/Conclusions	MMSE scores significantly increased by in patients on C-ACEIs and deteriorated by in those on NC-ACEIs, with no differences in survival. The authors concluded that in people with AD, already receiving AchE inhibitors, those also taking C-ACEIs had stronger initial improvement in cognitive function, but there was no evidence of longer-lasting influence on dementia progression.

20. Memory is preserved in older adults taking AT1 receptor blockers [138].
Study design	A longitudinal study
Patient population	1,626 participants without dementia, age 55–91 years
Study duration/ Follow-up	A period of 3 years
Treatments	ARBs, other AH meds (Diuretics, CCB, βB, ACEIs, α1-blockers, α2-agonists, or direct vasodilators)
Study end-pts	Cognition, MRI brain volume and WMH
Results/Conclusions	The non-ARB group performed worse than normotensives on all measures of cognition, verbal learning, immediate and delayed recall, over the 3-year follow-up, while ARB users did not differ from normotensive subjects on any measure of cognition and demonstrated better recognition memory than those taking other antihypertensive medications. These cognitive differences are especially notable, given that the ARB group had significantly more participants diagnosed with type 2 diabetes, which has been associated with a 1.5- to 2.5-fold greater risk of dementia. Even with this added risk factor, the ARB users demonstrated preserved memory function over 3 years of follow-up. In short, hypertensive participants demonstrated worse memory and executive function, as well as greater memory decline, over the 3-year follow-up than normotensives, unless they were ARB users, who showed preserved memory compared with those taking other antihypertensive drugs.

21. Pharmacogenetics of Angiotensin-Converting Enzyme Inhibitors in Patients with Alzheimer’s Disease Dementia [141].
ClinicalTrials.gov Identifier	Foreign (Brazil)
Study design	Prospective pharmacogenetics study
Patient population	Late onset AD patients mean age 65 yo
Study duration/ Follow-up	A period of 1 year
Treatments	ACEIs vs other meds
Study end-points:	Cognitive function
Results/Conclusions:	No functional impacts were found regarding any genotypes or pharmacological treatment. Either for carriers of ACE haplotypes, or for APOε4- carriers, ACEIs slowed cognitive decline independently of BP variations. APOε4+ carriers were not responsive to treatment with ACEIs. ACEIs may slow cognitive decline for patients with AD, more remarkably for APOε4- carriers of specific ACE genotypes

22. The association of multiple anti-hypertensive medication classes with Alzheimer’s disease incidence across sex, race, and ethnicity[145].
Study design	A retrospective cohort study
Patient population	1,343,334 users of six different AH drug treatments, age ≥ 67 years
Study duration/ Follow-up	Data from 2007–2013
Treatments	ARBs, other AH meds (Diuretics, CCB, βB, ACEIs)
Study end-pts	Cognition, MRI brain volume and WMH
Results/Conclusions	Results: RAS-acting AH meds were more protective against AD than nonRAS-acting ones for males. ARBs were superior to ACEIs for both white men and white and black women.The authors concluded that ARBs may, reduce AD risk, particularly for white and black women and white men.

23. Observational Study of Brain Atrophy and Cognitive Decline Comparing a Sample of Community-Dwelling People Taking Angiotensin Converting Enzyme Inhibitors and Angiotensin [152].
ClinicalTrials.gov Identifier	Foreign (Australia)
Phase	II and III
Study design:	A longitudinal study
Patient population:	565 participants with T2D, HTN or both age 55–90 years without dementia
Study duration/ Follow-up:	3.2 years
Treatments:	ARBs, ACEIs, other AH, no AH
Study end-pts:	Cognition, MRI brain volume
Results/Conclusions:	Neither ACEI nor ARB use was associated with cognitive decline. Patients taking an ARB had a slower rate of brain atrophy than those taking an ACEI, independent of BP control.

24. Exploiting Drug-Apolipoprotein ε Gene Interactions in Hypertension to Preserve Cognitive Function: The 3-City Cohort Study [153].
ClinicalTrials.gov Identifier	Foreign (Australia, France)
Study design	A Prospective multisite, population-based cohort study
Patient population	3359 persons using antihypertensive drugs (median age 74 yo)
Study duration/ Follow-up	10 years follow-up
Treatments	Centrally acting ACEI, (captopril, fosinopril, lisinopril, perindopril, rampril, and trandolapril), peripherally acting ACEIs (benazepril, enalapril, moexipril, and quinapril) ARB, βb, CCB and thiazide-like drugs
Study end-pts	Cognitive function, assessed at baseline, 2, 4, 7 and 10 years using a validated battery of test covering global cognition, verbal fluency, immediate visual recognition memory, processing speed and executive function.
Results/Conclusions	This study showed that exposure of APOε4 carriers to ACEIs or ARBs over time was associated with better general cognitive function, compared with other antihypertensive drugs. Findings did not support RASs’ lipophilicity or ability to cross the BBB as a potential mechanism. The authors concluded that the use of RAS blockers for hypertension in APOε4 carriers may improve long-term cognitive function in older populations at risk of cognitive decline and dementia