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Effects of AT-1 receptor blockers on cognitive decline and Alzheimer's disease

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Effects of AT-1 receptor blockers on cognitive decline and Alzheimer's disease

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EFFECTS OF AT-1 RECEPTOR BLOCKERS ON COGNITIVE DECLINE
AND ALZHEIMER’S DISEASE

BY
JEAN K. HO

THESIS
Submitted in partial fulfillment of the requirements
for the degree of Master of Arts in Psychology
in the USC Dana and David Dornsife College of Letters, Arts, and Sciences
at the University of Southern California

August 2016

Los Angeles, California

Master’s Committee:
Daniel A. Nation, Ph.D., Chair
Margaret Gatz, Ph.D.
John J. McArdle, Ph.D.
Richard S. John, Ph.D.
Effects of ARBs on cognition

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Abstract

Objective: Animal studies, observational studies, and randomized controlled trials examining the
relationship between antihypertensive drug use and cognition provide cumulative support for the
perspective that antihypertensive treatment may have beneficial effects on cognition and risk for
Alzheimer’s disease. However, some studies have also shown mixed results, suggesting a more
complex picture in which specific antihypertensive medicines may be of greater or lesser value
with regard to protective effects on cognition. Angiotensin II type 1 receptor blockers (ARBs)
have been highlighted as one antihypertensive drug class that may confer greatest benefit.
Participants and Methods: Participants in the present study were 1,626 non-demented adults,
ages 55-91, from the Alzheimer’s Disease Neuroimaging Initiative. Eight hundred and four
participants reported using antihypertensive drugs. Three groups were compared: ARB-users
(HTN-ARBs), other-antihypertensive-drug-users (HTN-Other) and Normotensives. Vascular risk
burden, cognition, florbetapir-fluorine-18 (F18) PET retention, and brain MRI measures were
compared using ANCOVA, multiple linear regression, chi-square tests, latent growth models,
and Cox regression.
Results: The HTN-Other group performed significantly worse than Normotensives on Rey
Auditory Verbal Learning Test (AVLT) Immediate Recall (p = .002), AVLT Delayed Recall (p
< .001), AVLT Recognition (p = .001), Trails A (p < .001), and Trails B (p = .01), but ARB-
users did not perform significantly worse than Normotensives on any measures except for Trails
A (p=.04). The ARB-users performed significantly better than HTN-Other group on Recognition
(p=.04). The HTN-Other group continued to perform worse than Normotensives on AVLT
Delayed Recall over a 3-year follow-up period (p = .01). At baseline and over a 3-year follow-up
period, the HTN-Other group exhibited significantly greater WMH volume compared to the
Effects of ARBs on cognition

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Normotensive group (p = .004). There were no gross group differences in relation to florbetapir-
F18 PET retention, amyloid positivity, or progression to dementia.
Conclusions: Participants on antihypertensive drugs demonstrated worse memory and executive
function compared to normotensives, unless they were ARB-users, who showed better
recognition memory than those on other antihypertensive medications. Those on other
antihypertensive drugs also showed significantly greater baseline WMH volume compared to
normotensives, and compared to ARB-users over a 3-year period. Findings suggest that the
potential impact of antihypertensive drug use may be partly independent of cerebral amyloidosis,
and any benefit of ARBs over other antihypertensive medications may be due instead to possible
stymieing of the effects of cerebrovascular disease.
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ACKNOWLEDGEMENTS

My sincerest thanks and appreciation go first of all to my advisor, Dr. Daniel Nation, for his
tireless guidance and support, without which none of this work would have been possible. I am
very grateful to work with you, Dan! Thank you also to my committee members, Dr. Margaret
Gatz, Dr. Jack McArdle, and Dr. Richard John, for your input and feedback on this project. Your
questions, suggestions, and feedback were invaluable. I am also indebted to my fellow students,
Sarfaraz Serang and Shannon Potts, who provided consultation on the statistical analyses used in
this project, and who patiently answered all of my many emails. Thanks to all the ADNI
participants for your generous contributions of time and energy to research surrounding
Alzheimer’s disease. Finally, thank you to my Mom & Dad, for being there since day one.

Effects of ARBs on cognition

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TABLE OF CONTENTS

ACKNOWLEDGEMENTS………………..………………………………………………………... 4
INTRODUCTION…………………………………………………………………………………... 7
METHODS……….……………..…………………………………………………………………... 13
Participants……………..…………………………………………………………………….. 14
Blood pressure medication groups…………..…………………………..…………………… 14
Physiological, clinical, and genetic data…………..…………………………………………. 15
Vascular risk factors…………..…………………………..…………………………………. 15
Neuropsychological battery…………..……………………………………………………… 16
Florbetapir-fluorine-18 (
18
F) PET data…………..………………………………………….. 16
Brain volume estimation…………..…………………………..…………………………….. 17
Statistical analyses: Cross sectional analyses…………..……………………………………. 19
Statistical analyses: Longitudinal analyses…………..………………………………………. 19
Rates of change from baseline through 9-year follow-up…………..……………………. 19
Mean differences from baseline through 3-year follow-up…………..………………….. 21
Progression to dementia…………..…………………………..………………………….. 21
RESULTS…………..…………………………..…………………………..……………………….. 21
Physiological, clinical, and genetic data…………..…………………………………………. 21
Vascular risk factors…………..…………………………..………………………………….. 22
Cross-sectional analyses…………..…………………………..……………………………... 22
Neuropsychological function…………..…………………………..…………………….. 22
Brain MRI measures…………..…………………………..……………………………... 23
Florbetapir-fluorine-18 (
18
F) PET retention and amyloid status…………..……………... 23
Longitudinal analyses…………..……………….…………..……………………………….. 23
Differences in rate of change from baseline…………..…………………………............ 23
1. Neuropsychological function…………..…………………..…………………… 23
2. Brain MRI measures…………..………………………………………………... 23
Mean differences in performance, from baseline through 3-year follow-up……………. 24
Effects of ARBs on cognition

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1. Neuropsychological function…………..……………………………………….. 24
2. Brain MRI measures…………..…………………………..……………………. 24
Progression to dementia…..…………………………..…………………………………. 26
DISCUSSION…………..…………………………..…………………………..…………………… 26
REFERENCES…………..…………………………..…………………………..…………………... 32
TABLE 1: CLINICAL AND DEMOGRAPHIC DATA…………..………………………………...

46
TABLE 2: NEUROPSYCHOLOGICAL DATA IN THE TOTAL SAMPLE………………..…….. 47
FIGURE 1: NEUROPSYCHOLOGICAL PERFORMANCE FOR THE THREE MEDICATION
GROUPS ACROSS THE TOTAL SAMPLE.……………………………………………………….

48
FIGURE 2: WHITE MATTER HYPERINTENSITY (WMH) VOLUME FOR THE THREE
MEDICATION GROUPS ACROSS THE TOTAL SAMPLE……………………………………...

49
FIGURE 3: AVLT DELAYED RECALL PERFORMANCE FOR THE THREE MEDICATION
GROUPS ACROSS THE TOTAL SAMPLE, EXAMINED OVER A 3 YEAR FOLLOW-UP
PERIOD…………………………………………………………………………………………….

50
FIGURE 4: WHITE MATTER HYPERINTENSITY (WMH) VOLUME FOR THE THREE
MEDICATION GROUPS ACROSS THE TOTAL SAMPLE, EXAMINED OVER A 3 YEAR
FOLLOW-UP PERIOD……………………………………………………………………………...

51

APPENDIX A: FLOWCHART OF INCLUSION / EXCLUSION OF PARTICIPANTS…………. 52
APPENDIX B: MISSING DATA AT VARIOUS TIMEPOINTS…………..……………………...

53
APPENDIX C: BASELINE CHARACTERISTICS OF PARTICIPANTS WITH MISSING VS.
NON-MISSING DATA AT 3-YEAR FOLLOW-UP VISIT………………………………………..

54
APPENDIX D: CONVERSION TO DEMENTIA AT VARIOUS TIMEPOINTS…………………

55

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Introduction
Hypertension represents the most common condition observed in primary care and one of
the most treatable risk factors for illness (Veglio et al., 2008). The 8th and most recent report of
the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High
Blood Pressure (JNC) recommends pharmacologic treatment of hypertension to achieve blood
pressure goals of less than 140/90 mmHg in young adults and 150/90 mmHg in older adults
(James et al., 2014). Hypertension is also an established risk factor for cognitive decline,
Alzheimer’s disease, and Vascular Dementia (Duron and Hanon, 2008). These and other findings
support the vascular hypothesis of Alzheimer’s disease, which postulates that cerebrovascular
disease and dysfunction, due to hypertension and other vascular risk factors, contribute to this
dementing illness through effects on cerebral perfusion and blood-brain barrier (BBB)
compromise (de la Torre, 2002; Zlokovic, 2011). Therefore, work surrounding antihypertensive
treatments and their possible salutary effects on preserving cognition through improved vascular
health forms a promising area of research (Skoog and Gustafson, 2006).
Hypertension and vascular risk factors have been linked to decreased performance on
various measures of cognition (Novak and Hajjar, 2010) that go beyond those expected by age
alone (Brady et al., 2005). Studies comparing hypertensives to normotensives indicate that
hypertensives exhibit worse performance in many domains of cognitive function, including
episodic memory (Waldstein et al., 2008), working memory and executive function (Saxby et al.,
2003), attention and psychomotor speed (Waldstein, 2003), and language (Nation et al., 2010).
There are many pathophysiological mechanisms by which hypertension may promote
cognitive decline and eventual clinical expression of Alzheimer’s disease, including alterations
in cerebral hemodynamics and cerebrovascular disease (Iadecola and Davisson, 2008).
Effects of ARBs on cognition

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Hypertension initiates changes in the cellular architecture of cerebral arterioles, the
primary source of vascular resistance to pressure in the brain. These changes lower the amount
of stress exerted on vessel walls to protect capillary microvessels downstream. These changes
include eutrophic and hypertrophic remodeling. Eutrophic remodeling consists of the
rearrangement of smooth muscle cells which line the inside of arteries. Hypertrophic remodeling
consists of the increased proliferation of these cells and their inward growth. Both processes
reduce the size of the arterial lumen to counter changes in the rate of flow induced by
hypertension (Baumbach & Heistad, 1988). Although these changes can assist the arterioles in
adapting to chronic increases in pressure, these processes change the hemodynamic and
mechanical properties of vessels, and can lead to increased cerebrovascular resistance
(Mathiassen et al, 2007), decreased distensibility, and increased vessel stiffening (Izzard et al,
2006). This can further lead to weakening of vessel walls, hemorrhage, and lacunar and
microscopic infarcts (Lammie, 2002).
Functional implications of these vascular changes have been demonstrated in mouse
models, where arterial hypertension has been found to increase the permeability and dysfunction
of the BBB as well as reduce cerebral blood flow (CBF) (Gentile et al., 2009). It has also been
hypothesized that these vascular changes may directly exacerbate Alzheimer’s disease
pathophysiology through increased influx and decreased efflux of amyloid-beta (Aβ) across the
BBB (Sagare et al., 2012) and impairment of Aβ clearance along perivascular pathways (Iliff and
Nedergaard, 2013; Kress et al., 2014). The average CNS clearance rates of both Aβ 1-42 and Aβ1-
40 are slower in Alzheimer’s disease patients compared to cognitively normal controls,
suggesting that impaired Aβ clearance may be a major factor contributing to the disease
(Mawuenyega et al., 2010). This failure of Aβ removal is associated with cerebral amyloid
Effects of ARBs on cognition

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angiopathy (CAA) and the aggregation of Aβ as plaques in artery walls and extracellular spaces
of the brain parenchyma (Weller, Subash, Preston, Mazanti, & Carare, 2008).
In support of the hypothesis that hypertension impairs Aβ clearance, PET studies in
cognitively normal individuals have found positive associations between blood pressure,
including systolic blood pressure and pulse pressure, and fibrillar Aβ burden (Langbaum et al.,
2012; Rodrigue et al., 2013). These associations are not fully accounted for by genetic or
vascular risk factors. Brachial artery pulse pressure has also been linked to reduced CSF Aβ 1-42
(Nation et al., 2013), indicating increased cerebral Aβ1-42 retention (Fagan et al., 2006). Our own
recent work indicates that pulse pressure is associated with increased levels of phosphorylated
tau (P-tau) in cognitively healthy individuals (Nation et al., 2013) and those with MCI (Nation et
al., 2015). Thus, accumulating evidence indicates that blood pressure elevation may play a role
in cognitive and biological changes occurring during the earliest stages of Alzheimer’s disease.
Despite these clear links between blood pressure and both dementia and Alzheimer’s
disease, studies investigating the cognitive benefits of blood pressure control have been mixed.
While the MRC-Elderly, SHEP, PROGRESS, SYST-EUR and SYST-EUR 2 trials indicated
some benefit, the HYVET-COG, TRANSCEND and ONTARGET trials and a Cochrane review
found no benefit (for reviews, see Fournier et al., 2009; McGuinness et al., 2009). In studies
suggesting possible protective effects, treated hypertensives have been found to have less
Alzheimer’s disease neuropathology when compared to both untreated hypertensives and
normotensives (Hoffman et al., 2009), evidenced in lower neuritic plaque counts, which are
extracellular protein deposits of Aβ that result from the misprocessing of the amyloid precursor
protein (APP) by γ- and β-secretases (Solfrizzi et al., 2006). Findings also included fewer
neurofibrillary tangles (NFTs) of abnormally hyperphosphorylated tau protein. In its soluble
Effects of ARBs on cognition

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form, tau normally promotes the stability of microtubules in axons and enhances vesicle
transport. In hyperphosphorylated form, tau is insoluble and aggregates into paired helical
filaments which lack affinity for microtubules (Querfurth & LaFerla, 2010).
When compared with individuals who have never taken any antihypertensive drugs,
individuals treated with these medications exhibit decreased risk of all cause dementia, with an
8% risk reduction for every year of use in individuals <75 years old, and a 4% risk reduction in
those >75 years, with similar estimates for Alzheimer’s disease (Haag et al., 2009). A recent
meta-analysis of 19 randomized trials and 11 studies examining the relationships among
antihypertensive drug use, cognition, and dementia incidence provided support for the
perspective that antihypertensive treatment may have beneficial effects on cognition (Levi
Marpillat et al., 2013). Of the many antihypertensive drug classes available, angiotensin II type I
receptor blockers (ARBs) in particular were highlighted as the one class that may potentially
confer the greatest benefit (Levi Marpillat et al., 2013). ARBs have been found to be associated
with improved performance on measures of executive function (Hajjar et al., 2013), immediate
and delayed memory (Fogari, 2003), and global cognitive function (Tedesco et al., 1999; Hanon
et al., 2008). These improvements were found to be superior to those of other antihypertensive
drug classes, such as ACE inhibitors, diuretics, and beta blockers.
Both ARBs and ACE inhibitors are recommended as frontline drugs in non-black patients
younger than 60 and as third options, after calcium channel blockers and thiazide diuretics, in
non-black patients aged 60 and older (Weber et al., 2014). If hypertension remains uncontrolled,
ARBs and ACE inhibitors are recommended as second or third drugs in non-black patients of all
ages, if not already prescribed. In black patients of all ages, ARBs and ACE inhibitors are
recommended as supplementary drugs in addition to frontline drugs of calcium channel blockers
Effects of ARBs on cognition

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or thiazides (Weber et al., 2014). Of the two classes of drugs, ARBs are less commonly
prescribed, given that ACE inhibitors are an older class of drugs with more affordable, generic
forms (Ashby and Kehoe, 2013).
Several mechanisms may be responsible for the observed association between ARB use
and improved neuropsychological functioning. ARBs may work through blood pressure
controlling influence on the RAAS, which regulates blood pressure through its effects on fluid
homeostasis and vascular tone. While the RAAS is more commonly associated with endocrine
and vascular-renal functions, research has also established the presence of a paracrine RAAS
within the CNS that acts largely independently of peripheral function (Ciobica et al., 2009). The
RAAS in the brain is believed to be involved in processes beyond mere blood pressure control,
including processes of learning and memory (Llorens and Mendelsohn, 2002). ARBs target the
locally-acting brain RAAS and block AT1Rs, allowing greater AT2R binding (Furiya et al.,
2013), thus exerting their effects by both interrupting AT1 receptor activity and promoting AT2
receptor activity.
AT1 receptor activity includes the generation of free radicals and the activation of
multiple inflammatory pathways, all of which lead to tissue damage (Suzuki et al., 2003).
Greater AT2 receptor activity decreases vasoconstriction, thus increasing CBF, which is
protective against inflammation and ischemia (Iwai et al., 2004). Evidence from mouse model
studies of ARBs suggest that AT2 receptor activation protects against ischemia-induced neuronal
damage (Li et al., 2005; McCarthy et al., 2009), which manifests as alterations in neuronal spine
and dendritic morphology (Maul et al., 2008). A recent mouse model study reported that
hypertensive levels of angiotensin II in transgenic APPPS1 mice were associated with reduced
Effects of ARBs on cognition

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performance in memory tasks and increased Alzheimer’s disease pathology and cerebrovascular
impairment not observed in normotensive mice (Cifuentes et al., 2015).
Further animal studies suggest that ARBs may directly impact mechanisms involved in
Alzheimer’s disease pathophysiology independent of blood pressure control. For example, in a
transgenic Alzheimer’s disease mouse model (Tg2576) study of 55 antihypertensive
medications, Wang and colleagues (2007) found that treatment with only one medication –
valsartan (an ARB) – disrupted the oligomerization of Aβ and resulted in a two-to-threefold
decrease of extracellular plaque deposits. This was associated with significant overall reductions
in total soluble Aβ and Aβ1-40 in the brain, improvements in spatial memory abilities, and slower
development of Aβ-related cognitive decline, despite failure of the drug to produce any
significant changes in systolic, diastolic, or mean arterial blood pressure. Treatment also
increased levels of membrane-bound IDE activity and IDE-related proteolytic cleavage of Aβ in
the cerebral cortex.
Therefore, a convergence of evidence from animal studies (Li et al., 2005; Wang et al.,
2007; Mogi et al., 2008; Tota et al., 2009; Tsukuda et al., 2009; Danielyan et al., 2010; Tian et
al., 2012; Kishi et al., 2012; Ongali et al., 2014), observational studies (Hanon et al., 2008; Li et
al., 2010; Davies et al., 2011; Hajjar et al., 2012; Chiu et al., 2014; Goh et al., 2014), and
randomized clinical trials (Fogari et al., 2003; Kume et al., 2012; Hajjar et al., 2013) have
provided support for the perspective that antihypertensive treatment with ARBs in particular may
have potential for preserving cognition against a backdrop of vascular risk factors for cognitive
decline. There are many mechanistic pathways which ARBs may modulate which are implicated
in Alzheimer’s disease pathophysiology, including AT1R and AT2R activation, IDE activity
(Wang et al., 2007), cerebrovascular regulation (Ito et al., 2002; Takeda et al., 2009; Kume et
Effects of ARBs on cognition

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al., 2012), PPAR-gamma activity (Mogi et al., 2008; Tsukuda et al., 2009; Kishi et al., 2012),
Aβ aggregation, clearance, and breakdown (Wang et al., 2007; Zhu et al., 2011), as well as
attenuation of tau phosphorylation, (Tian et al., 2012). Influence on these multiple pathways may
make ARBs a potent choice for antihypertensive intervention that could also yield positive
effects on maintaining cognition. Hence, the present study sought to investigate whether use of
ARBs would confer protective effects on cognition greater than those of other antihypertensive
drugs.
Our specific hypotheses were that: (1) normotensives would show the best preservation
of neuropsychological function, followed by ARB-users, who in turn would outperform other-
antihypertensive-drug users; (2) ARB-users would show better memory and executive function
than other-antihypertensive-drug users, in line with positive effects reported elsewhere (Fogari et
al., 2003; Hajjar et al., 2013); (3) in comparison to users of other antihypertensive drugs, ARB
users will show attenuation of cognitive decline over time, particularly on tests of memory and
executive function.
Methods
Data were obtained from the ADNI database (adni.loni.usc.edu). The primary goal of
ADNI is to test whether neuroimaging, other biological markers, and clinical and
neuropsychological assessment can be combined to measure the progression of MCI and early
Alzheimer’s disease. ADNI is the result of efforts of many co-investigators from a range of
academic institutions and private corporations, and subjects have been recruited from more than
50 sites across the United States and Canada. Participants are recruited via newsletters, Web-
based communication, direct mail, and press releases. Inclusion criteria include: age 55 to 91
years, permitted medications stable for 4 weeks, study partner who can accompany participant to
Effects of ARBs on cognition

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visits, Geriatric Depression Scale less than 6, Hachinski Ischemic Score less than or equal to 4,
adequate visual and auditory acuity, good general health, 6 grades of education or work history
equivalent, and ability to speak English or Spanish fluently. Exclusion criteria for cognitively
normal and MCI participants include any significant neurologic disease or history of significant
head trauma. For more information, see www.adni-info.org.
Participants
Participants were 1,626 nondemented ADNI-1 (recruitment and data collection from
2004-2010), ADNI-Grand Opportunity (2009-2011), and ADNI-2 participants (2011-2016), ages
55-91, who were classified as either cognitively normal or having MCI at their screening
evaluations. Participants were followed at various timepoints: baseline, and 6, 12, 18, 24, 36, 48,
60, 72, 84, 96, 108, and 120 months from baseline. Efforts were made to follow-up with each
participant enrolled for each timepoint, regardless of dementia status; however, data are not
available on reasons for attrition over this time period (see Appendices A, B, and C for more
information). Criteria for MCI were (1) subjective memory complaint reported by the participant
or informant; (2) Mini-Mental State Examination scores between 24 and 30 (inclusive); (3)
global Clinical Dementia Rating score of 0.5; (4) scoring below education-adjusted cutoffs for
delayed free recall on story A of the Wechsler Memory Scale-Revised (WMS-R) Logical
Memory II subtest; (5) general cognition and functional performance preserved to the extent that
one would not qualify for a diagnosis of Alzheimer’s disease (Petersen et al., 2010).
Blood pressure medication groups
Eight-hundred four participants (49.4% of the total sample) reported using at least one of
eight classes of antihypertensive drugs: ARBs, ACE-inhibitors, beta-blockers, calcium channel
blockers, alpha-1-adrenergic blockers, alpha-2-agonists or other centrally acting drugs, diuretics,
Effects of ARBs on cognition

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or direct vasodilators. Of these, 182 (11.2% of the total sample) were taking ARBs and were
classified as ARBs-users (HTN-ARBs). Six-hundred twenty-two (38.3% of the total sample)
were taking other antihypertensive medications and were classified as other-antihypertensive-
drug-users (HTN-Other). The remaining 822 (50.5% of the total sample) had no documented
history of hypertension and were classified as Normotensive. To ensure that some of these
participants did not represent a group of untreated hypertensives, blood pressure measures were
used to exclude those with values at or above Stage 2 hypertension (160/100, n=40) (Weber et
al., 2014). We did not use the more conservative cutoffs recommended for treatment of older
adults (150/90) due to the unreliability of a single blood pressure measure and the likelihood that
the research environment may have artificially produced transient, mild elevations in blood
pressure in normotensive individuals. Thus, the final sample consisted of 1,586 participants.
Physiological, clinical, and genetic data
Physiological measures included seated brachial artery systolic and diastolic blood
pressures. Pulse pressure was computed as systolic minus diastolic pressure. Data on blood
pressure indices were available for 98.8% of the sample. BMI was calculated as weight (kg)
divided by height (meters) squared. Data on BMI were available for 98.8% of the sample. Blood
samples were utilized to determine APOE-ε4 carrier status, and participants were categorized
into those with or without one or more copies of the APOE-ε4 allele. APOE genotype data were
available for 85.3% of the sample.
Vascular risk factors
Vascular risk factor burden for participants was assessed from medical history data
collected at baseline and screening visits. Criteria for assessment were adapted from the
Framingham Stroke Risk Profile (Wolf et al., 1991) and Framingham Coronary Risk Profile
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(Wilson et al., 1998). The following vascular risk factors were included: cardiovascular disease
(myocardial infarction, intermittent claudication, angina, heart failure, or other evidence of
coronary disease), dyslipidemia (low levels of high-density lipoprotein cholesterol, high levels of
low-density lipoprotein cholesterol, or hypertriglyceridemia), type 2 diabetes, atrial fibrillation,
evidence of carotid artery disease, and transient ischemic attack or minor stroke.
Neuropsychological battery
Cognitive measures consisted of scores from participants’ screening and baseline
evaluations. Baseline evaluations were conducted within 1 month of recruitment and screening
and included: (1) WMS-R Logical Memory II subtest: immediate and delayed recall on Story A;
(2) Rey Auditory Verbal Learning Test (AVLT): total immediate recall score for Trials 1-6,
delayed recall score, recognition score; (3) Wechsler Adult Intelligence Scale-Revised (WAIS-
R) Digit Span: forward and backward scores and spans; (4) Trail Making Test: parts A and B,
times to completion; (5) Animal Fluency: total score, (6) Vegetable Fluency: total score, (7)
Boston Naming Test (BNT): total score. These tests were selected to assess various domains of
cognition: memory (WMS-R Logical Memory II, AVLT), attention (WAIS-R Digit Span
forward, Trails A), executive function (WAIS-R Digit Span backward, Trails B), and language
(Animal fluency, Vegetable fluency, BNT). Scores on the WAIS-R Digit Span and Vegetable
fluency tests were only available for participants from ADNI-1 as these tests were subsequently
dropped.
Florbetapir-fluorine-18 (
18
F) PET data
PET scans producing the imaging data were obtained 50-70 min following intravenous
injection of 10 mCi (370 MBq) of florbetapir-18F. Details of the PET scanners used, imaging
protocol, and quality control measures are published elsewhere (Landau et al., 2012). Complete
Effects of ARBs on cognition

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details on ADNI PET image data can be accessed online (adni.loni.ucla.edu/about-data-
samples/image-data), in addition to details regarding processing (adni.loni.ucla.edu/wp-
content/uploads/2011/03/ADNI_AV45_Methods_JagustLab_0417.12.pdf). Briefly, Freesurfer
v. 4.50 (surfer.nmr.mgh.harvard.edu) was used to segment and parcellate images into individual
cortical regions of interest. Images were averaged, spatially aligned, interpolated to a standard
voxel size, and smoothed to a uniform resolution of 8 mm full width at half maximum (Landau et
al., 2012). Mean florbetapir uptake from gray matter relative to uptake in the whole cerebellum
(white and gray matter) was extracted and used as the florbetapir cortical mean for each
participant. Mean regional standardized uptake value ratio (SUVR) values were derived from the
scans for the frontal, temporal, parietal, anterior cingulate, posterior cingulate, and precuneus
regions. Florbetapir-F18 amyloid PET data were available for 44.5% of the sample.
Participants were categorized as abnormal (“Aβ positive”) or normal (“Aβ negative”) on
florbetapir following results from a study by Joshi et al. (2012), which found 1.10 to be the upper
limit of the 95% confidence interval for the distribution of florbetapir means in a group of young
and healthy controls. Joshi et al. (2012) proposed this value as the cutoff for classification of Aβ
positive and Aβ negative cases. This cutoff has also been supported in an imaging-to-autopsy
correlation study by Clark et al. (2011) which found that no participants with a florbetapir
cortical mean lower than 1.10 during life had intermediate to high likelihoods of Alzheimer’s
disease post-mortem, following neuropathology-at-autopsy criteria by the National Institute on
Aging and the Reagan Institute.
Brain volume estimation
Participants had MRI at 1.5T. The data were obtained at ADNI sites following a
standardized MRI protocol (http://www.loni.ucla.edu/ADNI/Research/Cores/index.shtml) that
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was developed following an initiative to evaluate and compare 3D T1-weighted sequences for
morphometric analyses (Jack et al., 2008). Briefly, each participant had two T1-weighted MRI
scans collected using a sagittal volumetric magnetization prepared rapid gradient echo (3D MP-
RAGE) sequence with the acquisition parameters: echo time (TE) of 4 ms, repetition time (TR)
of 9 ms, flip angle of 8 degrees, acquisition matrix size of 256 x 256 x 166 (x-, y-, and z-
dimensions). The normal voxel size was 0.94 x 0.94 x 1.2 mm.
Anatomical boundaries of the hippocampi and ventricles were traced using a semi-
automated brain mapping method, developed based on a high-dimensional fluid transformation
algorithm (Christensen et al., 1997). This combines a coarse, and then fine, transformation of a
marked hippocampal MRI template from a reference brain to match the target images provided
by each participant. The pixels corresponding to the hippocampal regions were then labeled and
counted to obtain a volume measure. A commercially accessible version of the mapping tool was
used (Medtronic Surgical Navigation Technologies, Louisville, CO). This method has a reported
reliability of an intraclass coefficient exceeding .94 (Hsu et al., 2002).
White matter hyperintensities (WMH) were detected on co-registered T1-, T2-, and PD-
weighted images using automated methods described elsewhere (Schwarz et al., 2009;
Carmichael et al., 2010). WMH were detected in MDT space at each voxel according to the PD,
T1, and T2 intensities there, as well as the prior probability of WMH there, and the conditional
probability of WMH there based on the presence of WMH in adjacent voxels. The resulting map
of voxels of WMH across the brain was then summarized as an estimate of total WMH volumes.
Brain volume measures were available for the baseline visit and follow-up visits at 12, 24, and
36-months from baseline. To correct for observed kurtosis in the distribution of the WMH
volumes, we applied a log-transformation prior to analyses.
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Statistical analyses: cross-sectional analyses
Data were screened for departures from normality using indices of skewness and kurtosis.
Scores from Trails A, Trails B, and the BNT exhibited significant skewness, which was
corrected by log-transformation. Log-transformed values were used in all subsequent analyses,
except for multivariate, longitudinal analyses later described. Groups were compared on clinical
and demographic variables using chi-square tests for nominal variables and one-way ANOVA
for continuous variables. Performance on neuropsychological measures, as well as measures of
hippocampal volume, ventricle volume, and white matter hyperintensity (WMH) volume, were
compared using both one-way ANOVA and analyses of covariance (ANCOVA), controlling for
age, sex, education, APOE-ε4 carrier status, and BMI. Both analyses produced the same pattern
of results, hence, only the corrected analyses are presented in Table 2. Differences between
groups were examined using post-hoc LSD tests and chi-square analyses. All analyses were two-
tailed with significance set at p < .05.
To investigate whether the use of ARBs was associated with less florbetapir-18F PET
retention, we used multiple linear regression and ANCOVA with post-hoc LSD tests for
continuous data and chi-square tests for categorical data (Aβ positivity). Analyses investigated
the relationship between medication group and amyloid PET in frontal, temporal, parietal,
anterior cingulate, posterior cingulate, and precuneus regions. Both controlled and uncontrolled
analyses were conducted. For controlled analyses, covariates were age, APOE-ε4 carrier status
and BMI. Analyses were two-tailed with alpha set at p < .10 for interaction effects.
Statistical analyses: longitudinal analyses
Rates of change from baseline through 9 year follow-up. Multiple-group latent growth
models were used to estimate the rate of change over time in AVLT Immediate Recall, AVLT
Effects of ARBs on cognition

20
Delayed Recall, AVLT Recognition, Trails A, and Trails B performance. These tests were
assessed given significant differences in performance found at baseline. The slope of the growth
models represented average rate of change. Data from all available follow-up visits, from
neuropsychological testing at 6, 12, 18, 24, 36, 48, 60, 72, 84, 96, 108, and 120 months from
baseline were used. The Maximum Likelihood Robust estimator was used to account for missing
data. Data from the final timepoint (t=120) were dropped as there were too few cases (n=6) with
data from this timepoint for the models to converge. Covariates in the models included age
(assessed at each timepoint), sex, BMI, and APOE e4 carrier status.
For each measure of cognition, initial analyses estimated two multigroup models so that
the intercepts and slopes could be compared across the three medication groups (HTN-ARBs,
HTN-Other, and Normotensives). The first multigroup model was unconstrained, allowing both
the intercept and slope of the three medication groups to be freely estimated. This unconstrained
model was then compared, using the Satorra-Bentler Scaled Chi-Square test (Satorra & Bentler,
2001), with the second model. The second model constrained intercepts and slopes to equality
across the three medication groups. The comparison of the unconstrained and constrained models
tested the hypothesis of differences among the performance of the medication groups for the 9-
year period. Given that measurement error, conceptualized as random variance between observed
and predicted scores on a construct, is typically assumed to the independent and equal over time
(i.e., homoscedastic), both models constrained residual variances to be equal across time.
However, the unconstrained model allowed residual variances to be different across the
medication groups, while the constrained model specified the residual variances to be equal
across both time and medication groups. Post-hoc model comparisons were conducted if the
initial analyses indicated significant differences among the medication groups. Further follow-up
Effects of ARBs on cognition

21
model comparisons, comparing fully constrained (null) models to fully constrained models in
which only slopes were free to vary across groups, were conducted to evaluate whether the
change in performance over time was significantly different.
Mean differences from baseline through 3-year follow-up. Cognitive performance and
brain volume measures were also analyzed using 2-way ANCOVA with repeated measurement
using data from baseline through follow-up examinations conducted 3 years later. The first factor
was medication group, and the second repeated factor was time. Further timepoints were not
examined given the substantial decrease in sample size. Covariates were age, sex, education,
APOE-ε4 carrier status, and BMI. In the case of significant effects, between-subjects
comparisons were examined using post-hoc LSD tests for pairwise comparisons. The assumption
of sphericity was tested using Mauchly’s test of sphericity, and homogeneity of variance was
tested using Levene’s test. Analyses were two-tailed with alpha set at p < .05.
Progression to dementia. Cox regression was used to investigate the relationship
between antihypertensive drug class and progression and conversion to dementia, after
controlling for age, education, sex and APOE-ε4 carrier status. Months to diagnosis was used as
the time variable.
Results
Physiological, clinical, and genetic data
Three groups were compared: ARB-users (HTN-ARBs), other-antihypertensive-drug-
users (HTN-Other), and a Normotensive group that did not take any antihypertensive drugs, had
no history of hypertension and exhibited normal or mildly elevated blood pressure values at
screening (see Blood pressure medication groups, above). As shown in Table 1, there were
significant group differences in terms of sex and diastolic blood pressure (p’s < .05), age, BMI,
Effects of ARBs on cognition

22
systolic blood pressure, pulse pressure (all p’s < .001), and education (p = .005). The
Normotensive group had significantly fewer males than the HTN-Other group (p = .004), was
significantly younger (p < .05), and more educated (p <.05). It also had better vascular health, as
demonstrated in significantly lower diastolic blood pressure (p < .05), BMI scores, systolic blood
pressure, and pulse pressure (all p’s < .001), compared to both treated hypertensive groups.
Vascular risk factors
Evaluation of vascular risk burden revealed significant group differences in history of
cardiovascular disease, dyslipidemia, type 2 diabetes, TIA/minor stroke (all p’s < .001), and
atrial fibrillation (p = .002). Both hypertensive groups had significantly more participants with
prior cardiovascular disease (p < .001), dyslipidemia (p < .001), and type 2 diabetes (p < .001),
compared to the Normotensive group. The HTN-Other group also had significantly more
participants with history of atrial fibrillation (p < .001) and TIA/stroke (p < .001) compared to
the Normotensive group. Between the hypertensive groups, the ARB group had significantly
more participants diagnosed with type 2 diabetes than the HTN-Other group (p < .001).
Cross-sectional analyses
Neuropsychological function. As shown in Table 2, there were significant group
differences on measures of memory, attention, and executive function, after correcting for
covariates. Specifically, the HTN-Other group performed worse than the normotensive group on
all of these measures (see Figure 1): AVLT Immediate Recall (p = .002), AVLT Delayed Recall
(p < .001), AVLT Recognition (p = .001), Trails A (p < .001), and Trails B (p = .01). However,
hypertensives treated with ARBs (HTN-ARBs) performed worse than the Normotensive group
only on Trails A (p = .04). Notably, the HTN-ARBs group performed significantly better than
the HTN-Other group on a measure of memory (AVLT Recognition, p = .04), and displayed a
Effects of ARBs on cognition

23
non-significant trend towards outperforming the HTN-Other group on AVLT Delayed Recall (p
= .058).
Brain MRI measures. As shown in Figure 2, there were significant group differences on
WMH volume, F(2, 1252) = 4.413, p = .01, ηp
2
= .01, with the HTN-Other group exhibiting
significantly greater WMH volume compared to the Normotensive group (p = .004). The HTN-
ARBs group showed lower mean WMH volume compared to the HTN-Other group, but this
difference was not significant (p = .08). There were no differences in total ventricular volume,
F(2, 552) = 0.216, p = .81, or left hippocampal volume, F(2, 552) = 0.479, p = .62, or right
hippocampal volume, F(2, 552) = 0.932, p = .40.
Florbetapir-fluorine-18 (
18
F) PET retention and amyloid status. There were no
differences by medication group on global Aβ retention, F(2, 693) = 0.296, p = .744, ηp
2
= .001.
There were no differences among the three medication groups in relation to amyloid positivity,
χ
2
= 2.933, p = .23.
Longitudinal analyses
Differences in rates of change from baseline.
1. Neuropsychological function. Latent growth model comparisons indicated significant
differences among the three medication groups on performance on AVLT Recognition (χ
2
=
34.225, p = .05, df = 22) and Trails B (χ
2
= 35.343, p = 0.04, df = 22) over a 9-year follow-up
period.
On AVLT Recognition, over time, the HTN-Other group performed significantly
differently compared to the HTN-ARBs group (χ
2
= 20.993, p = .03, df = 11), as well as the
Normotensive group (χ
2
= 22.238, p = .02, df = 11). However, further follow-up model
comparisons did not reveal any specific differences in rates of change over time between the
Effects of ARBs on cognition

24
HTN-Other group and the HTN-ARBs group (χ
2
= 8.544, p = .13, df = 5), or the HTN-Other
group and the Normotensive group (χ
2
= 5.756, p = .33, df = 5). Notably, the HTN-ARBs group
performance over time was not significantly different compared to the Normotensive group (χ
2
=
4.950, p = .93, df = 11), which was consistent with findings from our cross-sectional analysis of
performance at baseline.
On Trails B, model comparisons again indicated once again that the HTN-Other group
performed significantly differently compared to the Normotensive group (χ
2
= 21.066, p = .03, df
= 11). However, further follow-up model comparisons similarly showed that there were no
significant differences in specific rates of change over time between the HTN-Other group and
the Normotensive group (χ
2
= 5.354, p = .37, df = 5). The HTN-ARBs group again did not
perform significantly differently compared to the Normotensive group (χ
2
= 17.861, p = .08, df =
11), which was once more consistent with findings from analyses of baseline performance.
There were no significant differences among the three medication groups on AVLT
Immediate Recall (χ
2
= 29.007, p = .14, df = 22), AVLT Delayed Recall (χ
2
= 22.092, p = .45, df
= 22), or Trails A performance (χ
2
= 26.804, p = .22, df = 22).
2. Brain MRI measures. There were no significant differences among the three
medication groups on changes in mean left hippocampal volume (χ
2
= 18.461, p = .68, df = 22),
or right hippocampal volume (χ
2
= 18.530, p = .67, df = 22) over a 3-year follow-up period.
Models could not converge for evaluating differences across this period on WMH volume or
ventricle volume.
Mean differences in performance, from baseline through 3 year follow-up.
1. Neuropsychological function. As shown in Figure 3, main effects of medication group
were found for AVLT Delayed Recall, F(2, 702) = 4.046, p = .02, ηp
2
= 0.1, such that the HTN-
Effects of ARBs on cognition

25
Other group performed significantly worse than the normotensive group (p = .01). Performance
of the HTN-ARBs group fell between that of Normotensives and the HTN-Other group. Hence,
the preservation of memory performance on this measure, which was observed at baseline,
remained over this 3-year period. Mauchly’s test indicated that the assumption of sphericity had
been violated (χ
2
(5) = 19.583, p = .001), therefore, degrees of freedom were corrected using
Greenhouse-Geisser estimates of sphericity (ε = .981). Levene’s test indicated unequal variances
at each timepoint (all p’s < .001).
Over the 3 year follow-up, there were no significant main effects of medication group for
performance on the other measures: AVLT Immediate Recall, F(2, 707) = 2.026, p = .13, AVLT
Recognition, F(2, 697) = 2.423, p = .09, Trails A, F(2, 702) = 1.264, p = .28, or Trails B, F(2,
667) = 0.746, p = .48.
2. Brain MRI measures. As shown in Figure 4, main effects of medication group were
found for WMH volume, F(2, 283) = 3.118, p < .05, ηp
2
= 0.2. The HTN-Other group showed
significantly greater WMH volume than the Normotensive group (p < .05) as well as the HTN-
ARBs group (p < .05). Mauchly’s test indicated that the assumption of sphericity had been
violated (χ
2
(5) = 26.555, p < .001), therefore, degrees of freedom were corrected using
Greenhouse-Geisser estimates of sphericity (ε = .983). Levene’s test was not significant, (all p’s
> .05), indicating that the assumption of homogeneity of variance was not violated.
There were significant main effects of time for ventricle volume, F(3, 129) = 38.814, p <
.001, ηp
2
= .5, left hippocampal volume, F(3, 129) = 51.015, p < .001, ηp
2
= .5, and right
hippocampal volume, F(3, 129) = 39.482, p < .001, ηp
2
= .5, but not for WMH volume.
Ventricle volume significantly increased at each follow-up point, whereas both left and right
Effects of ARBs on cognition

26
hippocampal volume significantly decreased at each follow-up point. There were no significant
interactions between time and medication group.
There were no significant main effects of medication group over the 3 year follow-up for
ventricle volume, F(2, 131) = 0.751, p = . 47, left hippocampal volume, F(2, 131) = 0.75, p = .
93, or right hippocampal volume, F(2, 131) = 0.701, p = . 50.
Progression to dementia. Cox regression analyses indicated no differences in
progression to dementia between the HTN-ARBs group and the Normotensive group (p = .71,
hazard ratio = .932), the HTN-Other group and the Normotensive group (p = .56, hazard ratio =
1.074), or the HTN-ARBs group and the HTN-Other group (p = .50, hazard ratio = .875). See
Appendix C for more information.
Discussion
Findings of the present study provide some support for our hypothesis that ARBs may
confer protective effects on cognition greater than those of other antihypertensive drugs.
Specifically, our cross-sectional analyses showed that participants taking other antihypertensive
medications performed worse on tests of memory and executive function compared to
normotensives, but ARB users did not differ from normotensives on any measure of memory
function, and demonstrated better recognition memory than those taking other antihypertensive
medications. These findings are underscored by the fact that both hypertensive groups exhibited
elevated vascular risk factor burden relative to the normotensive group, as evidenced in higher
systolic and diastolic blood pressure, pulse pressure, and BMI scores, as well as prior diagnoses
of cardiovascular disease, dyslipidemia, and type 2 diabetes. Therefore, the hypertensive groups
as a whole were potentially more vulnerable to cognitive impairment, but only the subset taking
ARBs demonstrated intact memory performance. The cognitive differences between the
Effects of ARBs on cognition

27
medicated hypertensive groups are especially notable given that the ARB group had significantly
more participants diagnosed with type 2 diabetes, which has been associated with a 1.5-2.5-fold
greater risk of dementia (Strachan et al., 2011). Even with this added risk factor, the ARB-users
outperformed the group taking other antihypertensive medicines on memory testing.
Additionally, when examined longitudinally over a 3-year-period, the hypertensive
patients continued to show worse performance on delayed recall measures, unless they were
taking ARBs. The performance of ARB users on delayed recall measures during this period fell
between that of normotensives and users of other antihypertensive drugs. Results from our latent
growth analyses over a longer 9-year period also indicated that the group taking other
antihypertensive drugs showed significantly different recognition memory and executive
function compared to the normotensives, while ARB users showed maintenance of performance
on these measures which was not significantly different from that displayed by normotensives.
While our analyses could not establish any significant differences in rates of change in
performance over time, the absence of differences among the group slopes suggests that the
differences among the groups, found in the initial analyses, (a) may not lie in the rates of change
over time, but in some other parameter(s), or that (b) several parameters all differ slightly across
the groups, not sufficiently to reject on their own.
Interestingly, the group taking other antihypertensive drugs had significantly greater
baseline WMH volume compared to normotensives, but there were no group differences in
hippocampal or ventricle volume. When examined over a 3 year follow-up period, the group
taking other antihypertensive drugs continued to show significantly greater WMH volume
compared to not only the normotensive group, but the ARB users as well. Additionally, we found
no significant group differences in baseline florbetapir-fluorine-18 PET retention or amyloid
Effects of ARBs on cognition

28
positivity, despite differences in cognitive performance. These findings collectively suggest that
the potential impact of antihypertensive drug use may be partly independent of cerebral
amyloidosis, and any benefit of ARBs over other antihypertensive medications may be due
instead to possible stymieing of the effects of cerebrovascular disease.
The inconsistencies between the results of our cross-sectional and longitudinal analyses
might be explained by the time period during which ARBs may convey the most benefit. It is
possible that ARBs may have the greatest impact earlier on in the disease course of
cerebrovascular disease, and that our cross-sectional findings thus represent the cumulative
effects of a prior benefit against cerebrovascular pathophysiology. This is consistent with
findings that vascular disease has the most detriment in midlife, in terms of effects on cognition
(Qiu, Winblad, & Fratiglioni, 2005). It has been suggested that the relationship between blood
pressure and cognition is non-linear, and that any departure from an optimal level of blood
pressure increases risk of cognitive decline (Tedesco, Ratti, Di Salvo, & Natale, 2002). Optimal
levels may differ according to age and chronicity of hypertension. At midlife, high blood
pressure is suggestive of a long-term, compounded effect, which may lead to more severe
atherosclerosis, large-artery stiffness, and comorbid vascular risk factors in later life, which have
in turn been linked to AD-pathology (Qiu, Winblad, & Fratiglioni, 2005). Individuals in a
hypertensive group <65 years old were found to be approximately seven times more likely to
have cognitive decline than individuals of the same age who did not have hypertension. In
contrast, hypertensive individuals >65 years old did not show a difference in cognitive decline
from normotensives (Bellew et al, 2004).
There is less evidence to show that these effects of hypertension observed in midlife are
present in older individuals. Mild hypertension in fact appeared to enhance cognition after the
Effects of ARBs on cognition

29
age of 70 in a study of independently living older adults (Paran, Anson, & Reuveni, 2003). It has
been suggested that in the very elderly (>80 years), an appropriate elevation in blood pressure is
necessary to maintain sufficient cerebral perfusion for the maintenance of cognitive function
(Qiu, Winblad, & Fratiglioni, 2005). Nevertheless, it is also noted that findings from longitudinal
studies suggest that high blood pressure is a risk factor for cognitive impairment in both mid- and
later-life, and particularly when manifested as very high systolic and low diastolic pressures (i.e.,
high pulse pressure) in older adults (for a review, see Qiu, Winblad, & Fratiglioni, 2005).
In a recent longitudinal analysis of CSF biomarker data from ADNI, we reported an
attenuation of cerebral amyloid retention and progression to dementia among older adults taking
ARBs (Nation et al., 2016); however, there were no cross-sectional differences in amyloid
retention. The present study extends these findings by demonstrating specific benefits in memory
function among ARBs users at baseline, as well as in delayed recall over a 3-year period. This
preservation of memory function may play an important role in protecting ARBs users from
progressing to dementia. However, we did not replicate our finding of reduced progression and
conversion to dementia in ARB users in this study. This may due to the present study’s larger
sample size (1,626 vs. 871), longer follow-up period (9 years vs. 8 years), and variability in
participant follow-up or dropout rates.
It is notable that in our cross-sectional analyses the HTN-ARBs group performed
significantly better than the HTN-Other group on a test of recognition memory. It has been
suggested that memory impairment and the cortical dementia syndrome in Alzheimer’s disease
may be due to ineffective encoding, consolidation and retrieval of to-be-learned information
(Salmon, 2000), given that patients with Alzheimer’s disease are equally impaired on tests of
free recall and recognition (e.g. Delis et al., 1991). The superior performance of the ARBs group
Effects of ARBs on cognition

30
on a test of recognition memory suggests that encoding of information may be spared in this
group, and that difficulties in memory in hypertensive older adults may be due in larger part to
frontal-subcortical retrieval deficits often associated with cerebrovascular disease (Reed et al.,
2007).
Studies of the effects of antihypertensive medications on cognitive decline have reported
mixed findings. Many studies have suggested particular benefits of ARBs (e.g. Davies et al.,
2011; Levi Marpillat et al., 2013; Chiu et al., 2014) over other antihypertensive drug classes.
Few studies have examined specific neuropsychological domains. To our knowledge, this is the
first study to examine performance on a comprehensive neuropsychological battery among users
of various antihypertensive drugs. Our study benefits from the examination of performance on
multiple tests measuring four cognitive domains of memory, attention, executive function, and
language. Other strengths of the present study are its longitudinal analyses over 3- and 9-year
periods, as well as its large sample size and inclusion of neuroimaging markers of brain atrophy
and white matter disease.
Limitations to the study include that we did not account for multiple drug combinations,
and some ARB users were on another drugs (e.g. diuretics) as well. Another limitation is that the
ADNI sample is comprised of participants from over 50 sites in the United States and Canada
with varied sampling biases. Participants were excluded based on criteria that restricted
cerebrovascular disease. We cannot rule out a possible confound by indication since ARB use in
itself may be a risk indicator for the severity of hypertension. ARBs are prescribed as
supplementary drugs in older patients with hypertension that remains uncontrolled after use of
other drugs. However, if there had been a confound by indication, we would predict that the
ARB-users, at baseline, would demonstrate worse cognitive performance compared to the group
Effects of ARBs on cognition

31
taking other antihypertensive drugs, given that the ARB-users had potentially more severe
hypertension as well as a higher proportion of participants with type 2 diabetes. The superior
cognitive performance of the ARB group in light of this is therefore notable.
As current pharmaceutical treatments for dementia have only modest effects on symptom
improvement, modifying risk factors represents the most promising line of work toward
dementia prevention (Middleton and Yaffe, 2009). Hypertension is one of the most treatable risk
factors for cognitive decline, as well as one of the most common, as evidenced in half of our
sample being on antihypertensive medications. Results of the present study indicate that ARB
use holds potential for reducing decline in memory ability and dementia in older hypertensive
adults.
Effects of ARBs on cognition

32
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Table 1. Clinical and demographic data

Data are summarized as Mean (Standard Deviation), unless otherwise indicated.
Significant differences (p < .05) among medication groups are indicated in bold.

Abbreviations: APOE = apolipoprotein E; ARB = angiotensin II type 1 receptor blockers; BMI =
body mass index; BP = blood pressure; HTN-ARBs = participants who took angiotensin II type 1
receptor blockers; HTN-Other = participants who took other antihypertensive drugs that were not
ARBs; MCI = mild cognitive impairment; TIA = transient ischemic attack.
Clinical/
Demographic

Total
n = 1586
Normotensive
n = 782
HTN-ARBs
n = 182
HTN-Other
n = 622
F or χ
2
p-value
Age, yrs 73.1 (7.2) 71.9 (7.3) 73.3 (6.8) 74.6 (6.8) 25.737 <.001
Education, yrs 16.1 (2.8) 16.3 (2.7) 15.9 (3.2) 15.9 (2.8) 5.282 .005
Sex (% men) 53.8% 50.6% 51.6% 58.4% 8.685 .013
APOE Genotype
(% 4+)

42.3% 43.4% 36.8% 42.5% 2.365 .306
Diagnosis (% MCI) 60.3% 59.8% 54.4% 62.7% 4.216 .121
BMI (kg/m
2
) 27.1 (4.8) 26.4 (4.6) 28.0 (4.8) 27.6 (4.8) 14.844 <.001
Systolic BP (mmHg) 134.1 (15.7) 130.9 (14.4) 138.5 (16.4) 136.7 (16.2) 32.318 <.001
Diastolic BP (mmHg) 74.5 (9.4) 73.9 (8.9) 75.5 (9.7) 75.0 (9.8) 3.467 .031
Pulse pressure (mmHg) 59.6 (14.2) 57.1 (13.1) 63.0 (15.5) 61.7 (14.6) 25.014 <.001
Vascular risk factors
Cardiovascular disease 11.2% 3.7% 17.6% 18.8% 87.645 <.001
Dyslipidemia 46.2% 37.6% 59.3% 53.2% 48.249 <.001
Type 2 diabetes 8.6% 3.7% 23.1% 10.5% 75.236 <.001
Atrial fibrillation 3.3% 1.8% 3.3% 5.1% 12.293 .002
Carotid artery disease 0.6% 0.4% 0.5% 1.0% 1.888 .389
TIA / minor stroke 2.9% 1.3% 3.3% 4.8% 15.569 <.001

47
Table 2. Neuropsychological data in the total sample

a
Scores were log-transformed and are presented to 2 decimal places.
Data are summarized as Mean (Standard Deviation), unless otherwise indicated. All scores were corrected for age, sex, education, BMI, APOE e4 carrier status.
Significant differences (p < .05) among medication groups are indicated in bold.

Abbreviations: ARB = angiotensin II type 1 receptor blockers; AVLT = Rey Auditory Verbal Learning Test; BNT = Boston Naming Test; HTN-ARBs =
participants who took ARBs; HTN-Other = participants who took other antihypertensive drugs that were not ARBs.
Neuropsychological Test
Memory
Total
n = 1586
Normotensive
n = 782
HTN-ARBs
n = 182
HTN-Other
n = 622
F p-value ηp
2

Logical Memory:
Immediate recall 10.6 (4.3) 10.7 (4.4) 10.9 (4.3) 10.4 (4.2) 0.269 .764 <.01
Delayed recall 8.5 (5.0) 8.6 (5.1) 9.2 (5.0) 8.3 (4.8) 1.987 .137 <.01
AVLT:

Immediate recall 38.2 (11.6) 39.6 (11.8) 38.1 (11.8) 36.5 (11.1) 4.986 .007 .01
Delayed recall 5.3 (4.3) 5.8 (4.4) 5.5 (4.4) 4.5 (3.9) 9.642 <.001 .01
Recognition 11.4 (3.3) 11.7 (3.2) 11.7 (3.1) 11.0 (3.5) 5.692 .003 .01
Attention / Executive Function

Digit Span forward score

8.4 (2.0) 8.5 (1.9) 8.1 (2.2) 8.4 (2.1) 1.100 .402 <.01
Digit Span forward span 6.6 (1.1) 6.7 (1.0) 6.5 (1.1) 6.6 (1.1) 0.953 .386 <.01
Digit Span backward score

6.5 (2.1) 6.6 (2.2) 6.5 (2.1) 6.4 (2.1) 0.121 .886 <.01
Digit Span backward span

4.8 (1.2) 4.8 (1.2) 4.7 (1.1) 4.7 (1.2) 0.021 .979 <.01
Trails A score
a

1.56 (0.16) 1.53 (0.15) 1.58 (0.16) 1.58 (0.16) 8.363 <.001 .01
Trails B score
a
1.97 (0.21) 1.94 (0.21) 1.98 (0.20) 2.00 (0.21) 3.900 .020 .01
Language

Animal fluency

18.4 (5.5) 18.7 (5.4) 18.4 (5.3) 18.0 (5.7) 0.173 .841 <.01
Vegetable fluency

12.2 (4.1) 12.3 (3.9) 12.2 (4.2) 12.1 (4.3) 0.206 .814 <.01
BNT
a

0.48 (0.33) 0.47 (0.33) 0.47 (0.33) 0.51 (0.33) 1.385 .251 <.01

48

* p < .05; ** p < .01, *** p < .001
Figure 1. Neuropsychological performance for the three medication groups across the total
sample. Participants taking other antihypertensive medications performed worse on tests of
memory, attention, and executive function compared to normotensives. However, ARB-users did
not differ from normotensives on memory function, and demonstrated better recognition memory
than those on other antihypertensive medications.
Effects of ARBs on cognition

49

* p < .05; ** p < .01, *** p < .001
Figure 2. White matter hyperintensity (WMH) volume for the three medication groups across the
total sample. Participants taking other antihypertensive medications showed the greatest WMH
volume and significantly greater WMH volume compared to normotensives. However, ARB-
users did not differ from normotensives on WMH volume.
Effects of ARBs on cognition

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Figure 3. AVLT Delayed Recall performance for the three medication groups across the total
sample, examined over a 3 year follow-up period. Users of other antihypertensive medications
performed significantly worse than the normotensive group (p = .01). Performance of the ARB
users fell between that of Normotensives and the users of other antihypertensive drugs.

Effects of ARBs on cognition

51

Figure 4. White matter hyperintensity (WMH) volume for the three medication groups across the
total sample, examined over a 3 year follow-up period. Participants taking other antihypertensive
medications showed the greatest WMH volume and significantly greater WMH volume
compared to normotensives (p < .05) and ARB-users (p < .05). However, ARB-users did not
differ from normotensives on WMH volume.
Effects of ARBs on cognition

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APPENDIX A: FLOWCHART OF INCLUSION/EXCLUSION OF PARTICIPANTS

ADNI1 (September 2005 to Jan 2011)

822 participants
(230 Normal, 399 MCI, 193 AD)

ADNI-GO (April 2010 to October
2012)

129 participants
(2 Normal, 127 MCI)
ADNI-2 (March 2011 to December 2013)

868 participants
(412 Normal, 456 MCI)
207 participants removed
 193 participants with diagnoses of
AD at baseline
 14 participants with untreated
Stage 2 hypertension

615 participants
(227 Normal, 388 MCI)

2 participants removed
 2 participants with untreated
Stage 2 hypertension

127 participants
(1 Normal, 126 MCI)

24 participants removed
 24 participants with untreated
Stage 2 hypertension

844 participants
(401 Normal, 443 MCI)

Total = 1,586 participants
(629 Normal, 957 MCI)
451 participants were followed through at
ADNI-GO
230 participants were followed through at
ADNI-2
117 participants were followed through at
ADNI-2
Effects of ARBs on cognition

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APPENDIX B: MISSING DATA AT VARIOUS TIMEPOINTS

Timepoint
(months from
baseline)
Percentage
missing
1

N at each time
point
6 months 2.0% 1271
12 months 9.0% 1180
18 months 75.6% 317
24 months 15.8% 1092
36 months 41.1% 764
48 months 66.2% 439
60 months 81.0% 247
72 months 82.9% 222
84 months 86.5% 175
96 months 90.1% 128
108 months 95.0% 65
120 months 99.8% 3

1
Calculated as a percentage out of 1,297. Two hundred and nine participants were dropped from
the original sample for longitudinal analyses as they did not present for any follow-up visits and
only had baseline data. Data were not available for reasons for missing data or no-shows to
follow-up visits.

Effects of ARBs on cognition

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APPENDIX C: BASELINE CHARACTERISTICS OF PARTICIPANTS WITH MISSING VS.
NON-MISSING DATA AT 3-YEAR FOLLOW-UP VISIT

Clinical/
Demographic

Missing at 3-year
follow-up visit
n = 822
Presented at 3-year
follow-up visit
n = 764
F or χ
2
p-value
Age, yrs 73.9 (6.7) 73.3 (7.1) 2.161 0.142
Education, yrs 16.1 (2.9) 16.1 (2.7) 0.026 0.873
Sex (% men) 53.7% 56.8% 1.260 0.281
APOE Genotype
(% 4+)

43.0% 42.3% 0.061 0.806
Diagnosis (% MCI) 47.5% 72.1% 80.985 < .001
BMI (kg/m
2
) 27.0 (4.9) 27.1 (4.5) 0.062 0.804
Systolic BP (mmHg) 135.1 (15.6) 132.8 (15.9) 6.449 0.011
Diastolic BP (mmHg) 75.0 (9.2) 73.6 (9.6) 6.876 0.009
Pulse pressure (mmHg) 60.1 (14.4) 59.2 (14.3) 1.141 0.286
Vascular risk factors
Cardiovascular disease 12.9% 11.3% 0.851 0.356
Dyslipidemia 50.8% 45.9% 3.023 0.082
Type 2 diabetes 8.4% 8.1% 0.045 0.833
Atrial fibrillation 3.4% 3.3% 0.011 0.917
Carotid artery disease 0.0% 1.3% 7.031 0.008
TIA / minor stroke 2.8% 2.9% 0.005 0.945
Effects of ARBs on cognition

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APPENDIX D: CONVERSION TO DEMENTIA AT VARIOUS TIMEPOINTS

Timepoint
(months from
baseline)
Number converted
from MCI to AD
Number converted
from Normal to
MCI
Number converted
from MCI to
Normal
6 months 30 2 3
12 months 44 4 13
18 months 15 6 1
24 months 40 1 5
36 months 20 5 5
48 months 9 3 1
60 months 3 3 0
72 months 4 1 0
84 months 2 1 0
96 months 2 5 0
108 months 1 2 0
120 months 0 3 0
Total 170 36 28

Abstract (if available)

Abstract Objective: Animal studies, observational studies, and randomized controlled trials examining the relationship between antihypertensive drug use and cognition provide cumulative support for the perspective that antihypertensive treatment may have beneficial effects on cognition and risk for Alzheimer’s disease. However, some studies have also shown mixed results, suggesting a more complex picture in which specific antihypertensive medicines may be of greater or lesser value with regard to protective effects on cognition. Angiotensin II type 1 receptor blockers (ARBs) have been highlighted as one antihypertensive drug class that may confer greatest benefit. ❧ Participants and Methods: Participants in the present study were 1,626 non-demented adults, ages 55-91, from the Alzheimer’s Disease Neuroimaging Initiative. Eight hundred and four participants reported using antihypertensive drugs. Three groups were compared: ARB-users (HTN-ARBs), other-antihypertensive-drug-users (HTN-Other) and Normotensives. Vascular risk burden, cognition, florbetapir-fluorine-18 (F18) PET retention, and brain MRI measures were compared using ANCOVA, multiple linear regression, chi-square tests, latent growth models, and Cox regression. ❧ Results: The HTN-Other group performed significantly worse than Normotensives on Rey Auditory Verbal Learning Test (AVLT) Immediate Recall (p = .002), AVLT Delayed Recall (p < .001), AVLT Recognition (p = .001), Trails A (p < .001), and Trails B (p = .01), but ARB-users did not perform significantly worse than Normotensives on any measures except for Trails A (p=.04). The ARB-users performed significantly better than HTN-Other group on Recognition (p=.04). The HTN-Other group continued to perform worse than Normotensives on AVLT Delayed Recall over a 3-year follow-up period (p = .01). At baseline and over a 3-year follow-up period, the HTN-Other group exhibited significantly greater WMH volume compared to the Normotensive group (p = .004). There were no gross group differences in relation to florbetapir-F18 PET retention, amyloid positivity, or progression to dementia. ❧ Conclusions: Participants on antihypertensive drugs demonstrated worse memory and executive function compared to normotensives, unless they were ARB-users, who showed better recognition memory than those on other antihypertensive medications. Those on other antihypertensive drugs also showed significantly greater baseline WMH volume compared to normotensives, and compared to ARB-users over a 3-year period. Findings suggest that the potential impact of antihypertensive drug use may be partly independent of cerebral amyloidosis, and any benefit of ARBs over other antihypertensive medications may be due instead to possible stymieing of the effects of cerebrovascular disease.

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University of Southern California Dissertations and Theses

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Asset Metadata

Creator Ho, Jean K. (author)

Core Title Effects of AT-1 receptor blockers on cognitive decline and Alzheimer's disease

School College of Letters, Arts and Sciences

Degree Master of Arts

Degree Program Psychology

Publication Date 07/22/2016

Defense Date 05/11/2016

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag Alzheimer's disease,angiotensin receptor blockers,antihypertensive medication,AT1 receptor blockers,blood pressure,cognitive aging,dementia,memory,OAI-PMH Harvest

Format application/pdf (imt)

Language English

Contributor Electronically uploaded by the author (provenance)

Advisor Nation, Daniel A. (committee chair), Gatz, Margaret (committee member), John, Richard S. (committee member), McArdle, John J. (committee member)

Creator Email jean.ho@alumni.duke.edu,jeanho@usc.edu

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-272602

Unique identifier UC11279512

Identifier etd-HoJeanK-4584.pdf (filename),usctheses-c40-272602 (legacy record id)

Legacy Identifier etd-HoJeanK-4584.pdf

Dmrecord 272602

Document Type Thesis

Format application/pdf (imt)

Rights Ho, Jean K.

Type texts

Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

Access Conditions The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the a...

Repository Name University of Southern California Digital Library

Repository Location USC Digital Library, University of Southern California, University Park Campus MC 2810, 3434 South Grand Avenue, 2nd Floor, Los Angeles, California 90089-2810, USA