RETURN

Title: Midlife Hypertension and Alzheimer Disease: a Meta analysis

Charles L. Carter, PhD; Melanie Wiebe PT (2002) updated with 6 figures

California State University, Long Beach

Keywords: Midlife Hypertension, Alzheimer Dementia, Meta analysis,

Vascular Factors

Corresponding Author: Charles L. Carter, PhD

Abstract:

The result of the several studies of midlife hypertension (mHTN) and Alzheimer Disease (AD) have not bee

laid out in a convincing manner. Methods. Studies that were similar in design were selected. The papers

were then judged for inclusion in the study based on: 1) longitudinal study of three or more years 2) measure

of dementia via DSM-IV criteria, the MMSE, the 3MSE, the CASI, or the NINCDS-ADRDA criteria and 3)

published in a major journal. Results. Five studies were found that could be included in the analysis.

The combined odds ratio of 5 dementia studies was 1.09 suggesting hypertension is not a factor when all

are lumped together. However the odds ratio of all AD studies of both elevated midlife diastolic (>9otorr) an

elevated systolic (>160 torr) are much greater than 1.0 with a combined odds ratio of 1.84 suggesting that

midlife hypertension persists as a factor in AD. Conclusions. The possibility exists that AD has both vasculature

and neurological precursors and the elements that could tie them together are discussed.

Short title: Midlife Hypertension and Dementia

Keywords: Midlife Hypertension, Alzheimer Dementia, Meta analysis, Vascular

Factors

INTRODUCTION

The link between hypertension and AD has been elusive. The apparent inability of

presently available drugs to alter the course of AD could be a signal that it is time to

change the way we think about AD and its therapeutics [1]. Many extensive studies

have been undertaken however the data of the several studies have not been laid out in a

convincing manner. A major problem is that the abnormal presentation of blood pressure

is far more complex than envisioned [2]. The fact that we are struggling to demonstrate a

physiological effect that can take many paths in spite of the relatively rigid changes in

anatomy are reminiscent of causal relationship problems of CHD and essential

hypertension. The goal of Meta analysis is to standardize the differences between

treatment groups (effect size) by standardizing different but conceptually related studies,

allowing the comparison of dependent variables [3]. This analysis is a presentation of

previous longitudinal studies normalized in a way that would allow a fair comparison.

Dementia, and specifically Alzheimer's disease (AD), has been viewed as

primarily a neural disease but most studies have been unable to rule out vascular risk

factors [4-9]. There is a controversy in the literature regarding the relationship between

midlife hypertension and dementia [10,11]. The purpose ofthis meta-analysis is to

compare these studies and allow the reader to draw conclusions regarding the

relationships between dementia and hypertension and AD and hypertension.

While some suggest that vascular factors are associated solely with vascular

dementia as opposed to AD [12]. Recent literature however shows that vascular factors

may affect AD as well [13-15]. Launer et al conducted a prospective study of37354

subjects from Oahu, Hawaii who were part of the Honolulu Asia Aging Study (HAAS)

[4]. Participants had their blood pressures measured four times between 1968 and 1991,

at which time they took the Cognitive Abilities Screening Instrument (CASI). The CASI

is a composite of the Hasegawa Dementia Scale, the Mini Mental State Examination

(MMSE) and the Modified Mini Mental State Examination (3MSE). It has been

validated as a screening tool for dementia with 80% sensitivity and 77% specificity. The

MMSE is a screening tool for dementia with 87% sensitivity and 82% specificity. The

results of Launer's study showed that midlife diastolic blood pressure is not associated

with the development of dementia while midlife systolic blood pressure is associated with

the development of dementia. Kivipelto et ai, studied 1400 participants who were

randomly selected from two other trials [7]. The mean follow-up time was 21 years and

participants were diagnosed with AD using the National Institute of Neurological and

Communicative Disorders and Stroke-AD and Related Disorders Association (NINCDSADRDA)

criteria [16]. The investigators found that increased systolic blood pressure in

midlife was a significant risk factor for AD in later life. Guo et al measured blood

pressure and cognitive performance of 1736 participants aged 75-101 over a period of

40.5 months [17]. Cognitive performance was measured by the MMSE and cognitive

impairment was considered a score of less than 24 on the MMSE. Guo et al found that

systolic hypertension is positively related to cognitive performance and that low SBP

predicts poor cognitive function [17]. Morris et al, studied 378 subjects between 1973

and 1988 in a longitudinal cohort study in east Boston [6]. They diagnosed AD 13 years

after initial blood pressure measurements using NINCDS-ADRDA criteria. Morris et al

found no association between blood pressure measured 13 years before and AD.

Petrovich et al studied 210 dead participants from the HAAS [5]. The researchers

compared midlife blood pressure and later life dementia onset. They also studied the

number of neuritic plaques (NP) and neurofibrillary tangles (NFT) in the patients but

made no further diagnosis of AD other than the clinical diagnosis already given to the

patient before death. Petrovich et al, found a positive correlation between high midlife

systolic and diastolic blood pressure and NP and NFT [5].

METHODS

The methods for this meta-analysis involved five steps. First, all studies about

longitudinally measured blood pressure and later development of dementia were gathered

through an exhaustive search ofpublished literature using Medline, PubMed, the

Cochrane Collaboration, Cochrane Controlled Trials Register, National Research

judged for inclusion in the study. The inclusion criteria were: 1) longitudinal study of

three or more years 2) measure of dementia via DSM-IV criteria, the MMSE, the 3MSE,

the CASI, or the NINCDS-ADRDA criteria and 3) published in a major journal. Five

studies were found that could be included in this present analysis [4-7,17].

Four relevant studies were excluded from this analysis. Elias et ai, as part of the

Framingham Study, studied untreated blood pressure and cognitive functioning [18].

Though the study was longitudinal, the researchers did not measure dementia, but only

cognitive functioning. Glynn et al and Kilander et al also measured blood pressure and

cognitive functioning longitudinally and were excluded from the present study because

dementia was not diagnosed [2,19]. Skoog et al conducted a -year longitudinal study

of blood pressure and dementia [20]. Their research was excluded because the data

collected began at age 70 and was grouped in a manner that did not lend itself to metaanalysis.

Data was then extracted and placed in 2x2 tables representing dementia and

hypertension, dementia and no hypertension, no dementia and hypertension and no

dementia and no hypertension. The odds ratios and the 95% confidence interval were

calculated using the Peto method and a forest plot was drawn (Figure 1,2) [3]. NCSS

Number Croncher Statistical System, Kagsville Utah was utilized for the analysis and plot.

RESULTS

The forest plots (Figure 1,2) and Table 1 and 2 show the statistical results of the

meta-analysis. The grouping of dementia includes AD, vascular dementia and mixed

dementia. An odds ratio of 1.0 suggests that hypertension and dementia have no

relationship. An odds ratio of less than one indicates that midlife hypertension and

dementia occur together less than what one would expect by chance alone. An odds ratio

of more than one suggests that midlife hypertension and dementia occur together more

often than would be expected by chance alone. The combined odds ratio of 5 dementia

studies was 1.09. All AD studies of both elevated midlife diastolic (>90torr) and

elevated systolic (>160 torr) are greater than one with a combined odds ratio of 1.84.

The Galbraith plot (Fig.3.) as a estimate of publication bias does not show asymmetry

supporting the position that unreported studies would not alter the overall finding [21].

DISCUSSION

Drawing from the information in the forest plot and the odds ratios, it appears that

AD, but not dementia in general, is related to midlife hypertension. This is interesting

considering the fact that vascular dementias, of specifically a vascular origin are included

in the general dementia category. As other causes of dementia are ruled out in the

diagnosis of AD, midlife hypertension seems to be more and more a factor. These results

are highly suggestive of a vascular mechanism in AD, of which hypertension may be a

precursor.

The forest plot may be somewhat incomplete, as any unpublished data was not

included in this analysis. Also, it is quite possible that negative results have not been

submitted for publication. This is true with the study by Launer et al. [4]. The raw data

was available for their positive correlation with SBP, but not for DBP where no

correlation was found [4]. Mean follow-up times differ between each study making it

difficult to generalize the outcomes to a certain age or time period considered "midlife."

With the study by Guo et ai, follow up time was only 40.5 months [17]. This is a very

short time compared with 15-20 years in the other studies. Guo's study demonstrates the

finding that blood pressure tends to drop in the few years before dementia onset [17]. The

inclusion criteria may have been too lax or too strict. The need for data to be presented in

a certain fashion in the studies used may also limit this analysis, as one relevant paper

was excluded because the raw data could not be extracted [20]. While the Skoog et al

data (n~94) does not lend itself to this META analysis, those who developed dementia

with the DSM-III-R criteria at age 79-85 had significantly higher SBP at age 70 and

higher DBP at age 70-85 than those who did not develop dementia [20]. These authors

also found elevated DBP associated with AD at 79-85 and this elevated BP correlated

with white matter lesions in a subset of 15 patients who underwent CT scans.

While the included five studies do not allow us to pin down the precise age in

which hypertension becomes a factor, Posner et al does suggest that after age 65

hypertension by itself is no longer a factor [22].

The suggestion that mean pressure is a key factor cannot be supported nor can it

be ruled out by these odds ratios. The Diastolic odds ratios are no greater than the

systolic values.

AD as a slow continuously progressive disease would suggest failure in fine tuning

of control systems not complete chaos in that system. Certainly renewal and

repair must be under consideration. Cerebral hypo perfusion and cognitive decline has

been reported in a number of papers and has been reviewed [23,24]. Vessel

characteristics may take up to 6 years to return to normal after hypertension even though

B.P. has normalized so reduced local flow and abnormalities of vasomotion within

endothelial cell shape change may contribute to the hypo perfusion. The three major

cerebral arteries ofthe brain are end arteries without significant collateral circulation

[25]. After an early period of midlife hypertension, failure to maintain proper perfusion

pressure would lead to cerebral hypo perfusion, cortical infarcts, and rapid decline in the

AD patient if increased vascular resistance and disrupted flow control continued. Any

clear explanation for the specific anatomical regions and Braak progression, however is

not understood [26]. The critically attained threshold of cerebral hypoperfusion (CATCH

hypothesis) has been suggested for neurodegeneration [24,27,28] However beta-amyloid

(A beta) peptide increase in the hippocampus and the enterorhinal cortex would increase

local vascular resistance in cerebral micro-vessels and maintain or create a profound

local hypoperfusion possibly explaining while these regions that develop high A beta

peptide, would incur greater local ischemia and continued endothelial remodeling

failures. Endothelial cells (in tissue culture) live about as long as a RBC 120-130 days, so

a progressive inept replacement by circulating fibroblasts from bone marrow may create a

continuous deterioration in metabolic function in these memory active regions.

Instrument describing Dementia

It should be noted that the instruments used to define dementia are not without

controversy [29]. Some challenge the tools used to evaluate dementia presented in the

studies analyzed arguing that "executive function" among others are primary and

diminish the value of "memory mechanisms" as key [30]. It is interesting to speculate a

reduction in the variance by using a more tightly defined progression of regional PHF-tau

pathology in sync with serial blood pressure changes in a model linking the clinical

presentation of dementia with anatomy [30]. Function and anatomy almost never allow

perfect causal links but strong arguments can be made for resolutions between Braak and

Braak and Royall and others in pathological classification. Why can percent of arterial

stenosis explain 25% of the variance in Braak Stage, 36% of the variance in CERAD

Neural Plaque Score, and 22% of the variance in white matter score in a Sporadic AD

population [14]7

The evidence for low glucose availability in the Entorhinal cortex and

hippocampus is supported by studies that raise plasma insulin through intravenous

infusion while keeping plasma glucose at fasting levels. This gave striking memory

enhancement which suggests that neuroendocrine factors are quite important here [31].

How insulin is kept from these regions is a puzzle but normal endothelial function is a

major factor in insulin resistance, and diabetes mellitus was associated with lower

cognitive function where diabetes gave a 65% increase in risk (hazard ratio 1.65) of AD

compared with those without diabetes [32,33]. It is clear however that diabetes mellitus

clusters with other vascular risk factors in AD [11]. While some claim a direct correlation

between plasma insulin levels and resting blood pressure [34], more recently Jan 2020,

patterns of reduced glucose metabolism are often seen in brain scans of patients with

Alzheimer disease and other dementias. Now, a growing body of evidence suggests

that glucose hypometabolism may be more than just a biomarker on brain scans: it

may be a key player in dementia pathology.[35]
Others have found diastolic blood pressure during exercise was higher in hypertension-

prone and insulin-resistant patients which suggests a better measure to demonstrate this

relationship [36]. Possible Information present in the midlife Hypertension finding.

A vascular elevated pressure sign that appears early then essentially goes away in

many patients would appear to be an enigma. However this strange hypertension may be

an explanation that supports the hypothesis that progenitor endothelial cell involvement is

seminal in this dementia. The endothelial progenitor cell dysfunction in hypertension has

been reviewed [37]. The unique two layer embryology of the brain and the kidney, in

which vascular supply must come from outside these structures, together with the

description of endothelial progenitor cells (EPC) in the circulating blood points to

neovascularization occurring in early AD [38-39]. This points to a possible link between

renal hypertension mechanisms and hypertensive brain tissue changes. Endothelial cells

must be repaired and renewed, with endothelial protein turnovers in the brain (perhaps as

rapid as every 2 weeks) imply extremely dynamic renewal mechanisms. EPC

proliferation, migration, and adhesion as well as in vitro vasculogenesis has been found

impaired due to elevated homocystine, total cholesterol, LDL cholesterol, and C-reactive

Protein [40,41]. In addition the high angiotensin II levels present during hypertension

might indicate a control system overdriven to potentate VEGF-induced EPC proliferation

back into homeostatic conditions. It is not unreasonable to picture elevated local vascular

resistance, metabolic abnormalities, and proinflammatory cytokines in patients that

progress from Mild Cognitive Impairment to AD [42]. A reasonable supposition that

would explain abnormal skin fibroblast metabolism and perfusion in AD, would be

abnormal fibroblast progenitor endothelial cell function [43,44]. The case can be made

that the midlife hypertension may drive or represent this abnormality early in the

developing AD. Also the CV-19 attack virus would so alter the endothelium as to

accelerate the whole process because of the spike attachment to the ACE-2 receptors

in the vascular endothelium when the blood-brain barrier was compromised.

Loss of Hypertension symptom with severity

Studies of older patients and autopsy studies are likely to miss signs/symptoms of

hypertension. It is accepted that in severe Braak States IV and V the elevated pressures

have disappeared or have fallen low at late onset but the tortuous small vessels and

heterogeneity of brain blood flow is still present [22].

Consequences of hypo perfusion: A-beta peptides

Studies in gerbil forebrain ischemia and rat chronic (reduced 25%) hypo perfusion

Of the hippocampus has been shown sufficient to trigger amyloid precursor protein (APP)

cleavage into A-beta peptides [45]. Supporting the idea that atherosclerotic occlusion is

an important factor in pathogenesis of some sporadic AD [46]. Ischemia temporarily

induced amyloid peptide over-expression in reactive astrocytes and this over-expression

peaked at day 7 and 6 months [47]. These studies support the cerebrovasculature as a

clinically relevant site of AD which contributes to neuro-degeneration [48].

A-beta is known to induce transendothelial migration of monocytes/microglia in

culture that could be inhibited by the putative A-beta receptor for advanced glycation end

products (RAGE) suggesting peripheral blood monocytes/microglia would accumulate in

the brain of AD patients. And is a logical explanation for the low grade inflammation and

periventricular white matter lesions usually present. This migration is shown likely

reduced in normal brain vascular endothelium. By injecting antibodies to A-beta directly

in the brain of mice genetically engineered to make excess amyloid and tau found the

time constant of amyloid plaques and tangles is remarkably short [49]. Three days post

injection, amyloid plaques were gone. Two more days and tau tangles were gone showing

that plaques promote tangles. If tau is allowed to add phosphate groups it could not be

removed [49]. These short time constants force one to search for a prolonged

environmental challenge to the genetic environment. A stretch of midlife hypertension or

perhaps a very low B.P. might possibly be responsible [11].

Evidence of Hippocampal Atrophy with Hypertension

Further support of these findings can be found in a recent midlife blood pressure

study of Japanese-American men in the same population presented in the Launer et al

study relating the risk of hippocampal atrophy [50]. Untreated hypertensives had a

significantly increased risk for hippocampal atrophy (lowest quartile of hippocampal

volume). The volume of the CAl field of the hippocampus in hypertensive rats was

reduced but could be reversed with a calcium channel blocker [51]. Midlife changes in

estrogen and progesterone can demonstrate real vascular effects and these sex hormones

may directly effect calcium channels [52]. It is possible that hypertension that responds to

calcium channel blockers at midlife identifies a special subset of treatable early

Alzheimer patients.

Possibility that a population subset is present

There may be different initiating factors in these AD patients. An initiating factor

without the genetic environment would not result in a sustained disease. While fifty or

more genes may be implicated in dementia, hypertension coupled with sex hormone

changes of midlife create powerful forcing functions for altering the genetic

environment. There are many known changes in the hypertensive brain. However the

demand that the initiating factor(s) for AD are the same as the sustaining factors is not

necessary.

CONCLUSION

It seams there is an association between AD and hypertension but why this

association exists is not clear. Some may choose to continue to reject the idea that AD

may have a vascular origin. While there are a number of AD patients that do not have

classical hypertension, there seems to be a real interaction between AD and hypertension.

It is now understood that hypo-glucose metabolism is occurring as is insulin dysfunction

meaning reduced metabolic capacity mixed with reduced blood flow is underlying the

dementia. A clinical trial where hypertension is identified and treated would clarify with greater

certainty what removal of the hypertensive environment would mean for the development

of AD while AD is in the earliest stages would be helpful. Is it possible that mis-regulation

of APP proteolytic processing or RAGE removal of A-BETA is established by

a bout of midlife hypertension. The possibility exists that AD has vascular, metabolic, and

neurological precursors and the element that ties them together is endothelial

damage/repair rates and their interaction with folding missense for A beta misfo1ding in

an ischemic or hypo-perfusion environment of mid1ife hypertension.

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Legends to figures:

Guo(1736)

Petrovitch(210)

Launer (3735)

[Combined]

Average

Mean 95.0% 95.0% Percent

Method Follow Lower Upper Fixed

Of Up Odds Confidence Effects

BP Diagnosis Time Ratio Limit Limit Weight

SBP>160 MMSE 40.5 months 0.5326 0.3727 0.7611 25.3443

DBP> 95 MMSE 40.5 months 0.7159 0.4963 1.0325 24.0711

DBP> 95 DSM-IIIR 21 years 0.8590 0.2863 2.5776 02.6741

SBP>160 DSM-IIIR 21 years 1.1682 0.4175 3.2689 03.0495

SBP>160 CASI/DSM-IIIR 25 years 2.0768 1.5881 2.7158 44.8610

1.0924 0.91281.3075

Table.1. Forest Plot: Dementia Odds Ratio Detail Using Fixed Effects Model

1.8357 1.3153 2.5621

N BP

Morris (378) DBP>90

Morris (378) SBP>160

Kivipelto (1400) DBP>90

Petrovitch(210) DBP>95

Kivipelto (1400) SBP>160

Petrovitch(210) SBP>160

[Combined]

Average

Method

Diagnosis

NINCDS-ADRDA

Mean

Up Odds

Time Ratio

13 years 1.4556

13 years 1.5374

21 years 1.6763

21 years 2.0514

21 years 2.1091

21 years 3.1217

95.0% 95.0%

Lower Upper

Confidence

Limit Limit

0.6061 3.4961

0.5754 4.1078

0.9292 3.0241

0.4842 8.6922

1.1487 3.8723

0.856511.3776

Percer

Fixed

Effect!

Weigh

Forest Plot (2021) of drugs to reduce Amyloid. Aduhelm (Aducarimab) FDA approved 6/11/2021

See: https://www.bmj.com/content/bmj/372/bmj.n156/F2.large.jpg?width=800&height=600

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