Mid-life Hypertension and

Dementia

Author name: Morten Heath

Student ID no.: 20051087
Name of supervisor: Ebbe Bødtkjer
 Abstract
Hypertension has been associated with reduced cognitive function and the occurrence of vascular
dementia and possibly Alzheimer’s disease. While the connection between hypertension and the
development of dementia is still not clear, there is evidence suggesting that the management of
hypertension in mid-life can reduce the risk of developing dementia in late-life. This is through a
variety of hypertensive related factors such as the management of the renin-angiotensin-aldosteron
system, the clearance of amyloid-beta peptide from brain blood vessels and prolonging cerebral
vascular health. The correlation over the span of time between the development of hypertension
and dementia suggests that management of hypertension in mid-life can help prevent dementia in
late-life. As the population of the world is getting older, and the prevalence of dementia and
hypertension increases with old age, so will the percentage of individuals suffering of either disease
increase in the coming years.
The purpose of this paper is to provide an overview of the currently observed correlation between
the incidence of hypertension in mid-life and the development of dementia in late life.

Glossary:
HT = hypertension, BP = blood pressure, AD = Alzheimer’s disease, VaD = vascular dementia, sBP =
systolic blood pressure, dBP = diastolic blood pressure

Introduction
The connection between hypertension and increased risk of dementia is not conclusive. Neither is it
uniform across the span of a lifetime. Several reviews on the subject indicate that HT and high BP
in mid-life, i.e. in the ages 40-65, brings with it an increased risk of dementia later in life, whereas
hypertension and high BP in late-life in some cases does not seem to increase risk of dementia1, 2, 3.
Hypertension is a prevalent and damaging condition, established as a risk factor in both
cardiovascular and cerebrovascular disease. The prevalence of HT increases with old age and as
there is an increase in the proportion of elderly globally so too will we see an increase in the
proportion of the global populace who are subject to a hypertensive condition4.
The increase in life expectancy around the world also profess a rise in the number of individuals to
suffer from dementia. There are several different types of dementia but the most common cause of
dementia in the elderly is Alzheimer’s disease. AD is a multifaceted neurodegenerative disorder.
The two major pathological substrates are thought to be amyloid-beta peptides and intracellular
neurofibrillary tangles, which along with other factors leads to neuronal dysfunction and synaptic
loss5. Second to AD is vascular dementia which is a non-uniform aggregation of disorders in which
vascular lesions of the brain cause the damage. Some of these are atherosclerosis, stroke, lacunas
and micro bleeds. AD and VaD occur together in mixed variants with the pathogenesis seen in VaD
as also contributing to the development of AD6.
The role of HT and it’s degenerative effect on brain vasculature is believed to be a main factor in
development of vascular dementia. The effects of HT leading to non-vascular dementia and
Alzheimer’s is less clear. Vascular brain injury and particularly the subset of small-vessel disease
leading to white matter lesions are suspected to play a role in the development of the cerebral injury
leading to dementia1. Hypertension is believed to reinforce this damage to the cerebral vasculature,
and hereby contribute to the reduced clearance of amyloid-beta, a peptide associated with the
development of Alzheimer’s disease1, 2.
A number of challenges and issues exist in this connection, one being the temporal issue with a
condition such as dementia developing over several decades. Randomized trials focusing on the
connection between the two are very difficult to perform because of the duration of the follow up
needed, and in observational studies a lack of clear biomarkers along with differing criteria for
screening and diagnosis of dementia confound the comparability of different studies1.
Where the connection between the two conditions seem to exist the treatment of hypertension has in
some cases been found to not affect the development of dementia or may protect through direct
neurobiological effects instead of through lowering of BP2. This highlights the important distinction
of looking for the connection between the two conditions and looking for a way to prevent or delay
dementia through treatment of HT.

Methods
The initial search for data of the field was done on pubmed.org with a search of “hypertension AND
dementia”, “mid-life hypertension AND dementia”, “mid-life hypertension AND late-life
dementia” and “hypertension AND mid-life AND Alzheimer’s”. This led to the discovery of a
number of reviews and editorials from major publications in the field of hypertension and some
original research articles. Through the reviews were found additional original articles and
supportive articles on the broader subjects of HT and dementia / AD. References to diagnostic
criteria and the like has been found through the articles in which they were mentioned and reviewed
online.
The criteria for inclusion/exclusion were original research articles where the study population
included any participants within the range of middle-age: 45-65 years of age, where basis for
inclusion in the study population is hypertension and part of the outcome is dementia or
Alzheimer’s disease.
The inclusion and exclusion criteria were chosen to set boundaries for the scope of this paper.
Neither AD or dementia have a hard bound to their diagnosis and often arise after and in connection
with general cognitive decline6, which means there are many more perspectives and articles on the
subject, some of which are referenced here7, 8, 9, 10, 11,.

Hypertension at mid-life and the risk of dementia

The following section is a presentation of the results from the research articles included from above
criteria on the correlation between mid-life HT, temporal development of BP, treatment of HT and
late life dementia. Methods from the different studies will be highlighted as well.

Mid-life blood pressure and dementia

In the Framingham Offspring cohort study McGrath et al. found that mid-life systolic HT was
associated with a greater risk of incident dementia in late-life. A HR of 1.57, 95% CI 1.05–2.35 and
an increase in risk per 10 mmHg increment in sPB by HR 1.17, 95% CI 1.05–1.31. No correlation
was found between diastolic HT and dementia. The study adjusted for demographics and known
variates associated with greater risk of dementia; age, sex, education, cardiovascular disease and
APOE4 carrier status12. In the Honolulu-Asia Aging Study the authors found a correlation between
both mid-life systolic and diastolic HT and dementia. Outcomes were incident dementia, VaD and
AD with exclusions of dementia due to Parkinson’s, trauma, subdural hematoma. A correlation was
found for untreated diastolic HT in mid-life and AD and for untreated systolic HT and VaD. These
findings were after adjustment for age, education, apolipoprotein E, smoking and alcohol along
with cardiovascular factors13. In The Hisayama study by Ninomiya et al., a cohort examining both
mid- and late-life BP levels and dementia(VaD) and AD in Japan, a significant association was
found between all-cause dementia and HT. The association was significant for HT and VaD, but not
for HT and AD exclusively. For elevated sBP and dBP was seen an incremental effect with a 24%
and 37% increase in risk per 10 mmHg increase in BP, respectively. This was after adjustment for
age, sex, education level, use of anti-hypertensives, diabetes, chronic kidney disease, serum total
cholesterol, BMI, stroke, smoking and alcohol14. In the Kaiser Permanente Medical Care Program
of Northern California by Whitmer et al., a retrospective cohort study performed in California,
USA, researchers found an hazard ratio of 1.24 95% CI (1.04-1.48) for those with HT to have
dementia. This was after adjusting for age, sex, education and race15. The Linxian County Study,
China by Wu et al., did a nested case-control on their cohort by matching cases to controls on
gender, residential area and age (±2 years). Through this was found an OR of 1.97 95% CI (1.097-
3.541) p=0.0232 for those with HT to develop AD. In the broader comparison the prevalence of AD
was increasing with increases in BP, with the differences between high and borderline groups of
both sBP and dBP being significant. Trend tests showed a dose-response relationship between
rising BP and AD16. The Radiation Effects Research Foundation Adult Health Study by Yamada et
al., a cohort study from Hiroshima, Japan, showed results correlating increments of sBP of 10
mmHg to the prevalence of VaD but not AD. The result was an OR of 1.33, 95% CI(1.14-1.56)
p<0.01 for every 10 mmHg increase in sBP after adjustment for age, sex and educational level
among others17. In the North Karelia and FINMONICA studies by Kivipelto et al. high sBP had an
OR of 2.8 95% CI(1.1-7.2) for association with later development of AD. This was after adjustment
for age, body mass index, education, history of myocardial infarction and cerebrovascular
symptoms, smoking and alcohol18. To contrast the above the HUNT study by Gabin et al. found a
different and contradictory connection. The result was a found protective connection for those with
age 60 or older between high sBP and dementia. This connection was significant for the connection
with AD and a trend (not significant) in regards to all-cause dementia and mixed AD / VaD19.

Temporal development of hypertension and effect on dementia

Two of the examined studies found significant effect of changes in HT from mid-life to late-life and
the correlation of dementia. In the Framingham Offspring cohort was found an increase in risk for
dementia and AD for those without HT at midlife and a steep decline in dBP from mid- to late-life.
An increase in risk for dementia was found for those with a steep decline in sBP from mid- to late-
life regardless of HT status and persistent systolic HT was associated with increased risk for both
dementia and AD12. The Hisayama study found a significant risk for dementia and VaD with
persistent HT and decline in BP from mid-life HT14.

Treatment of HT and dementia

While treatment of HT is mentioned in all of the studies, not all examine it as an effect on the
outcome. Some adjust for it when examining the data12, 14, others did not adjust for this in analysis18,
17, 15
one included no participants with antihypertensive treatment16. Two examined the effects of
antihypertensive treatment on the outcome of dementia; White et al. and Gabin et al. White et al.
found that the treatment of HT was protective for those with HT, both elevated sBP and dBP13.
Gabin et al. found an adverse effect for those with high SBP, under the age of 60 and on anti-
hypertensive medication between high sBP and AD19.

Methods and criteria of the studies

The studies have varying definitions on what constitutes HT / high BP which also results in a
varying degree of stratification of the exposure. Some studies define non-HT/HT – or low/high BP
– as a dichotomy with the breaker being >140/90 mmHg for sBP/dBP12, 15. Others divide the data in
to strata with low, normal, borderline and high being at <110/80, 110-139/80-89, 140-159/90-94,
≥160/95 mmHg for sBP/dBP13, 14, 16. Two studies did not specify intervals for BP in their methods,
reporting findings as effect of incremental BP17, 19. The measurements used as representing mid-life
HT were for most of the studies carried out at one single occasion, except for the studies of Launer
et al. and McGrath et al.
Most studies used a definition of HT / high BP from the above criteria, however one defined HT as
being as diagnosed by a private physician, taking anti-hypertensive medication or fulfilling the
relevant BP criteria at measurements15.
Almost all studies report having done BP measurements after five minutes seated and 2-3 times at
one occasion. One study does not specify how measurements were optained17. One cites the JNC-7
criteria for BP measurements as their method14.
Diagnosis of dementia was done through screening and then diagnosis according to either DMS-
IIIR20 or DMS-IV21 criteria for dementia and for AD by the NINCDS-ADRDA22 criteria. Whitmer
et al used the ICD-9-CM criteria and Gabin et al the ICD-1023. While most diagnosis was either
done or verified in connection with the study and as per the criteria set forth in each study, Whitmer
et al based their diagnosis of dementia on records from clinical databases, and the diagnosis of
general practitioners15.
All but one13 study had both male and female participants. Between the studies are represented
European, Asian, Asian-American, Afro-American, Caucasian-American individuals. The design of
the studies eliminates any possibility of selection bias, as participants are selected retrospectively.
One study stands out in regards to study population; Yamada et al is a study based on a population
of individuals exposed to radiation. They report that this has no effect on the development of
dementia17.
 Study: name / Midlife systolic Midlife Decline in Treatment for HT in Never Comments on
authors HT or elevated diastolic sBP/dBP midlife treated for study
sBP HT or mid- to late- HT
elevated life
dBP
Framingham Dementia + -- Dementia -- -- Caucasian only.
Offspring / AD if [with or Several BP
McGrath et al. persistent into without measurements
late-life midlife HT] through midlife.
+ [AD
without
midlife HT]
The Honolulu- Dementia + Dementia -- Protective: no Dementia, Asian-American
Asia Aging Study VaD: for + AD: for significant connection AD and only. Men only.
/ White et al. untreated only untreated between HT => VaD for
only Dementia/AD/VaD either
diastolic or
systolic HT
The Hisayam Dementia + Dementia Dementia + -- -- BP
Study / Ninomiya VaD + VaD VaD (with measurements
et al. both decline done at only one
and occasion in
persistent midlife
HT)
Kaiser Dementia + Dementia -- -- -- HT defined as
Permanente VaD + AD + VaD + dichotomy.
Medical Care AD Mixed race
Program of population.
Northern
California /
Whitmer et al.
The Linxian AD AD -- -- AD Case-control
County Study / usage to show
Wu et al. dose-response
relationship.
The Radiation VaD -- -- -- -- Not necessarily
Effects Research externally valid
Foundation Adult due to radiation
Health Study / affected study
Yamade et al. population.
North Karelia and AD -- -- -- -- No
FINMONICA differentiation
studies / between
Kivipelto et al. hypertensive
treated / non-
treated.
The HUNT Study ÷AD for those -- -- AD ÷ AD w.
/ Gabin et al. ≥ 60 years of high sBP
age(trending and age ≥ 60
towards
dementia +
VaD)
Table 1: effects of HT, elevated BP, fluctuations in BP and treatment with antihypertensives on the development of
dementia, hypertension (HT) and vascular dementia (VaD). The above table is an attempted overview of the articles
presented in this paper and their results.
Discussion
As outlined in the section above and table 1 the correlations between mid-life HT and development
of dementia later in life is far from uniform. Differing levels of HT in mid-life is seen to correlate
with different types of dementia.
The criteria for defining HT / elevated BP is seen to be a factor with differing scales seen in the
articles reviewed above. The exposure in the articles stratification of HT is important for how the
correlation with outcome is viewed. While stratification cannot change the results, it can be a factor
in providing a more nuanced view of the results. As mentioned earlier, most of the longitudinal or
retrospective cohort studies reviewed here base the definition of mid-life HT / high BP on BP
measurements on a single occasion. This could be a source of misclassification possibly eliminated
by a change in study design. Several measurements done over a period of years might give a clearer
picture of the connection in the development of dementia, which could be achieved by detailing BP
fluctuations over time.
Some studies point to a decline in BP as a precursor for the development of dementia24, 1, 12. The
correlation between this drop in BP and development of dementia could be detailed by following
the development in BP closer, possibly by conducting measurements performed on more than one
occasion from mid- through to late-life. Following the development in BP and cognitive function
closely, in order to more accurately be able to assess the correlations in development.
The diagnosis for dementia and AD is another issue for the research in the field. The articles
presented here found varying forms of dementia – VaD, AD and mixed forms – correlating with HT
of elevated BP at midlife. Criteria for diagnosis should help alleviate this discrepancy and all
articles use diagnostic criteria and almost all of them cite specific screening methods. Even when
these are the same across several studies the results can differ12, 14, 16. This can be due to the design
of the study; who and how diagnosis is done. Or it can be due to the multifactorial nature of the
conditions possibly resulting in a lower accuracy for diagnosis25. Either way it affects the
connections seen between exposure and outcome across several studies. This has been pointed out
by others as well1. In addition some of the used screening tools such as the MMSE, utilized by half
the original studies cited here12, 14, 16, 18, have been reported to be insensitive2.
Effects of anti-hypertensive treatment are inconclusive as well with some studies showing
protective effect, some adjusting for their usage in data and lastly one showing adverse effect on
development of dementia19. Even when the treatment is seen to be protective it is still inconclusive
where one study will show protection from the calcium channel blocker (CCB) nitrendipine26 and
another shows no protection from the same drug but rather from a different CCB27. In this context
of contradictory effects treatment for HT could possibly be seen as a confounder, affecting both
exposure as in HT and outcome as in dementia; possibly factors leading to dementia. This could be
the case if the effects of anti-hypertensive treatments have an HT independent effect on the cerebral
structures associated with dementia, as suggested by others28.
The results of one study finding an inverse correlation between high BP / HT in mid-life and the
development of AD in individuals of ≥ 60 years of age19 opens the field, and suggests that the
correlation between HT and elevated BP is not cemented. Further it suggest that treating mid-life
HT might have an adverse effect, increasing the risk of AD later in life. This underlines the
difficulty of researching the overlapping fields of HT and dementia.

Perspectives
In summation this paper shows that a growing body of evidence suggests a connection between
mid-life HT and the development of dementia in some form later in life. One study found an inverse
connection between systolic HT at the edge of mid- to late-life and an adverse effect between
dementia and the treatment of HT in mid-life. Seen from the perspective of a temporal development
from HT on dementia, these articles stress the need for more detailed studies to be performed.
Focus on the measurements of exposure and outcome and the interrelated connections could bring
future longitudinal studies to more detailed conclusions.
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