Stroke is a common risk factor for cognitive decline associated with vascular dementia (VD). The causal link between high blood pressure (BP) or hypertension (HTN) and the incidence of stroke is well-establish (O’Donnell, Xavier et al. 2010). Several longitudinal studies have also reported the association between mid or late life HTN and dementia (Freitag, Peila et al. 2006, Alonso, Mosley et al. 2009). In recent decades, there has been a sudden rise in the prevalence of HTN among individuals in the mid-20s (Hinton, Adams et al. 2020). However, little is known what could be the long-term effects at such a young age. The high proportion of hypertensive individuals in the young population is specifically of concern because such individuals often remain untreated for more than a decade of suffering in the absence of accompanying comorbidities or a significantly lower incidence of stroke. Therefore, the present study aims to study the effect of early-life HTN on the incidence of non-vascular dementia in later life.

Specific objectives of the study are as follows:

1. Primary objective: To study the influence of early life (25-35 years) high blood pressure (SBP>90mg/Hg or DBP>140mm/Hg) on the incidence of non-vascular dementia compared to the remaining individuals in the same age group in a 50-year follow-up study.
2. Secondary objective: To study the influence of early life (25-35 years) high blood pressure (SBP>90mg/Hg or DBP>140mm/Hg) on the incidence of severe cognitive decline and VD compared to the remaining individuals in the same age group in a 50-year follow-up study.

The study findings may help educate the public on potential long-term ill-effects of poor lifestyle at an early stage of life and a need for early screening of blood pressure to introduce urgent interventions that could assist in controlling HTN.

Background

Dementia is an ageing-related comprehensive syndrome characterized by a progressive decline in cognitive abilities, which profoundly affects other thinking relating tasks (Chertkow, Feldman et al. 2013, Gale, Acar et al. 2018). According to a recent report released by the Global Burden of Diseases (GBD), more than 40 million people lived with dementia in 2016 (GBD, 2017). Several underlying neurodegenerative conditions could increase the susceptibility to dementia, including Alzheimer’s’ disease (AD) and vascular dementia (VD) (Raz, Knoefel et al. 2016). Other risk factors for dementia include high cholesterol, blood pressure and glucose levels (Arvanitakis, Tatavarthy et al. 2020, Mishra, Mohan et al. 2020).

High blood pressure or HTN in mid or late life is a common risk factor for cognitive decline in adults (Walker, Power et al. 2017). It has also been suggested that controlling blood pressure may help in the primary or secondary prevention of dementia (den Brok, van Dalen et al. 2021). A recent meta-analysis assessing the incidence of dementia among 649,790 participants enrolled across 15 prospective cohort studies, and seven randomized controlled trials (RCTs) showed a significantly lower risk of dementia in individuals treated with calcium channel blockers (CCBs) or angiotensin II receptor blockers (ARBs). With a rapidly increased prevalence of untreated blood pressure among individuals in their late 20s or early 30s, there is a need to understand the relationship between early-life blood pressure and cognitive function in later life (Hinton, Adams et al. 2020).

According to the United States consensus, considerable variability exists across its cities in terms of the median age of residents (Bureau 2020). While several cities across Florida top the list with median age ranging from 54-68, the two most populous cities in Utah have surprisingly lowest median age in the US with 25.0 and 28.8 years. The low median age for both these cities makes them ideal for studying long-term effects of HTN at an early age on neurocognitive abilities and dementia later.

Methods

Study design

The present proposal aims to conduct a 50-year old prospective cohort study to explore the relationship between HTN in individuals aged 25 to 35 years and the incidence of HTN from field centres in two US cities, Provo and Logan, Utah. The objectives of the project were advertised through local media, and study participants were selected randomly from those showing interest to participate in the study.  The study participants with a history of congenital heart diseases or neuropsychiatric illness were excluded. Baseline data will be collected from all the study participants, including the data on mental health and cardiovascular parameters, after obtaining the informed consent. The participants will be contacted by telephone and/or email after every five years and invited for additional clinical check-ups for neurocognitive assessment. If an individual has migrated to another city or country, appropriate arrangements will be made to get the local clinician’s assessment.

Data collection

At the baseline visit, sitting blood pressure will be measured three times using a random-zero sphygmomanometer. An average of all the measures will be treated as blood pressure. Hypertension will be defined as SBP ≥140 mm Hg or DBP ≥90 mm Hg (Walker, Sharrett et al. 2019). Also, data on covariates including age, gender, ethnicity, education level, history of smoking, alcohol use, physical activity, body mass index, presence of diabetes mellitus, or coronary heart conditions, and ongoing treatments will be collected. Additionally, blood samples will be collected to perform genotype testing for Apolipoprotein E alleles, known to be implicated in AD and lipid profiling, associated with high blood pressure. Dementia will be diagnosed using a standardized questionnaire according to International Classification of Diseases, Ninth Revision (ICD-9) codes: 290.0, 290.1, 290.4, 290.2, 290.3, 290.9, 294.1, 294.2, 294.8, 294.9, 331.03, 31.1, 331.2, 331.8, and 331.9). Lastly, the date of onset of dementia will be recorded (Alonso, Mosley et al. 2009).

Data analysis

Diagnosis of dementia was treated as the primary endpoint of the study. All the data management and statistical procedures will be performed using IBM Statistical Package for the Social Science (SPSS) for Windows, Version 21.0. (SPSS Inc, Chicago, Illinois). The categorical variables such will be expressed in proportions. The distribution of categorical variables will be compared between the person living with dementia and the person not showing any signs of significant cognitive decline using Chi-square tests. The distribution of continuous variables will be compared between different groups using a t-test. Hazards ratio (HRS) will be computed using the cox proportional hazards regression model adjusted for relevant confounding variables. Confidence intervals (CI) will be computed at the 95% significance level. A p-value below 0.05 will be considered statistically significant. The strata specific ORs will be reported after stratifying based on types of dementia.

Strengths and Limitations

The present study proposal has several strengths and limitations. Firstly, being a cohort study, the possible role of unaccounted confounding factors cannot be ruled out. Nevertheless, the present study also gains its strength for its comprehensive data collection plan, including genetic predisposition to dementia. Secondly, participants who are highly concerned about their health are more likely to have enrolled themselves in the study, leading to selection bias with an over-representation of such participants. Thirdly, knowledge of the ill effects of high blood pressure gained through participation in the present study may make participants more conscious about their lifestyle throughout the study duration. Hence, the study findings from this study may not be generalizable to other study populations. Fourthly, participants who have been diagnosed with dementia is the recent past may not be able to provide an accurate estimate of the onset of dementia due to recall bias. However, a shorter interval between successive follow-ups in this study would ensure the minimum effect of such a recall bias. It is also expected that a large number of study participants may be lost to follow-up due to possible migration or death. However, the study is expected to enrol a large number of subjects and plans to maintain a continuous connection with the family through the local physicians and added health benefits of comprehensive check-up’s, and thereby ensuring that the drop-out rate remains below a health rate of 10-15%.

References

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