Hypertension Associated With Increased Risk of Dementia Regardless of Genetic Background

Thomas Littlejohns, PhD, BSc, MSc

Findings from a large population-based cohort of almost 200,000 adults aged at least 60 years old showed that hypertension was associated with an increased risk of dementia, regardless of genetic risk based on either non-apolipoprotein (APOE) polygenic risk or presence of APOE ε4. Investigators concluded that blood pressure control in middle life may reduce dementia risk across all categories of inherited predisposition.

Using Cox proportional hazards models, lead investigator Thomas Littlejohns, PhD, BSc, MSc, senior epidemiologist, University of Oxford, and colleagues, found the presence of hypertension to be associated with a 19% increased risk of dementia. The cumulative incidence of dementia over 12 years was 8 times higher for those with the highest genetic risk of dementia and hypertension compared with those with the lowest genetic risk and no hypertension.

As prior investigations into the relationship between hypertension, genetics, and dementia have shown conflicting results, Littlejohns et al noted that “the interpretation of the findings from previous studies is complicated by the different approaches used to define hypertension.” This study included current blood pressure and history (via self-reported doctor diagnosis and antihypertensive use), "as a one-off blood pressure measure does not account for treatment history or the various factors that influence the likelihood of hypertension treatment and control,” they wrote.

"We found that antihypertensive use was associated with an increased risk of dementia and this likely reflects confounding by indication, that is, antihypertensive use is associated with a history of high blood pressure which in turn is associated with dementia. Studies with repeat measures of blood pressure as well as more detailed information on length and intensity of blood pressure treatment could help elucidate these complex relationships,” Littlejohns et al wrote. They did also acknowledge that those with hypertensive often have two or more comorbid conditions, thus "future studies investigating hypertension in the context of other diseases, and whether genetic risk modifies any associations with dementia, are warranted."

After exclusions, the study sample included 198,965 participants, 153,795 (77.3%) of whom had hypertension. Hypertension was defined as either self-reported doctor diagnosis (53%), self-reported use of antihypertensive medication (47%), or measured systolic blood pressure of at least 140 mm of mercury or diastolic blood pressure at least 90 mm Hg (81%). A total of 6270 (3.2%) participants developed incident dementia over 2,353,031 person-years of follow-up.

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After adjusting for age and sex, a Kaplan-Meier plot continued to show hypertension’s association with increased risk of dementia (HR, 1.19; 95% CI, 1.12-1.27). The direction and strength of this association remained the same when fully adjusting for additional covariates such as age, sex, ethnicity, Townsend deprivation index, education, household income, country, smoking status, alcohol intake, physical activity, body mass index, and number of comorbidities (HR, 1.19; 95% CI, 1.11-1.27).

When restricting analysis to participants who were censored within 5 years, 5 to 10 years, and 10 or more years, the fully adjusted HRs were 1.15 (95% CI, 0.93-1.42), 1.25 (HR, 1.13-1.38), and 1.14 (95% CI, 1.03-1.27), respectively. After splitting patients based on age (45-65 years or >65 years), there was no interaction between hypertension and risk of dementia. “The lack of association in later-life might be due to reverse causation, for example, ill health and weight loss resulting in lower blood pressure, or it might be due to more aggressive treatment in at-risk individuals,” Littlejohns et al wrote.

To determine the genetic risk for dementia, investigators used a polygenic risk score (PRS) based on 38 non-APOE ε single nucleotide polymorphisms and APOE ε4 status. After adjusting for APOE, the associations between risk of incident dementia remained highly similar for those with intermediate dementia PRS (HR, 1.31; 95% CI, 1.21-1.43) and high dementia PRS (HR, 1.83; 95% CI, 1.67-2.01) when compared to those with low dementia PRS. Furthermore, APOE ε4 carriers had an increased risk of dementia compared with noncarriers (fully adjusted HR, 3.17 [95% CI, 3.01-3.34]; additional adjustment for dementia PRS HR, 3.15 [95% CI, 2.97-3.33]).

In the fully adjusted models, there was no statistically significant interaction between hypertension and dementia PRS (interaction, P =.20) or hypertension and APOE ε4 (interaction, P =.16) and risk of incident dementia. The association between hypertension and dementia remained similar to the original findings when stratified by low, intermediate, and high dementia PRS, as well as for APOE ε4 carrier status. The findings also remained similar after excluding individuals with non-White genetic ancestry, which have been shown to be at an elevated risk in previous studies.

Over a 12-year period, the incidence of dementia was 4.3% for those with high dementia PRS and hypertension compared with 2.8% of those without hypertension. Among APOE ε4 carriers, the incidence increased to 6.2% for those with hypertension vs 4.7% for those without. Additionally, the 12-year cumulative incidence of dementia was lower within each combination of dementia PRS and APOE ε4 stratum for those without hypertension compared with those with hypertension.

REFERENCES
1. Littlejohns TJ, Collister JA, Liu X, Clifton L, Tapela NM, Hunter DJ. Hypertension, a dementia polygenic risk score, APOE genotype, and incident dementia. Alzheim & Dement. Published online April 19, 2022. doi:10.1002/alz.12680.