Hypertension may lead to cognitive dysfunction in older adults via methylmalonic acid: evidence from NHANES 2011-2014 population

Abstract

Background: An enriched understanding is necessary concerning the association between hypertension and cognitive impairment in older adults, particularly regarding the potential underlying mechanisms at a biological level. This study aimed to explore the mediating role of methylmalonic acid (MMA) in the hypertension-cognition link in the older population.

Methods: A total of 2762 adults (age > = 60 years) from the National Health and Nutrition Examination Survey (NHANES) 2011-2014 participated. Cognitive function was assessed using a combination of the Animal Fluency Test (AFT), the Digit Symbol Substitution Test (DSST), and the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Word List Learning Test. Self-reported hypertension diagnosis, antihypertensive medications use, and blood pressure examinations were used to identify hypertension. Serum MMA (sMMA) levels were collected. Weighted multiple linear regressions and mediation analysis were applied. A subgroup analysis by sex and age was performed.

Results: After adjusting for potential confounding factors, we observed a significant mediating effect of the sMMA level in the hypertension-cognition link, accounting for 11.14% (95% CI 4.09%-14.00%, p < 0.001) of the relationship in older adults. The proportion mediated by the sMMA level in the relationship between hypertension and cognitive function was higher in males (15.23%, 95%CI 1.32%-27.00%, p < 0.001) than in females (6.61%, 95%CI 2.12%-10.00%, p < 0.001). This mediating effect of sMMA was observed only in individuals aged 68 years and older (11.31%, 95%CI 3.80%-16.00%, p < 0.001), with no significant mediation detected in those younger than 68 years.

Conclusion: Hypertension may lead to cognitive dysfunction in older adults through MMA. Apart from its role as a biomarker reflecting vitamin B12, MMA may act as an independent neurotoxin capable of inducing brain injury and cognitive impairment. Addressing MMA accumulation, such as through Vitamin B12 supplementation, may have a potential to mitigate hypertension-induced cognitive decline in older adults. Special attention could be paid to hypertensive males with an advanced age (> = 68) to address MMA-related cognitive decline.

Keywords: Cognitive impairment; Hypertension; Mediation analysis; Methylmalonic acid; Older adults.

Fig. 1

Flowchart of the study population. Figure 1 presents the flow chart of identifying the study population

Fig. 2

Theoretical diagram of the mediation analysis. Figure 2 shows the theoretical model of the mediation analysis for the association between hypertension and cognitive function with the serum methylmalonic acid (sMMA) level as a potential mediator

Fig. 3

Mediating role of methylmalonic acid between hypertension and cognitive function. Figure 3 shows the results of the mediation analyses for the association between hypertension and cognitive function with the serum methylmalonic acid (sMMA) level as a potential mediator, with subgroup analyses for age and sex

Fig. 4

A hypothesized mechanistic pathway between hypertension and cognitive decline via methylmalonic acid. Figure 4 illustrates a proposed mechanistic pathway linking hypertension to cognitive decline, highlighting the potential mediating role of MMA. (This illustration was created with BioRender.com)