Associations between cardiometabolic multimorbidity and cerebrospinal fluid biomarkers of Alzheimer's disease pathology in cognitively intact adults: the CABLE study

Abstract

Background: Cardiometabolic multimorbidity is associated with an increased risk of dementia, but the pathogenic mechanisms linking them remain largely undefined. We aimed to assess the associations of cardiometabolic multimorbidity with cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology to enhance our understanding of the underlying mechanisms linking cardiometabolic multimorbidity and AD.

Methods: This study included 1464 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database. Cardiometabolic diseases (CMD) are a group of interrelated disorders such as hypertension, diabetes, heart diseases (HD), and stroke. Based on the CMD status, participants were categorized as CMD-free, single CMD, or CMD multimorbidity. CMD multimorbidity is defined as the coexistence of two or more CMDs. The associations of cardiometabolic multimorbidity and CSF biomarkers were examined using multivariable linear regression models with demographic characteristics, the APOE ε4 allele, and lifestyle factors as covariates. Subgroup analyses stratified by age, sex, and APOE ε4 status were also performed.

Results: A total of 1464 individuals (mean age, 61.80 years; age range, 40-89 years) were included. The markers of phosphorylated tau-related processes (CSF P-tau181: β = 0.165, P = 0.037) and neuronal injury (CSF T-tau: β = 0.065, P = 0.033) were significantly increased in subjects with CMD multimorbidity (versus CMD-free), but not in those with single CMD. The association between CMD multimorbidity with CSF T-tau levels remained significant after controlling for Aβ42 levels. Additionally, significantly elevated tau-related biomarkers were observed in patients with specific CMD combinations (i.e., hypertension and diabetes, hypertension and HD), especially in long disease courses.

Conclusions: The presence of cardiometabolic multimorbidity was associated with tau phosphorylation and neuronal injury in cognitively normal populations. CMD multimorbidity might be a potential independent target to alleviate tau-related pathologies that can cause cognitive impairment.

Keywords: Alzheimer’s disease; Biomarkers; Cardiometabolic multimorbidity; Cerebrospinal fluid; Phosphorylated tau; Tau.

Fig. 1

CSF tau-related biomarkers in three CMD status groups. Bar graphs show mean, and error bars represent standard deviations. Bee swarm plots visualize the distribution of biomarkers data. CSF tau-related biomarkers were Box-Cox power transformed, and then, the z-score normalized. One-way ANOVA was used to test group differences in biomarkers, followed by the Tukey HSD posthoc test. CSF P-tau181, T-tau significantly differed among groups (all P values < 0.05). We observed that the levels of CSF P-tau181 and T-tau were highest in the CMD multimorbidity group, followed by an intermediate level in the single CMD group, and lowest in the CMD-free group (all P values < 0.05). P > 0.05: NS; P ≤ 0.05: *; P ≤ 0.01: **; P ≤ 0.001: ***; P ≤ 0.0001: ****. Abbreviations: CMD, cardiometabolic disease; CSF, cerebrospinal fluid

Fig. 2

Stratified analyses of associations between CSF AD biomarkers and CMD status. Multiple linear regression models were employed with adjustment for age, sex, education years, MMSE, APOE ε4 carrier status, BMI, cigarette use, alcohol use, and physical activity. In stratified analyses, CMD multimorbidity showed significant or suggestive associations with CSF T-tau levels in males, and APOE ε4 non-carriers. The association between hypertension and CSF AD biomarkers was found in mid-life, but not in late-life. Abbreviations: CMD, cardiometabolic disease; CSF, cerebrospinal fluid; AD, Alzheimer’s disease; MMSE, Mini-Mental State Examination; APOE ε4, apolipoprotein E; BMI, body mass index; HD, heart disease