Blood biomarkers of Alzheimer's disease in the community: Variation by chronic diseases and inflammatory status

Abstract

Introduction: We explored the variations of blood biomarkers of Alzheimer's disease (AD) by chronic diseases and systemic inflammation.

Methods: We explored the association of AD blood biomarkers with chronic diseases and systemic inflammation (interleukin-6 [IL-6]), in 2366 dementia-free participants of the Swedish National Study on Aging and Care-in Kungsholmen, using quantile regression models.

Results: A greater number of co-occurring chronic diseases was associated with higher concentrations of phosphorylated-tau 181 (p-tau181), total-tau (t-tau), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) (p < 0.01). Anemia, kidney, cerebrovascular, and heart diseases were associated with variations in the levels of AD blood biomarkers. Participants in the highest (vs. lowest) interleukin-6 (IL-6) tertile had higher NfL concentration. Systemic inflammation amplified the associations between several chronic diseases and p-tau181, t-tau, NfL, and GFAP.

Discussion: In the community, the concentration of AD blood biomarkers varies in relation to medical conditions and systemic inflammation. Recognizing these influences is crucial for the accurate interpretation and clinical implementation of blood biomarkers.

Highlights: Participants with a complex clinical profile (i.e., multiple co-occurring diseases or specific disease combinations) display elevated levels of AD blood-biomarkers. Anemia, heart, cerebrovascular, and kidney diseases are associated with variations is the levels of AD blood biomarkers in cognitively intact older adults. Systemic inflammation amplifies the association between several chronic diseases and AD blood biomarkers.

Keywords: Alzheimer's disease; blood biomarkers; chronic diseases; dementia; inflammation; population‐based study.

FIGURE 1

Distribution of blood biomarkers of Alzheimer's disease (z‐scores) by age groups. Box plots show the median (central line) and interquartile range (box) as well as the 2.5^th and 97.5^th percentiles (whiskers). p values are derived from Kruskal‐Wallis test; ns: non‐significant, *: < 0.05; **: < 0.01; ***: < 0.001; ****: < 0.0001. Aβ42/40, amyloid‐beta 42/40; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau181, phosphorylated‐tau181; t‐tau, total‐tau. Some outliers were not represented for graphical purposes (n = 2 for Aβ42/40 ratio, 3 for p‐tau181, 2 for t‐tau, 6 for NfL, and 5 for GFAP).

FIGURE 2

Correlation matrix showing Spearman's correlations between blood biomarkers of Alzheimer's disease. Aβ42/40, amyloid‐beta 42/40; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau181, phosphorylated‐tau181; t‐tau, total‐tau.

FIGURE 3

Associations between number of chronic diseases and blood biomarkers of Alzheimer's disease (AD). β coefficients with 95% confidence intervals are derived from quantile regression models on the 50th (median) percentile, adjusted for age, sex and education. Blood biomarkers of AD were z‐scored. p for trend: Aβ42/40: p 0.405; p‐tau181: p < 0.001; t‐tau: p 0.007; NfL: p < 0.001, GFAP p 0.001. Aβ42/40, amyloid‐beta 42/40; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau181, phosphorylated‐tau181; t‐tau, total‐tau.

FIGURE 4

Associations of chronic diseases and cardiovascular risk factors with blood biomarkers of Alzheimer's disease (AD). β coefficients with 95% confidence intervals are derived from quantile regression models on the 50th (median) percentile, adjusted for age, sex, and education. Blood biomarkers of AD were z‐scored. Aβ42/40, amyloid‐beta 42/40; GFAP, glial fibrillary acidic protein; NfL, neurofilament light chain; p‐tau181, phosphorylated‐tau181; t‐tau, total‐tau.

FIGURE 5

Associations between chronic diseases and blood biomarkers of Alzheimer's disease (AD), stratified by IL‐6 levels. β coefficients with 95% confidence intervals are derived from quantile regression models on the 50th (median) percentile adjusted for age, sex, and education. Blood biomarkers of AD were z‐scored. Low and high levels of IL‐6 were categorized based on tertiles (low IL‐6 = first and second IL‐6 tertiles, IL‐6 $\le$ 2.2 pg/mL; high IL‐6 = third IL‐6 tertile, IL‐6 $>$ 2.2 pg/mL). Heart disease includes atrial fibrillation, heart failure and ischemic heart disease. Aβ42/40, amyloid‐beta 42/40; GFAP, glial fibrillary acidic protein; IL‐6, interleukin 6; NfL, neurofilament light chain; p‐tau181, phosphorylated‐tau181; t‐tau, total‐tau.