Alzheimer’s blood-based biomarkers and 15-year trajectories of orthostatic blood pressure in individuals over 60

Background

Orthostatic hypotension (OH) is common in older adults and is associated with cardiovascular events, cognitive decline, and mortality. The biological drivers of progressive orthostatic blood pressure (BP) instability in ageing remain poorly defined. Blood-based biomarkers of Alzheimer’s disease (AD) reflect early neurodegenerative processes and may signal subclinical autonomic vulnerability. We hypothesized that higher concentrations of AD-related biomarkers would be associated with worsening orthostatic BP trajectories over time.

Purpose

To examine whether AD blood-based biomarkers are associated with longitudinal changes in orthostatic BP regulation in older adults.

Methods

We performed a longitudinal cohort analysis using data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a population-based study of community-dwelling adults aged ≥60 years, assessed between 2001 and 2016. Plasma levels of neurofilament light chain (NfL), glial fibrillary acidic protein (GFAP), and tau phosphorylated at T217 (pTau217) were measured at baseline. Participants with baseline dementia or parkinsonism were excluded.

Orthostatic systolic and diastolic BP differentials (ΔSBP and ΔDBP; supine–standing, mmHg) were repeatedly assessed over 15 years. Biomarkers were dichotomised using previously validated SNAC-K thresholds (NfL ≥20.171 pg/mL; GFAP ≥142.515 pg/mL; pTau217 ≥0.134 pg/mL) [1]. Longitudinal associations were evaluated using linear mixed-effects models with random intercepts and biomarker-by-time interaction terms, adjusted for age, sex, hypertension, diabetes, heart failure, education, physical activity, alcohol consumption, and polypharmacy. Sensitivity analyses excluded prevalent OH and incorporated joint longitudinal–survival modelling.

Results

The study included 1,492 participants (median age 66 years; 62% women). During follow-up, 613 individuals (41%) developed incident OH. Baseline demographic and cardiometabolic characteristics were comparable across biomarker categories.

Elevated NfL levels were associated with steeper worsening of orthostatic BP trajectories. In multivariable models, the biomarker-by-time interaction was significant for both ΔSBP (β=0.19, 95%CI 0.03–0.35; p=0.024) and ΔDBP (β=0.13, 95%CI 0.03–0.23; p=0.010). Associations remained consistent after excluding baseline OH. GFAP and pTau217 were not significantly associated with longitudinal orthostatic BP changes.

In joint longitudinal–survival analyses, greater underlying orthostatic BP differentials were independently associated with increased mortality risk (ΔSBP β=0.185, p<0.001; ΔDBP β=0.341, p<0.001).

Conclusions

Elevated NfL levels identify individuals with progressive orthostatic BP dysregulation independent of traditional cardiovascular risk factors. These findings suggest that subclinical neurodegeneration may contribute to age-related autonomic and vascular instability.Figure 1