Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span

Abstract

Importance: Age-related cognitive decline among older individuals with normal cognition is a complex trait that potentially derives from processes of aging, inherited vulnerabilities, environmental factors, and common latent diseases that can progress to cause dementia, such as Alzheimer disease and vascular brain injury.

Objective: To use cerebrospinal fluid (CSF) biomarkers to gain insight into this complex trait.

Design, setting, and participants: Secondary analyses of an academic multicenter cross-sectional (n = 315) and longitudinal (n = 158) study of 5 neuropsychological tests (Immediate Recall, Delayed Recall, Trail Making Test Parts A and B, and Category Fluency) in cognitively normal individuals aged 21 to 100 years.

Main outcomes and measures: To investigate the association of these cognitive function test results with age, sex, educational level, inheritance of the ε4 allele of the apolipoprotein E gene, and CSF concentrations of β-amyloid 42 (Aβ42) and tau (biomarkers of Alzheimer disease) as well as F2-isoprostanes (measures of free radical injury).

Results: Age and educational level were broadly predictive of cross-sectional cognitive performance; of the genetic and CSF measures, only greater CSF F2-isoprostane concentration was significantly associated with poorer executive function (adjusted R2 ≤0.31). Longitudinal measures of cognitive abilities, except Category Fluency, also were associated broadly with age; of the genetic and CSF measures, only lower baseline CSF Aβ42 concentration was associated with longitudinal measures of immediate and delayed recall (marginal R2 ≤0.31).

Conclusions and relevance: Our results suggest that age and educational level accounted for a substantial minority of variance in cross-sectional or longitudinal cognitive test performance in this large group of cognitively normal adults. Latent Alzheimer disease and other diseases that produce free radical injury, such as vascular brain injury, accounted for a small amount of variation in cognitive test performance across the adult human life span. Additional genetic and environmental factors likely contribute substantially to age-related cognitive decline.

Figure 1. Cross-sectional relationships between concentration of CSF Aβ₄₂ (Panel A), tau (Panel B), and F₂-IsoPs (Panel C) versus subject age at baseline for 315 cognitively normal subjects

Plotting symbols: orange open circle () = subjects with no clinical follow-up (n=153), black open square () = subjects who remained cognitively normal (n=135), magenta asterisk () = converted to MCI (n=14), blue solid triangle () = converted to AD (n=7), red solid circle () = converted to other dementias or cognitive impairments (n=6). Solid line is fitted least squares line unadjusted for any covariates; green dashed lines are 95% confidence bounds for the line. A) Aβ₄₂ slope = −0.3, 95% CI = [−1.2, 0.6], r² = 0.001, p = 0.54. B) tau slope = 0.2, 95% CI = [0.1, 0.3], r² = 0.06, p < 0.001. C) F₂-IsoPs slope = 0.1, 95% CI = [0.04, 0.15], r² = 0.04, p < 0.001.

Figure 2. Cross-sectional relationship between Trail Making Test, Part B scores and concentration of CSF F₂-IsoPs at baseline for 315 cognitively normal subjects

Plotting symbols: orange open circle () = subjects with no clinical follow-up (n=153), black open square () = subjects who remained cognitively normal (n=135), magenta asterisk () = converted to MCI (n=14), blue solid triangle () = converted to AD (n=7), red solid circle () = converted to other dementias or cognitive impairments (n=6). Solid line is fitted least squares line for log¹⁰ score unadjusted for any covariates; green dashed lines are 95% confidence bounds for the line. Slope = 0.005, 95% CI = [0.003, 0.007], r² = 0.06, p < 0.0001.