Lower eGFR tied to neurodegeneration

A study using data from the CARTaGENE cohort links lower estimated glomerular filtration rate (eGFR) to cognitive impairment and brain alterations.

“This study presents a 6-year investigation of how eGFR correlates with cognitive functions and brain structure, showing that lower eGFR is associated with diminished cognitive abilities and specific brain structural changes, potentially mediated by genetic and neurobiological factors related to neurodegeneration,” said the researchers.

The analysis included 15,897 participants. Of these, 1,397 (mean age 53.9 years, 49 percent women) underwent T1-weighted brain MRI 6 years after baseline (MRI subset). In the MRI subset, 47.5 percent had normal eGFR (≥90 mL/min/1.73 m²; G1), 49.3 percent had mildly reduced eGFR (60-89 mL/min/1.73 m²; G2), and 3.2 percent had moderately reduced eGFR (30-59 mL/min/1.73 m²; G3). [Alzheimers Dement (Amst) 2024;16(4):e70044]

Lower cognitive performance, structural brain changes

There were gradual declines in reaction time, working memory, and reasoning as eGFR levels dropped in the overall cohort after adjusting for covariates (p<0.001 for all). Lower cognitive performance was consistently associated with eGFR decline within each eGFR level (β_eGFR, -6.6; p=0.001, β_eGFR, -0.22; p=0.026, and β_eGFR, -0.086; p=0.001 for reaction time, working memory, and reasoning, respectively).

According to the investigators, these associations reflect the impact of chronic kidney disease (CKD) on attention and executive functions. [Nephrol Dial Transplant 2020;35:10-17] “Importantly, the mediation effect of eGFR on brain structure was observed only in individuals with reduced eGFR levels, suggesting early associations between kidney function, cognition, and brain structure.”

In the MRI subset, lower eGFR was associated with cortical thinning in the frontal and posterior regions of the brain and thickening in the temporal and cingulate areas. “The relationship between lower eGFR and cortical thinning was significant in the left frontoparietal cortex, precuneus, and cuneus, as well as in the right dorsolateral prefrontal cortex, precuneus, and inferior parietal cortex,” said the researchers.

eGFR mediates cognition-morphology association

Cortical thinning was associated with lower reasoning and longer reaction times but not with working memory. Specifically, lower reasoning was tied to reduced thickness in the sensorimotor, parietal, and posterior temporal cortices, while longer reaction times were tied to reduced thickness in the bilateral prefrontal, anterior temporal, parietal, and occipital cortices.

When comparing the G1 and G3 subgroups, the eGFR levels significantly mediated the association between reasoning performance and cortical thickness in the posterior superior temporal cortex.

No association was observed between reasoning performance and thickness in the G1 subset (r, -0.01; p=0.41), but significant associations did manifest in the G2 (r, 0.11; p=0.006) and G3 (r, 0.46; p=0.008) subgroups.

“No mediating effects of eGFR were found for reaction time, suggesting that eGFR specifically mediates the relationship between reasoning performance and brain morphology,” the researchers explained.

Kidney-brain axis

There is extensive evidence linking CKD to cognitive decline and neurodegenerative conditions. [Neurology 2021;96:e2956-e2965; Mov Disord 2019;34:1184-1191; Neuroepidemiology 2014;42:204-210; Metab Brain Dis 2021;36:1-12] “This suggests that CKD has systemic effects that may affect the brain, referred to as the kidney-brain axis. However, the mechanisms associating CKD with cognition and neurodegeneration remain unclear,” the researchers said.

“This study demonstrates the relationship between eGFR, cognitive performance, and brain structure in healthy individuals,” they said. “It supports the idea that the effect of eGFR on brain structure is not random and targets regions with distinct gene expression patterns.”

However, the results may not be extrapolated to individuals with more severe kidney disease, as most participants had very mild CKD with eGFR levels within a narrow range. Nonetheless, the researchers noted that the associations were significant even within this narrow range.

The use of T1-weighted imaging and performance of cognitive testing at baseline may have also limited their understanding of white matter tracts and how cognitive decline over time relates to baseline eGFR levels, the investigators said. Further studies should thus include diffusion MRI, advanced tractography, and longitudinal cognitive assessments to reinforce the results.

“[Moreover,] future research should investigate the effects of eGFR on other brain metrics of structure and function to have a more comprehensive understanding of the kidney-brain axis,” they said.