Authors' Reply: Do Amyloid and Tau Ratios Mitigate the Impact of Reduced eGFR on Blood Alzheimer's Biomarkers?

We thank Drs. Yin and Zhang1 for their thoughtful comments on our JASN study, “Kidney Function and Blood and Cerebrospinal Fluid Biomarkers in Alzheimer's Disease and Related Dementias: A Systematic Review and Meta-Analysis.”2 We agree that ratio-based biomarkers may be comparatively robust to kidney dysfunction. In our review, ratio-based biomarkers were extracted when available, with the plasma Aβ42/Aβ40 ratio being the most frequently reported. Across five studies (N=2228) reporting raw correlations between eGFR and Aβ42/Aβ40, correlation coefficients ranged from 0.03 to 0.18, 95% confidence intervals (CIs) crossed zero in four studies, while one reported a modest positive association (rho=0.15; 95% CI, 0.02 to 0.27). An exploratory pooled analysis combining reported correlation coefficients (Pearson, Spearman, and partial) yielded an overall nonsignificant association of 0.05 (95% CI, −0.02 to 0.11). Across six studies reporting multivariable regression estimates (N=7058), β coefficients ranged from −0.02 to 0.00, centered near the null. Across three studies (N=2398) examining the association between CKD status and Aβ42/Aβ40 ratio, the pooled β coefficient was 0.08 (95% CI, −0.00 to 0.17), suggesting a borderline significant association. Owing to the limited number of eligible studies, we did not meta-analyze other composite ratios (e.g., tau/amyloid or p-tau/t-tau). However, emerging evidence suggests that these may be less affected by kidney dysfunction.3,4 For example, Janelidze et al. observed no association between CKD and plasma p-tau217/tau217 ratios, while associations with p-tau181/tau181 were attenuated among cognitively impaired individuals.2 Similarly, Javier et al. reported no differences in p-tau217/Aβ42 across eGFR categories, although absolute p-tau217 concentrations were higher in individuals with reduced kidney function.3 Limited cerebrospinal fluid data show a comparable pattern, with no significant associations between eGFR and cerebrospinal fluid t-tau/Aβ42 or p-tau/Aβ42 ratios.5 Overall, available evidence indicates that ratio-based biomarkers, particularly plasma Aβ42/Aβ40, demonstrate minimal associations with kidney dysfunction, whereas several single-analyte biomarkers are more strongly affected. These findings support the potential utility of ratio-based measures to mitigate kidney-related shifts in biomarker concentrations. Nonetheless, larger, harmonized studies are needed to compare single and ratio-based biomarkers across kidney function strata, particularly among individuals with advanced CKD. Given the high and growing prevalence of both CKD and dementia in aging populations, clarifying these interactions is essential to ensure accurate biomarker interpretation and equitable diagnostic evaluation.