Association of hemoglobin with plasma neurofilament light and white matter hyperintensities in Alzheimer's disease continuum

Objective: This study aimed to investigate the association of hemoglobin (Hb) with axonal injury marker plasma neurofilament light (PNFL) and brain structure measurements in the Alzheimer's disease (AD) continuum. Methods: The data used in this study were collected from the Alzheimer's Disease Neuroimaging Initiative database. Participants with cognitively normal, mild cognitive impairment, and mild dementia were included in the data analyses. All participants had available data on blood tests, PNFL levels, neuropsychological assessments, brain structure measurements (including volumes of white matter hyperintensities [WMH], hippocampus, gray matter, and total brain), and A beta positron emission tomography standardized uptake value ratio (SUVR) at baseline. A beta-positive was defined as SUVR threshold value > 1.11. Linear regression, restricted cubic spline, and causal mediation analyses were conducted to investigate the association of Hb concentration with PNFL levels and brain structure measurements. Stratified analyses were also employed to evaluate the association between Hb concentration and PNFL levels across different APOE genotypes and sex. Results: In the A beta-positive group, Hb concentration was associated with PNFL levels (beta = -0.022, p = 0.002). Stratified analyses suggested an association between Hb concentration and PNFL in APOE epsilon 4 carriers (beta = -0.031, p < 0.001) and males (beta = -0.030, p <0.001) but not in noncarriers and females (p > 0.05). Hb concentration was also associated with WMH volume (beta = -0.04, p = 0.028), especially in APOE epsilon 4 carriers, with mediation analysis revealing that PNFL mediated the association between Hb concentration and WMH volume. The association of Hb concentration with other brain structure measurements was minimal. Conclusion: In the AD continuum, Hb was associated with axonal injury marker PNFL and WMH volume, particularly in APOE epsilon 4 carriers.