Independent associations of plasma Aβ42 and plasma neurofilament light with white matter hyperintensity volume in non‐demented older individuals

Abstract Background Plasma biomarkers have potential to capture features of Alzheimer’s disease (AD)‐related pathophysiology, but less is known about how they might associate with an imaging measure of cerebral small vessel disease (cSVD). The present study examined independent and combined associations of plasma markers of AD pathology (Aβ42, P‐tau181), axonal damage (neurofilament light [NfL]), and astrocytic activation (glial fibrillary acidic protein [GFAP]) with white matter hyperintensity (WMH) volume in adults without dementia. Method Plasma Aβ42, P‐tau181, NfL, and GFAP (Quanterix Simoa) were measured in 151 older adults without dementia (124 cognitively unimpaired, 27 mild cognitive impairment; aged 52 ‐ 91, 57% female, 95% non‐Hispanic white) who underwent MRI with T2‐weighted FLAIR. Controlling for age, sex, APOE genotype, and intracranial volume, linear regressions first examined WMH volume as a function of each plasma biomarker separately, and next in a combined model with independent and interactive effects of biomarkers associated with WMH from the individual models. Result In individual models, higher WMH volumes were associated with lower plasma Aβ42 (β = ‐0.17, p = 0.032, model R 2 = 19.4%) and higher NfL concentrations (β = 0.21, p = 0.013, model R 2 = 20.3%). Plasma P‐tau181 (β = ‐0.015, p = 0.851) and GFAP (β = 0.05, p = 0.593) were not significantly associated with WMH volume. Aβ42 and NfL did not demonstrate an interaction but both remained independently associated with WMH volume (Aβ42: β = ‐0.19, p = 0.015; NfL: β = 0.24, p = 0.005; model R 2 = 22.7%). No significant interactions between other biomarkers were found. Conclusion Plasma Aβ42 and NfL concentrations associate with burden of cSVD as quantified by WMH load on MRI in non‐demented older adults. As a non‐specific marker of axonal injury, plasma NfL may have utility in studies of brain degeneration related to cSVD. Future studies are warranted to identify factors that may be mediating the effect of plasma amyloid on WMH.