Plasma biomarkers of Alzheimer’s disease and their association with disproportionately enlarged subarachnoid space hydrocephalus

Individuals with both Alzheimer’s Disease (AD) and cerebrospinal fluid (CSF) dynamics disorders, such as idiopathic normal-pressure hydrocephalus (iNPH), exhibit reduced CSF Aβ42 levels, complicating the interpretation of AD biomarkers. However, the influence of CSF dynamics on blood-based AD biomarkers remains unclear. This study investigated whether immunoprecipitation mass spectrometry (IP-MS)-based AD plasma biomarkers were associated with disproportionately enlarged subarachnoid space hydrocephalus (DESH) on MRI. This retrospective, cross-sectional study included 509 participants from the Mayo Clinic Study of Aging who underwent MRI, [¹¹C] Pittsburgh compound B (Aβ) PET imaging, and plasma assessments of phosphorylated tau 217 (p-Tau 217), Aβ40, and Aβ42. Age-adjusted logistic regression analyses were conducted to evaluate whether abnormal levels of p-Tau 217, %p-Tau 217 (ratio of phosphorylated to non-phosphorylated tau × 100%), Aβ42, or the Aβ42/40 ratio were associated with DESH, as identified by a previously validated automated algorithm. In addition, combinations of binary amyloid PET and plasma biomarkers to create 4 categories were tested for an association with DESH as a sensitivity analysis. Average age was 72.2 (8.8), with 54% male participants, and 30% were APOE4 carriers. Thirty-two participants (6.3%) were classified as having DESH. Abnormal (low) plasma Aβ42 (OR: 2.56 [95% CI: 1.19, 5.74]) and abnormal (high) p-tau217 (OR: 2.74 [95% CI: 1.09, 7.85]) were associated with DESH, but not the respective ratios of Aβ42/40 (OR: 1.95 [95% CI: 0.94, 4.17]) or %p-tau (OR: 1.82 [95% CI: 0.74, 4.20]). Analysis of the combined variables (amyloid PET and plasma biomarkers) demonstrated that an association with DESH was observed only in participants who were abnormal on both measures, compared with participants who were negative on both plasma biomarkers and PET. This association was attenuated when biomarker ratios were used. The observed association between abnormal plasma biomarker levels and DESH aligns with previous CSF studies and can be mitigated by utilizing the biomarker ratios. However, further validation is needed in populations with more severe CSF flow abnormalities to better understand the role of plasma biomarkers in this population.