Cerebrovascular reactivity and plasma p‐tau181 in Alzheimer's disease: Insights into APOE‐related vascular phenotypes

Abstract INTRODUCTION Vascular dysfunction is increasingly recognized as a key contributor to Alzheimer's disease (AD). This study explored cerebrovascular reactivity (CVR), measured by the breath‐holding index (BHI) via Transcranial Doppler (TCD), in relation to plasma AD biomarkers, metabolic dysfunction, cardiovascular burden, and apolipoprotein E (APOE) genotype. METHODS We enrolled 64 patients with cerebrospinal fluid (CSF)‐confirmed AD (30 APOE ε3, 34 APOE ε4) and 28 age‐matched healthy controls in a cross‐sectional blinded study. All participants underwent TCD to assess middle cerebral artery flow velocity and BHI. AD patients were further evaluated for insulin resistance (TyG index), magnetic resonance imaging markers of small vessel disease (SVD), and plasma biomarkers (phosphorylated tau 181 [p‐tau181], amyloid beta [Aβ]42/Aβ40 ratio – AmyR). Multivariate regressions examined associations between BHI and AD‐related parameters, stratified by APOE genotype. RESULTS BHI was significantly reduced in both AD groups compared to controls ( p < 0.001), with no difference between ε3 and ε4 carriers. In ε3 patients, lower BHI was independently associated with higher plasma p‐tau181. In the MRI subgroup analysis, ε3 patients showed a negative correlation between BHI and both TyG and mCSVD while showing a positive correlation with AmyR. None of these associations were observed in ε4 carriers. DISCUSSION Our findings indicate that CVR impairment is present across AD genotypes but more strongly linked to AD pathology and vascular‐metabolic dysfunction in APOE ε3 carriers. CVR may represent a non‐invasive biomarker of early vascular contributions to cognitive decline in AD.