BackgroundWhite matter hyperintensities (WMH) in subjects across the Alzheimer’s disease (AD) spectrum with minimal vascular pathology suggests that amyloid pathology—not just arterial hypertension—impacts WMH, which in turn adversely influences cognition. Here we seek to determine the effect of both hypertension and Aβ positivity on WMH, and their impact on cognition.MethodsWe analysed data from subjects with a low vascular profile and normal cognition (NC), subjective cognitive decline (SCD), and amnestic mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study (n= 375, median age 70.0 [IQR 66.0, 74.4] years; 178 female; NC/SCD/MCI 127/162/86). All subjects underwent a rich neuropsychological assessment. We focused on baseline memory and executive function—derived from multiple neuropsychological tests using confirmatory factor analysis—, baseline preclinical Alzheimer’s cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over the course of three years (ΔPACC5).ResultsSubjects with hypertension or Aβ positivity presented the largest WMH volumes (pFDR< 0.05), with spatial overlap in the frontal (hypertension: 0.42 ± 0.17; Aβ: 0.46 ± 0.18), occipital (hypertension: 0.50 ± 0.16; Aβ: 0.50 ± 0.16), parietal lobes (hypertension: 0.57 ± 0.18; Aβ: 0.56 ± 0.20), corona radiata (hypertension: 0.45 ± 0.17; Aβ: 0.40 ± 0.13), optic radiation (hypertension: 0.39 ± 0.18; Aβ: 0.74 ± 0.19), and splenium of the corpus callosum (hypertension: 0.36 ± 0.12; Aβ: 0.28 ± 0.12). Elevated global and regional WMH volumes coincided with worse cognitive performance at baseline and over 3 years (pFDR< 0.05). Aβ positivity was negatively associated with cognitive performance (direct effect—memory: − 0.33 ± 0.08,pFDR< 0.001; executive: − 0.21 ± 0.08,pFDR< 0.001; PACC5: − 0.29 ± 0.09,pFDR= 0.006; ΔPACC5: − 0.34 ± 0.04,pFDR< 0.05). Splenial WMH mediated the relationship between hypertension and cognitive performance (indirect-only effect—memory: − 0.05 ± 0.02,pFDR= 0.029; executive: − 0.04 ± 0.02,pFDR= 0.067; PACC5: − 0.05 ± 0.02,pFDR= 0.030; ΔPACC5: − 0.09 ± 0.03,pFDR= 0.043) and WMH in the optic radiation partially mediated that between Aβ positivity and memory (indirect effect—memory: − 0.05 ± 0.02,pFDR= 0.029).ConclusionsPosterior white matter is susceptible to hypertension and Aβ accumulation. Posterior WMH mediate the association between these pathologies and cognitive dysfunction, making them a promising target to tackle the downstream damage related to the potentially interacting and potentiating effects of the two pathologies.Trial registrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015).Supplementary InformationThe online version contains supplementary material available at 10.1186/s13195-023-01243-4.