Arterial hypertension and β-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity volume: a cross-sectional study

Jose Bernal, Stefanie Schreiber, Inga Menze, Anna Ostendorf, Malte Pfister, Jonas Geisendörfer, Aditya Nemali, Anne Maass, Renat Yakupov, Oliver Peters, Lukas Preis, Luisa Schneider, Ana Lucia Herrera, Josef Priller, Eike Jakob Spruth, Slawek Altenstein, Anja Schneider, Klaus Fliessbach, Jens Wiltfang, Björn H. SchottAyda Rostamzadeh, Wenzel Glanz, Katharina Buerger, Daniel Janowitz, Michael Ewers, Robert Perneczky, Boris Stephan Rauchmann, Stefan Teipel, Ingo Kilimann, Christoph Laske, Matthias H. Munk, Annika Spottke, Nina Roy, Laura Dobisch, Peter Dechent, Klaus Scheffler, Stefan Hetzer, Steffen Wolfsgruber, Luca Kleineidam, Matthias Schmid, Moritz Berger, Frank Jessen, Miranka Wirth, Emrah Düzel, Gabriel Ziegler

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


Background: White 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. Methods: We 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). Results: Subjects 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). Conclusions: Posterior 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 registration: German Clinical Trials Register (DRKS00007966, 04/05/2015).

Original languageEnglish
Article number97
JournalAlzheimer's Research and Therapy
Issue number1
StatePublished - Dec 2023
Externally publishedYes


  • Alzheimer’s disease
  • Cognitive performance
  • MRI
  • Vascular risk
  • White matter hyperintensities


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