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

Background Posterior 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, adversely influencing 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 70.2 [IQR 66.0-74.4] years; 176 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 course of three years (ΔPACC5). Results Subjects with hypertension or Aβ positivity presented the largest WMH volumes ( p FDR <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). Hypertension, Aβ positivity, and WMH were connected to cognition. First, WMH coincided with worse cognitive performance and outcomes ( p FDR <0.05), regardless of Aβ and hypertension. Accelerated cognitive decline was associated with WMH in the genu of the corpus callosum and segments of the forceps major and inferior fronto-occipital longitudinal fasciculus ( p FDR <0.05). Second, hypertension was indirectly linked to cognitive performance at baseline and over time via splenial WMH ( indirect-only effect ; memory: −0.05±0.02, p FDR =0.029; executive: −0.04±0.02, p FDR =0.067; PACC5: −0.05±0.02, p FDR =0.030; ΔPACC5: −0.09±0.03, p FDR =0.043). Third, the relationship between Aβ positivity and baseline and longitudinal cognitive performance was independent of WMH burden. Conclusions Posterior white matter is susceptible to hypertension and Aβ accumulation and it mediates the association between hypertension and cognitive dysfunction. Posterior WMH could be 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) ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This research was supported by the German Center for Neurodegenerative Diseases (DZNE; reference number BN012) and funded by the German Research Foundation (Deutsche Forschungsgemeinschaft, DFG; Project IDs 425899996 and 362321501/RTG 2413 SynAGE). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study protocol was approved by the ethical committees of the medical faculties of all participating sites: the ethical committees of Berlin (Charite, University Medicine), Bonn, Cologne, Goettingen, Magdeburg, Munich (Ludwig-Maximilians-University), Rostock, and Tuebingen. The process was led and coordinated by the ethical committee of the medical faculty of the University of Bonn. All commitees gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript * Aβ : β-amyloid AD : Alzheimer’s disease ATN : Amyloid/Tau/Neurodegeneration B : regression coefficient CAA : Cerebral amyloid angiopathy CERAD : Consortium to Establish a Registry for Alzheimer’s Disease CN : Non-complaining healthy controls CSF : Cerebrospinal fluid CSVD : Cerebral small vessel disease FDR : False discovery rate FLAIR : Fluid Attenuated Inversion Recovery GM : Grey matter IQR : Interquartile range MCI : Mild cognitive impairment MRI : Magnetic resonance imaging NC : Normal cognition PACC5 : Preclinical Alzheimer’s Cognitive Composite 5 ROI : Region of interest SCD : Subjective cognitive decline SD : Standard deviation SE : Standard error SPM : Statistical parametric mapping TICV : Total intracranial volume WM : White matter WMH : White matter hyperintensities