Arterial hypertension and Aβ-amyloid accumulation have spatially overlapping effects on posterior white matter hyperintensity presence and volume

BackgroundPosterior white matter hyperintensities (WMH) in subjects across the Alzheimers 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 A{beta} 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 70.2 [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 Alzheimers cognitive composite 5 (PACC5) scores, and changes in PACC5 scores over course of three years ({Delta}PACC5). ResultsSubjects with hypertension or A{beta} positivity presented the largest WMH volumes (pFDR<0.05), with spatial overlap in the frontal (hypertension: 0.42{+/-}0.17; A{beta}: 0.46{+/-}0.18), occipital (hypertension: 0.50{+/-}0.16; A{beta}: 0.50{+/-}0.16), parietal lobes (hypertension: 0.57{+/-}0.18; A{beta}: 0.56{+/-}0.20), corona radiata (hypertension: 0.45{+/-}0.17; A{beta}: 0.40{+/-}0.13), optic radiation (hypertension: 0.39{+/-}0.18; A{beta}: 0.74{+/-}0.19), and splenium of the corpus callosum (hypertension: 0.36{+/-}0.12; A{beta}: 0.28{+/-}0.12). Hypertension, A{beta} positivity, and WMH were connected to cognition. First, WMH coincided with worse cognitive performance and outcomes (pFDR<0.05), regardless of A{beta} 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 (pFDR<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, pFDR=0.029; executive: -0.04{+/-}0.02, pFDR=0.067; PACC5: -0.05{+/-}0.02, pFDR=0.030; {Delta}PACC5: -0.09{+/-}0.03, pFDR=0.043). Third, the relationship between A{beta} positivity and baseline and longitudinal cognitive performance was independent of WMH burden. ConclusionsPosterior white matter is susceptible to hypertension and A{beta} 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 RegistrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015)