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

Importance 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. Objective To characterise the effects of AD pathology, namely {beta}-amyloid (A{beta}) and hypertension on WMH and cognition. Design Cross-sectional and longitudinal Setting Multicentre Participants We analysed data from subjects with normal cognition (NC), subjective cognitive decline (SCD), and mild cognitive impairment (MCI) enrolled in the ongoing observational multicentre DZNE Longitudinal Cognitive Impairment and Dementia Study. We focused on participants with available magnetic resonance imaging (MRI), cerebrospinal fluid biomarkers, and cognitive and hypertension information. We conducted analyses between 02.2022 and 06.2022. Intervention(s) (for clinical trials) or Exposure(s) (for observational studies): NA Main Outcomes and Measures Spatial distribution and volume of MRI WMH in relation to A{beta}42/40 levels and arterial hypertension. Mediation of the relationship between A{beta} positivity and hypertension on cognition by the regional WMH volume. Results We included 355 participants (median age 70.3 [IQR 66.0-74.4] years; 168 female; 121 NC, 154 SCD, 80 MCI). Hypertension and A{beta} positivity were positively associated (p_FDR<0.05) with WMH volume, with large spatial overlap in the occipital lobes (regression coefficient {+/-} standard error; hypertension: 0.49 {+/-} 0.14; A{beta}: 0.41 {+/-} 0.15), parietal lobes (hypertension: 0.62 {+/-} 0.23; A{beta}: 0.61 {+/-} 0.24), corona radiata (hypertension: 0.55 {+/-} 0.19; A{beta}: 0.61 {+/-} 0.24), optic radiation (hypertension: 0.64 {+/-} 0.19; A{beta}: 0.50 {+/-} 0.20) and splenium (hypertension: 0.38 {+/-} 0.13; A{beta}: 0.39 {+/-} 0.13). Global and occipital WMH volumes were strongly associated cognitive changes over a three-year period, estimated with preclinical Alzheimer's cognitive composite 5 (PACC5) (global: 2.18 {+/-} 0.61, p_FDR<0.01; occipital: 3.31 {+/-} 0.75, p_FDR<0.01), regardless of A{beta} and hypertension status. The association between A{beta} positivity and baseline cognitive performance (direct-memory: -0.42 {+/-} 0.08, p_FDR<0.01; executive: -0.28 {+/-} 0.28, p_FDR<0.01) was partially mediated by WMH in the corona radiata (indirect-memory: -0.04 {+/-} 0.02, p_FDR<0.05; executive: -0.04 {+/-} 0.02, p_FDR<0.01) and splenium (indirect-memory: -0.02 {+/-} 0.02, p_FDR<0.01; executive: -0.04 {+/-} 0.02, p_FDR<0.01). Evidence supporting hypertension affected cognition was insufficient (direct-memory: 0.03 {+/-} 0.07, p_FDR=0.683; executive: -0.05 {+/-} 0.07, p_FDR=0.499; PACC5 change: 0.01 {+/-} 0.02, p_FDR=0.588). Conclusions and Relevance Posterior white matter is susceptible to vascular disease and A{beta} accumulation. Its deterioration is involved in the association between A{beta} and cognitive dysfunction. Posterior WMH could be a promising target to tackle the downstream damage related to the interacting and potentiating effect of these two pathologies. Trial Registration German Clinical Trials Register (DRKS00007966, 04/05/2015)