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 (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). Hypertension, Aβ positivity, and WMH were connected to cognition. First, WMH coincided with worse cognitive performance and outcomes (pFDR<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 (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; ΔPACC5: -0.09 ± 0.03, pFDR=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)

ImportancePosterior 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.ObjectiveTo characterise the effects of AD pathology, namely β-amyloid (Aβ) and hypertension on WMH and cognition.DesignCross-sectional and longitudinalSettingMulticentreParticipantsWe 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)NAMain Outcomes and MeasuresSpatial distribution and volume of MRI WMH in relation to Aß42/40 levels and arterial hypertension. Mediation of the relationship between Aβ positivity and hypertension on cognition by the regional WMH volume.ResultsWe included 355 participants (median age 70.3 [IQR 66.0-74.4] years; 168 female; 121 NC, 154 SCD, 80 MCI). Hypertension and Aβ positivity were positively associated (pFTR<0.05) with WMH volume, with large spatial overlap in the occipital lobes (regression coefficient ± standard error; hypertension: 0.49±0.14; Aβ: 0.41±0.15), parietal lobes (hypertension: 0.62±0.23; Aβ: 0.61±0.24), corona radiata (hypertension: 0.55±0.19; Aβ: 0.61±0.24), optic radiation (hypertension: 0.64±0.19; Aβ: 0.50±0.20) and splenium (hypertension: 0.38±0.13; Aβ: 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, pFDR<0.01; occipital: 3.31±0.75, pFDR<0.01), regardless of Aβ and hypertension status. The association between Aβ positivity and baseline cognitive performance (direct-memory: -0.42±0.08, pFDR<0.01; executive: - 0.28±0.28, pFDR<0.01) was partially mediated by WMH in the corona radiata (indirect-memory: -0.04±0.02, pFDR<0.05; executive: -0.04±0.02, pFDR<0.01) and splenium (indirect-memory: -0.02±0.02, pFDR<0.01; executive: -0.04±0.02, pFDR<0.01). Evidence supporting hypertension affected cognition was insufficient (direct-memory: 0.03±0.07, pFDR=0.683; executive: -0.05±0.07, pFDR=0.499; PACC5 change: 0.01±0.02, pFDR =0.588).Conclusions and RelevancePosterior white matter is susceptible to vascular disease and Aβ accumulation. Its deterioration is involved in the association between Aβ 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 RegistrationGerman Clinical Trials Register (DRKS00007966, 04/05/2015)Key PointsQuestionIs the spatial distribution and volume of cerebral white matter hyperintensities (WMH) related to arterial hypertension, amyloid pathology, and cognition?FindingsIn this cross-sectional and longitudinal cohort study, WMH increased with hypertension and amyloid, with a spatial overlap in occipital and parietal lobes. Amyloid is involved in the relationship between WMH in corona radiata and splenium on cognitive performance. Global, occipital, and frontal WMH were strongly associated cognitive performance and worsening, regardless of hypertension and amyloid status.MeaningPosterior white matter is susceptible to vascular disease and amyloid pathology; its damage plays a role in the effect of amyloid pathology on cognition.

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).