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. 2024 Oct;20(10):6810-6819.
doi: 10.1002/alz.14126. Epub 2024 Sep 4.

White matter hyperintensity on MRI and plasma Aβ42/40 ratio additively increase the risk of cognitive impairment in hypertensive adults

Adam de Havenon  1 , Rebecca F Gottesman  2 , Jeff D Willamson  3 , Natalia Rost  4 , Richa Sharma  1 , Vivian Li  1 , Lauren Littig  1 , Eric Stulberg  5 , Guido J Falcone  1 , Shyam Prabhakaran  6 , Andrea L C Schneider  7 , Kevin N Sheth  1 , Nicholas M Pajewski  8 , Adam M Brickman  9
Affiliations

White matter hyperintensity on MRI and plasma Aβ42/40 ratio additively increase the risk of cognitive impairment in hypertensive adults

Adam de Havenon et al. Alzheimers Dement. 2024 Oct.

Abstract

Introduction: Dementia often involves comorbid Alzheimer's and vascular pathology, but their combined impact warrants additional study.

Methods: We analyzed the Systolic Blood Pressure Intervention Trial and categorized white matter hyperintensity (WMH) volume into highest versus lowest/mid tertile and the amyloid beta (Aβ)42/40 ratio into lowest versus mid/highest ratio tertile. Using these binary variables, we created four exposure categories: (1) combined low risk, (2) Aβ risk, (3) WMH risk, and (4) combined high risk.

Results: In the cohort of 467 participants (mean age 69.7 ± 7.1, 41.8% female, 31.9% nonwhite or Hispanic) during 4.8 years of follow-up and across the four exposure categories the rates of cognitive impairment were 5.3%, 7.8%, 11.8%, and 22.6%. Compared to the combined low-risk category, the adjusted hazard ratio for cognitive impairment was 4.12 (95% confidence interval, 1.71 to 9.94) in the combined high-risk category.

Discussion: This study emphasizes the potential impact of therapeutic approaches to dementia prevention that target both vascular and amyloid pathology.

Highlights: White matter hyperintensity (WMH) and plasma amyloid (Aβ42/40) are additive risk factors for the development of cognitive impairment in the SPRINT MIND trial. Individuals in the high-risk categories of both WMH and Aβ42/40 had a near fivefold increase in risk of cognitive impairment during 4.8 years of follow-up on average. These findings suggest that treatment strategies targeting both vascular health and amyloid burden warrant further research.

Keywords: Alzheimer's disease biomarkers; Aβ42/40 ratio; cerebrovascular pathology; cognitive impairment risk; dementia; vascular and amyloid pathways; white matter hyperintensity (WMH).

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Conflict of interest statement

Dr. de Havenon has received consultant fees from Novo Nordisk, royalty fees from UpToDate, and has equity in TitinKM and Certus. Dr. Sheth reports compensation from Sense and Zoll, for data and safety monitoring services; compensation from CereVasc, CSL Behring, Rhaeos, and Astrocyte for consultant services; a patent for Stroke wearables licensed to Alva Health. Dr. Brickman serves as a scientific advisor/consultant to Cognito Therapeutics, Cognition Therapeutics, and Cogstate. He serves on data safety and monitoring boards for Albert Einstein College of Medicine and University of Illinois. Dr. Brickman has a patent for white matter hyperintensity quantification (patent # 9867566) and a patent pending for microbleed detection (publication #20230298170). Dr. Sharma has a provisional patent for an ischemic stroke etiology classification algorithm (No.63/505,006). Dr. Schneider reports serving as an Associate Editor for the journal Neurology from the American Academy of Neurology. Dr. Pajewski reports serving as an Assistant Editor for the Journal of the American Geriatrics Society and as a Statistical Editor for the journal Hypertension from the American Heart Association. He also serves on data and safety monitoring boards for Atrium Health, Brigham and Women's Hospital, Indiana University School of Medicine, Medical University of South Carolina, University of California–San Francisco, and the University of Texas–San Antonio. Vivian Li reports no disclosures. Lauren Littig reports no disclosures. Dr. Gottesman reports no disclosures. Dr. Gottesman reports no disclosures. Dr. Williamson reports no disclosures. Dr. Rost reports no disclosures. Dr. Stulberg reports no disclosures. Dr. Falcone reports no disclosures. Dr. Prabhakaran reports no disclosures. Author disclosures are available in the supporting information.

Figures

FIGURE 1
FIGURE 1
Scatter plot and linear fit with 95% confidence interval between white matter hyperintensity in mL and plasma amyloid beta (Aβ)42/40 ratio.
FIGURE 2
FIGURE 2
Flowchart of the derivation of the study cohort. Aβ, amyloid beta; MoCA, Montreal Cognitive Assessment; MRI, magnetic resonance imaging; SPRINT, Systolic Blood Pressure Intervention Trial; WMH, white matter hyperintensity.
FIGURE 3
FIGURE 3
Tertiles of white matter hyperintensity (WMH) in mL and plasma amyloid beta (Aβ)42/40 ratio with ranges reported for each tertile, showing near completely balanced overlap of categories with the number of individuals in each flow shown on the right of the figure.
FIGURE 4
FIGURE 4
Kaplan–Meier curve for cognitive impairment by baseline category of white matter hyperintensity (WMH) in mL and plasma amyloid beta (Aβ)42/40 ratio. To assist in visual interpretation the index time was set at 1.9 years from enrollment when the follow‐up cognitive assessment started.
FIGURE 5
FIGURE 5
White matter hyperintensity (WMH) volume in mL and amyloid beta (Aβ)42/40 ratio as continuous variables after cube‐root transformation, introduced as an interaction term in the Cox model fit to cognitive impairment. Marginal effects of their centered mean plus or minus two standard deviations are shown.
See this image and copyright information in PMC

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