양현식 (Brigham and Women's Hospital, Harvard Medical School)

한빛사논문

조회459

Brigham and Women's Hospital, Harvard Medical School

CV File 162 kb

Brain, Feb 05 2024, awae034 | https://doi.org/10.1093/brain/awae034 Plasma VEGFA and PGF impact longitudinal tau and cognition in preclinical Alzheimer's disease

Hyun-Sik Yang^1,2,3, Wai-Ying W Yau ^1,2,3, Becky C Carlyle ^3,4,5, Bianca A Trombetta⁴, Can Zhang ^3,4,6, Zahra Shirzadi ^1,3, Aaron P Schultz ^1,3,7, Jeremy J Pruzin^1,2,3,8, Colleen D Fitzpatrick ¹, Dylan R Kirn ^1,2, Jennifer S Rabin ^9,10, Rachel F Buckley ^1,2,3, Timothy J Hohman ^11,12, Dorene M Rentz ^1,2,3, Rudolph E Tanzi^3,6, Keith A Johnson^1,2,3,7, Reisa A Sperling ^1,2,3,7, Steven E Arnold ^3,4, Jasmeer P Chhatwal ^1,2,3

¹Department of Neurology, Massachusetts General Hospital, Boston, MA 02114, USA.

²Center for Alzheimer Research and Treatment, Department of Neurology, Brigham and Women's Hospital, Boston, MA 02115, USA.

³Harvard Medical School, Boston, MA 02115, USA.

⁴Alzheimer's Clinical and Translational Research Unit, Department of Neurology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

⁵Department of Physiology, Anatomy & Genetics, and Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.

⁶Genetics and Aging Research Unit, McCance Center for Brain Health, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.

⁷Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA 02129, USA.

⁸Department of Neurology, Banner Alzheimer's Institute, Phoenix, AZ 85006, USA.

⁹Harquail Centre for Neuromodulation and Hurvitz Brain Sciences Program, Sunnybrook Research Institute, Toronto, Ontario, Canada.

¹⁰Division of Neurology, Department of Medicine, Sunnybrook Health Sciences Centre, University of Toronto, Canada and Rehabilitation Sciences Institute, University of Toronto, Toronto, Ontario, Canada.

¹¹Vanderbilt Memory and Alzheimer's Center, Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

¹²Vanderbilt Genetics Institute, Vanderbilt University Medical Center, Nashville, TN 37212, USA.

Hyun-Sik Yang and Wai-Ying W. Yau contributed equally to this work.

Correspondence to: Jasmeer P. Chhatwal, MD, PhD

Abstract

Vascular dysfunction is increasingly recognized as an important contributor to the pathogenesis of Alzheimer's disease. Alterations in vascular endothelial growth factor (VEGF) pathways have been implicated as potential mechanisms. However, the specific impact of VEGF proteins in preclinical Alzheimer's disease and their relationships with other Alzheimer's disease and vascular pathologies during this critical early period remain to be elucidated. We included 317 older adults from the Harvard Aging Brain Study, a cohort of individuals who were cognitively unimpaired at baseline and followed longitudinally for up to 12 years. Baseline VEGF family protein levels (VEGFA, VEGFC, VEGFD, PGF, and FLT1) were measured in fasting plasma using high-sensitivity immunoassays. Using linear mixed effects models, we examined the interactive effects of baseline plasma VEGF proteins and amyloid PET burden (Pittsburgh Compound-B) on longitudinal cognition (Preclinical Alzheimer Cognitive Composite-5). We further investigated if effects on cognition were mediated by early neocortical tau accumulation (Flortaucipir PET burden in the inferior temporal cortex) or hippocampal atrophy. Lastly, we examined the impact of adjusting for baseline cardiovascular risk score or white matter hyperintensity volume. Baseline plasma VEGFA and PGF each showed a significant interaction with amyloid burden on prospective cognitive decline. Specifically, low VEGFA and high PGF were associated with greater cognitive decline in individuals with elevated amyloid, i.e. those on the Alzheimer's disease continuum. Concordantly, low VEGFA and high PGF were associated with accelerated longitudinal tau accumulation in those with elevated amyloid. Moderated mediation analyses confirmed that accelerated tau accumulation fully mediated the effects of low VEGFA and partially mediated (31%) the effects of high PGF on faster amyloid-related cognitive decline. The effects of VEGFA and PGF on tau and cognition remained significant after adjusting for cardiovascular risk score or white matter hyperintensity volume. There were concordant but non-significant associations with longitudinal hippocampal atrophy. Together, our findings implicate low VEGFA and high PGF in accelerating early neocortical tau pathology and cognitive decline in preclinical Alzheimer's disease. Additionally, our results underscore the potential of these minimally-invasive plasma biomarkers to inform the risk of Alzheimer's disease progression in the preclinical population. Importantly, VEGFA and PGF appear to capture distinct effects from vascular risks and cerebrovascular injury. This highlights their potential as new therapeutic targets, in combination with anti-amyloid and traditional vascular risk reduction therapies, to slow the trajectory of preclinical Alzheimer's disease and delay or prevent the onset of cognitive decline.

논문정보

형식Research article
게재일2024년 02월 (BRIC 등록일 2024-02-06)
연구진국외 연구진
분야 의약학 > 신경의학

댓글 작성 로그인

CV 열람하기

연락처 보기