The role of vascular endothelial growth factor in neurodegeneration and cognitive decline: exploring interactions with biomarkers of Alzheimer disease.
OBJECTIVE
A subset of older adults present post mortem with Alzheimer disease (AD) pathologic features but without any significant clinical manifestation of dementia. Vascular endothelial growth factor (VEGF) has been implicated in staving off AD-related neurodegeneration.


OBJECTIVE
To evaluate whether VEGF levels are associated with brain aging outcomes (hippocampal volume and cognition) and to further evaluate whether VEGF modifies relations between AD biomarkers and brain aging outcomes.


METHODS
Biomarker analysis using neuroimaging and neuropsychological outcomes from the Alzheimer's Disease Neuroimaging Initiative. This prospective longitudinal study across North America included individuals with normal cognition (n = 90), mild cognitive impairment (n = 130), and AD (n = 59) and began in October 2004, with follow-up ongoing.


METHODS
Cerebrospinal fluid VEGF was cross-sectionally related to brain aging outcomes (hippocampal volume, episodic memory, and executive function) using a general linear model and longitudinally using mixed-effects regression. Alzheimer disease biomarker (cerebrospinal fluid β-amyloid 42 and total tau)-by-VEGF interactions evaluated the effect of VEGF on brain aging outcomes in the presence of enhanced AD biomarkers.


RESULTS
Vascular endothelial growth factor was associated with baseline hippocampal volume (t277 = 2.62; P = .009), longitudinal hippocampal atrophy (t858 = 2.48; P = .01), and longitudinal decline in memory (t1629 = 4.09; P < .001) and executive function (t1616 = 3.00; P = .003). Vascular endothelial growth factor interacted with tau in predicting longitudinal hippocampal atrophy (t845 = 4.17; P < .001), memory decline (t1610 = 2.49; P = .01), and executive function decline (t1597 = 3.71; P < .001). Vascular endothelial growth factor interacted with β-amyloid 42 in predicting longitudinal memory decline (t1618 = -2.53; P = .01).


CONCLUSIONS
Elevated cerebrospinal fluid VEGF was associated with more optimal brain aging in vivo. The neuroprotective effect appeared strongest in the presence of enhanced AD biomarkers, suggesting that VEGF may be particularly beneficial in individuals showing early hallmarks of the AD cascade. Future work should evaluate the interaction between VEGF expression in vitro and pathologic burden to address potential mechanisms.
Vanderbilt Memory & Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Timothy J
TJ
Hohman
Vanderbilt Memory & Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, Tennessee2Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee3Center for Quality Aging, Di.
Susan P
SP
Bell
Vanderbilt Memory & Alzheimer's Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
Angela L
AL
Jefferson
D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000134:cerebrospinal fluid* / Q000473:pathology / Q000502:physiology; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000473:pathology / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid; D001284:Atrophy / Q000473:pathology; D015415:Biomarkers / Q000134:cerebrospinal fluid*; D060825:Cognitive Dysfunction / Q000134:cerebrospinal fluid* / Q000473:pathology / Q000503:physiopathology; D003430:Cross-Sectional Studies; D056344:Executive Function / Q000502:physiology*; D005260:Female; D006624:Hippocampus / Q000473:pathology*; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D061212:Memory, Episodic; D010446:Peptide Fragments / Q000134:cerebrospinal fluid; D042461:Vascular Endothelial Growth Factor A / Q000134:cerebrospinal fluid*; D016875:tau Proteins / Q000134:cerebrospinal fluid
D016229:Amyloid beta-Peptides; D015415:Biomarkers; D010446:Peptide Fragments; D042461:Vascular Endothelial Growth Factor A; C075222:amyloid beta-protein (1-42); D016875:tau Proteins