Retinal Microvascular Alterations as the Biomarkers for Alzheimer Disease: Are We There Yet?

Abstract

Alzheimer disease (AD) is a heterogeneous and multifactorial disorder with an insidious onset and slowly progressive disease course. To date, there are no effective treatments, but biomarkers for early diagnosis and monitoring of disease progression offer a promising first step in developing and testing potential interventions. Cerebral vascular imaging biomarkers to assess the contributions of vascular dysfunction to AD are strongly recommended to be integrated into the current amyloid-β (Aβ) [A], tau [T], and neurodegeneration [(N)]-the "AT(N)" biomarker system for clinical research. However, the methodology is expensive and often requires invasive procedures to document cerebral vascular dysfunction. The retina has been used as a surrogate to study cerebral vascular changes. There is growing interest in the identification of retinal microvascular changes as a safe, easily accessible, low cost, and time-efficient approach to enhancing our understanding of the vascular pathogenesis associated with AD. A systemic review of the literature was performed regarding retinal vascular changes in AD and its prodromal stages, focusing on functional and structural changes of large retinal vessels (vessels visible on fundus photographs) and microvasculature (precapillary arterioles, capillary, and postcapillary venules) that are invisible on fundus photographs. Static and dynamic retinal microvascular alterations such as retinal arterial wall motion, blood flow rate, and microvascular network density were reported in AD, mild cognitive impairment, and even in the preclinical stages of the disease. The data are somewhat controversial and inconsistent among the articles reviewed and were obtained based on cross-sectional studies that used different patient cohorts, equipment, techniques, and analysis methods. Retinal microvascular alterations exist across the AD spectrum. Further large scale, within-subject longitudinal studies using standardized imaging and analytical methods may advance our knowledge concerning vascular contributions to the pathogenesis of AD.