Developing retinal biomarkers for the earliest stages of Alzheimer's disease: What we know, what we don't, and how to move forward

Abstract

The last decade has seen a substantial increase in research focused on the identification, development, and validation of diagnostic and prognostic retinal biomarkers for Alzheimer's disease (AD). Sensitive retinal biomarkers may be advantageous because they are cost and time efficient, non-invasive, and present a minimal degree of patient risk and a high degree of accessibility. Much of the work in this area thus far has focused on distinguishing between symptomatic AD and/or mild cognitive impairment (MCI) and cognitively normal older adults.Minimal work has been done on the detection of preclinical AD, the earliest stage of AD pathogenesis characterized by the accumulation of cerebral amyloid, absent clinical symptoms of MCI or dementia. The following review examines retinal structural changes, proteinopathies, and vascular alterations that have been proposed as potential AD biomarkers, with a focus on studies examining the earliest stages of disease pathogenesis. In addition, we present recommendations for future research to move beyond the discovery phase and towards validation of AD risk biomarkers that could potentially be used as a first step in a multi-step screening process for AD risk detection.

Investigating Vascular Complexity and Neurogenic Alterations in Sectoral Regions of the Retina in Patients With Cognitive Impairment

“…Retinal vascular parameters such as fractal dimension (FD) reflect the optimality of the vascular network. As reported by several studies, retinal vascular network changes have been found in patients with CI (Cheung et al, 2014a,b;Alber et al, 2020).…”

“…Also, we found that there were significant differences in multifractal dimension and spectra, and lacunarity between the study groups in the optic disk region. Although these significant differences were observed cross-sectionally, showing smaller generalized FDs and larger parameters, they may indicate a potential functional alteration from a space filling vasculature which nurtures the retina to a less dense vasculature as it degenerates in individuals with CI (Cheung et al, 2014a,b;Arthur et al, 2019;Alber et al, 2020). Our results also exposed that the sectoral region analysis revealed better the alterations in the multifractal analysis parameters for individual areas of the retina and their significant correlations with flicker-IT.…”

Fluid Candidate Biomarkers for Alzheimer’s Disease: A Precision Medicine Approach

“…Lewy-related pathology (LRP), primarily consisting of α-synuclein (α-syn) aggregates, has been detected in more than half of autopsied AD brains, and higher levels of α-syn in the CSF of patients with MCI and AD have been associated with AD pathology and cognitive decline [248,249]. Moreover, CSF total α-syn (t-α-syn) and oligomeric α-synuclein (o-α-syn) levels were higher in AD [250] compared to PD, PD dementia and DLB individuals [251,252]. The use of standard ELISA methods to assess CSF α-syn levels does not ensure good diagnostic accuracy in discriminating AD from synucleinopathies [250].…”

“…Moreover, CSF total α-syn (t-α-syn) and oligomeric α-synuclein (o-α-syn) levels were higher in AD [250] compared to PD, PD dementia and DLB individuals [251,252]. The use of standard ELISA methods to assess CSF α-syn levels does not ensure good diagnostic accuracy in discriminating AD from synucleinopathies [250]. Nevertheless, RT-QuIC [253] and protein misfolding cyclic amplification (PMCA) [254] are promising tools to identify AD individuals with α-syn co-pathology.…”

Ganglion Cell-Inner Plexiform Layer Thickness is Associated with Persistently Cognitive Decline -The Rugao Longevity and Aging Study

“…Hence, overwhelming studies demonstrated the possible role of retinal thickness in diagnosis and detection of MCI and AD. However, it was still lacking powerful evidences to draw conclusions with respect to the reliability or clinical utility of any potential retinal biomarkers with CD in repeated assessments [15,16]. Therefore, we aimed to investigate the association of retinal thickness with CD using repeated assessments among 5-years follow-up.…”