Retinal imaging biomarkers of Alzheimer's disease: A systematic review and meta-analysis of studies using brain amyloid beta status for case definition

Abstract

Introduction: We performed a systematic review and meta-analysis of the association between retinal imaging parameters and Alzheimer's disease (AD).

Methods: PubMed, EMBASE, and Scopus were systematically searched for prospective and observational studies. Included studies had AD case definition based on brain amyloid beta (Aβ) status. Study quality assessment was performed. Random-effects meta-analyses of standardized mean difference, correlation, and diagnostic accuracy were conducted.

Results: Thirty-eight studies were included. There was weak evidence of peripapillary retinal nerve fiber layer thinning on optical coherence tomography (OCT) (p = 0.14, 11 studies, n = 828), increased foveal avascular zone area on OCT-angiography (p = 0.18, four studies, n = 207), and reduced arteriole and venule vessel fractal dimension on fundus photography (p < 0.001 and p = 0.08, respectively, three studies, n = 297) among AD cases.

Discussion: Retinal imaging parameters appear to be associated with AD. Small study sizes and heterogeneity in imaging methods and reporting make it difficult to determine utility of these changes as AD biomarkers.

Highlights: We performed a systematic review on retinal imaging and Alzheimer's disease (AD).We only included studies in which cases were based on brain amyloid beta status.Several retinal biomarkers were associated with AD but clinical utility is uncertain.Studies should focus on biomarker-defined AD and use standardized imaging methods.

Keywords: Alzheimer's disease; amyloid; biomarkers; dementia; early detection; fundus photography; hyperspectral imaging; optical coherence tomography; optical coherence tomography angiography; retina; retinal imaging.

FIGURE 1

Study selection.

FIGURE 2

(A) OCT RNFL parameters. I² only available for estimates derived from >1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of true value for each parameter. (B) OCT parameters other than RNFL. I² only available for estimates derived from > 1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of the true value for each parameter. RNFL, retinal nerve fiber layer; OCT, optical coherence tomography.

FIGURE 2

(A) OCT RNFL parameters. I² only available for estimates derived from >1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of true value for each parameter. (B) OCT parameters other than RNFL. I² only available for estimates derived from > 1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of the true value for each parameter. RNFL, retinal nerve fiber layer; OCT, optical coherence tomography.

FIGURE 3

OCTA parameters. I² only available for estimates derived from >1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of true value for each parameter. OCTA, optical coherence tomography angiography.

FIGURE 4

Fundus photography parameters. I² only available for estimates derived from >1 study. Vertical line indicates standard mean difference of 0 (i.e., no effect), horizontal lines indicate the 95% confidence interval for each parameter and the square indicates point of estimate of true value for each parameter.