Retinal Biomarkers for Alzheimer Disease: The Facts and the Future

Abstract

Alzheimer disease (AD) is a significant cause of morbidity and mortality worldwide, with limited treatment options and considerable diagnostic challenges. Identification and validation of retinal changes that correlate with clinicopathologic features of AD could provide a noninvasive method of screening and monitoring progression of disease, with notable implications for developing new therapies, particularly in its preclinical stages. Retinal biomarkers that have been studied to date include structural changes in neurosensory retinal layers, alterations in vascular architecture and function, and pathologic deposition of proteins within the retina, which have all demonstrated variable correlation with the presence of preclinical or clinical AD. Evolution of specialized retinal imaging modalities and advances in artificial intelligence hold great promise for future study in this burgeoning field. The current status of research in retinal biomarkers, and some of the challenges that will need to be addressed in future work, are reviewed herein.

Figure 1:

Early histopathologic evidence of ganglion cell degeneration in Alzheimer’s disease (AD). Retinal cross sections from normal (A) and AD (B) patients demonstrates marked thinning of ganglion cell layer (GCL) and nerve fiber layer (NFL) in the AD patient. Reproduced with permission from Ref. 15.

Figure 2:

(A) Cross-sectional view of retina captured by optical coherence tomography (OCT). Assessment of the macular ganglion cell-inner plexiform layer (GC-IPL) and peripapillary retinal nerve fiber layer (RNFL) and in a patient with mild cognitive impairment and positive amyloid PET imaging is demonstrated in (B) and (C) respectively. Choroidal thinning in a cognitively normal patient compared to a patient with Alzheimer’s disease is demonstrated in (D) and (E), respectively (red arrows delineate the thickness of the choroid). Reproduced with permission from Ref. 75.