Research on AD ocular biomarkers spans three major areas: (1) retinal structural changes (e.g., retinal nerve fiber layer [RNFL] and ganglion cell–inner plexiform layer thinning), (2) Aβ/tau proteinopathies, and (3) vascular alterations.
25 Among these, early detection of ocular Aβ and tau is crucial for developing a sensitive, cost-effective biomarker for screening Aβ/tau-positive, asymptomatic individuals at risk of AD. In the mouse retina, Aβ is detected in the inner and outer nuclear layer, inner plexiform layer, and ganglion cell layer, whereas APP spans the ganglion cell layer to inner nuclear layers.
26 In previous investigations of the physiologic roles of Aβ and APP in the normal visual functions,
27 APP is essential for retinal synaptogenesis, glial differentiation, angiogenesis, and neuronal survival in rodents.
28,29 Genetic and AD risk factors, such as apolipoprotein E and iron overload, can disrupt retinal APP processing, leading to Aβ plaque overproduction.
30 Aβ has been detected in both mouse and human retinas, although inconsistencies across studies may reflect differences in species, age, sex, genetics, disease severity, sample size, or staining methods. Williams et al.
31 found no evidence of tau, Aβ, TDP-43, ubiquitin, or α-synuclein in the eyes of 17 patients with AD, regardless of disease severity. In contrast, a postmortem cohort from the Netherlands Brain Bank identified Aβ-positive structures in the human retina, including aggregates in vessel walls, globular deposits in the photoreceptor layer, and cytoplasmic granular deposits in ganglion cells.
32 While the co-occurrence of pathological proteins observed in the brain is only partially reflected in the retina, these findings nonetheless support the presence of hallmark neurodegenerative disease proteins in retinal tissue.
32 Histologic studies of postmortem human eyes have identified neuritic plaques in the retinas of patients with AD using Gallyas silver and 6E10 antibody staining.
33,34 Similarly, Moncaster et al.
8 demonstrated Aβ pathology in the lenses of both patients with AD and Tg2576 transgenic mice, highlighting its potential as an accessible biomarker for early detection and monitoring of AD. Supporting this, fluorescent ligand eye scanning successfully distinguished patients with AD from healthy individuals with 85% sensitivity and 95% specificity by detecting exogenous ligands bound to lens Aβ.
35 Koronyo-Hamaoui et al.
5 identified retinal Aβ with high diagnostic accuracy in postmortem samples from patients with AD (sensitivity = 1.00, specificity = 1.00, diagnostic odds ratio ≥ 187.00). In vivo imaging of transgenic APPSWE/PS1ΔE9 mice treated with curcumin and Aβ antibody clones further suggested that retinal Aβ plaque formation precedes brain deposition.
5 Sampani et al.
36 reported higher concentrations of AD biomarkers in ocular fluids compared to plasma, with significant correlations between the two compartments.