Layer Specific Retinal Thickness as a Marker of Cerebral Amyloid Burden

Macular OCT reveals a depth-dependent retinal signature of cerebral amyloid: inner layers thin while outer layers thicken with increasing amyloid burden

Background:

o AD pathology begins decades before symptoms, creating demand for early, scalable, non-invasive biomarkers.

o PET/CSF quantify amyloid but are invasive, costly, and unsuitable for broad screening.

o The retina, as a CNS extension, shows amyloid deposition and structural/vascular changes detectable in vivo.

o OCT provides rapid, reproducible, layer-resolved metrics linked to AD-related neurodegeneration, though findings vary across studies.

o Few studies have related retinal structure to quantitative cerebral amyloid burden (centiloid) in cognitively unimpaired individuals.

Aim:

o To determine whether layer and regionspecific retinal thickness is associated with cerebral amyloid burden in cognitively unimpaired adults.

Methods:

Participants

o 52 cognitively unimpaired adults

o Aβ status: 16 Aβ+, 36 Aβ

Imaging

o PET: [18F-Florbetaben]; global amyloid burden (centiloid)

o OCT: SD-OCT macular & optic-disc scans (OD/OS)

o Retinal metrics: Layer-resolved thickness (ETDRS subfields)

Results:

o OD disc: Two nasal subfields showed positive associations with centiloid (r ≈ 0.300.36).

o OD macula: Clear depth-dependent pattern, IRL negative (r ≈ –0.40 to –0.53), ORL positive (r ≈ 0.500.56).

o OS disc:  One nasal IPL subfield significant (r ≈ 0.30).

o OS macula: Strong, consistent IRL negative associations (r ≈ –0.47 to –0.66).

o Overall: Inner thinning and outer thickening with increasing centiloid; spatial extent differed between eyes.

Conclusions:

o Analyses highlighted consistent depth dependent associations with centiloid, where moderate negative IRL correlations and strong positive ORL correlations were observed across macular subfields.

o Divergent IRL thinning and ORL thickening patterns may reflect separate biological processes, aligning with evidence of amyloid-related IRL vulnerability and tau or gliosis related ORL changes.

o These findings highlight a potential dual-signature retinal profile in preclinical AD, warranting validation in larger, prodromal, and symptomatic cohorts