Retinal vascular abnormalities may be surrogate biomarkers of Alzheimer’s Disease before symptom onset


Increased levels of p-tau181 and p-tau127 and a decreasing cerebrospinal fluid Aβ42/40 ratio better defines progression from preclinical to manifest Alzheimer’s disease.

(Image Credit: AdobeStock/crevis)

(Image Credit: AdobeStock/crevis)

A recent study of changes in retinal structures suggested that significant vascular loss in cognitively healthy individuals before the onset of Alzheimer’s disease symptoms might be important biomarkers to identify presymptomatic Alzheimer’s disease,1 according to first author Giulia Corradetti and colleagues. Corradetti is from the Doheny Eye Institute, Pasadena, and the Department of Ophthalmology David Geffen School of Medicine, University of California Los Angeles.

The investigators pointed out that increased levels of serum phosphorylated tau (p-tau181 and p-tau127)2 and a decreasing cerebrospinal fluid (CSF) Aβ42/40 ratio better defines progression from preclinical to manifest Alzheimer’s disease."3

The eye is a good mirror of the brain status, in that the disease’s pathology in the retinal vasculature and retinal layers is the same as in the brain and, they noted, has provided the basis for in vivo optical coherence tomography angiography (OCTA) to capture the disease process in greater detail in real-time. Aβ40 found inside and around all blood vessel layers in the brain and retina were correlated with the beta-amyloid plaque load in the entorhinal cortex that is predictive of cognitive decline.4

In this study, swept-source (SS) OCTA was performed on 23 cognitively healthy subjects who had previously undergone analysis of the cerebrospinal fluid. Of those, 13 subjects had a pathological Aβ42/tau ratio (<2.7132), indicating presymptomatic Alzheimer's disease, and 10 had a normal Aβ42/tau ratio (≥2.7132).

The investigators then binarized and skeletonized the OCTA en-face images of the superficial vascular complex (SVC) and deep vascular complex to quantify the perfusion density (PD), vessel length density (VLD), and fractal dimension (FrD). The foveal avascular zone (FAZ) area was calculated using the SVC slab. Choriocapillaris flow deficits (CCFDs) were computed from the en-face OCTA slab of the choriocapillaris. They then compared these between the cognitively healthy patients with a pathological Aβ42/tau ratio and the cognitively healthy patients with a normal Aβ42/tau ratio.

The investigators reported, “Compared to the cognitively healthy patients with a normal ratio, those with a pathological ratio showed significantly decreased PD, VLD, and FrD in the SVC, with a significantly increased FAZ area and CCFDs.”

In commenting on their findings, the authors said, “The SS-OCTA measurements of the SVC and choriocapillaris showed significant abnormalities suggestive of attenuation of the superficial retinal and inner choroidal circulation in the earliest stages of pre-Alzheimer’s disease, as defined by an abnormal cerebrospinal fluid Aβ/total tau ratio with normal cognition.”

The take-home message of the study is that these retinal vascular abnormalities might serve as surrogate biomarkers of Alzheimer’s disease before the symptom onset.

The difference between the 2 groups of cognitively healthy individuals is suggestive of the synergistic effect between beta-amyloid–dependent and beta-amyloid–independent pathways of normal aging in the progression of Alzheimer’s disease vasculopathy.5

“Identifying early pathological biomarkers in preclinical AD is especially crucial for optimizing the design of clinical trials aimed at early interventions before irreversible cognitive impairment even begins. SS-OCTA is not yet widely available for clinical use, yet it allows for enhanced, high-resolution, high-definition, and more detailed visualization of the CC and retinal vascular complex, permitting more reliable quantitative analyses of OCTA metrics,” they said.

They also suggested that standardizing imaging methods and the pre-Alzheimer’s disease stage with serum biomarkers, such as p-tau217 and p-tau181,6 would facilitate identification of study subjects for recruitment into future pre-symptomatic clinical trials.

  1. Corradetti G, Oncel D, Kadomoto S, et al. Choriocapillaris and retinal vascular alterations in presymptomatic Alzheimer's disease. Invest Ophthalmol Vis Sci. 2024;65:47; doi:
  2. Milà-Alomà M, Ashton NJ, Shekari M, et al. Plasma p-tau231 and p-tau217 as state markers of amyloid-β pathology in preclinical Alzheimer's disease. Nat Med. 2022;28:1797–1801.
  3. Olsson B, Lautner R, Andreasson U, et al. CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-analysis. Lancet Neurol. 2016;15:673–684.
  4. Shi H, Koronyo Y, Rentsendorj A, et al. Retinal vasculopathy in Alzheimer's disease. Front Neurosci. 2021;15:731614.
  5. Zlokovic BV. Neurovascular pathways to neurodegeneration in Alzheimer's disease and other disorders. Nat Rev Neurosci. 2011;12:723–738.
  6. Therriault J, Servaes S, Tissot C, et al. Equivalence of plasma p-tau217 with cerebrospinal fluid in the diagnosis of Alzheimer's disease. Alzheimers Dement. 2023;19:4967–4977.
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