October 2020


Ocular connections to Alzheimer’s disease

by Maxine Lipner Contributing Writer

When it comes to Alzheimer’s disease, several new studies share a common thread—they all involve the eye.
One recent study involved macular degeneration and Alzheimer’s, both of which are related to age and have abnormal extracellular deposits connected with neuronal degeneration, drusen, and plaques in common.1 Another study indicated that there was an inverse connection between macular ganglion cell complex thickness and dementia.2 A third studied a connection between amyloid plaques in the brain and aqueous humor, showing that in mice synthetic amyloid plaques injected into the cerebral spinal fluid were immediately found in the aqueous humor.3 A fourth study demonstrated that those with Alzheimer’s had decreased retinal blood vessel density compared to those with mild cognitive impairment (MCI) or those with normal cognition.4
Prompting this research is the huge unmet need for better Alzheimer’s disease diagnosis, said Dilraj Grewal, MD, who recently investigated a possible connection between Alzheimer’s and retinal blood vessel density.5 Their investigation showed that those with MCI or Alzheimer’s disease had decreased blood vessel density in the macula.
The eye affords a potentially unique diagnostic opportunity for several neurodegenerative diseases. “You can directly, quickly, and in a non-invasive manner image the retina, which is an extension of the central nervous system, in high resolution using OCT and OCT angiography,” Dr. Grewal said, adding that with advances in such technology, there is interest that changes could be detected earlier and in greater detail and could also be used to monitor change over time.
Sharon Fekrat, MD, a co-investigator with Dr. Grewal, said approximately 400 clinical trials looking at therapeutic medications for Alzheimer’s disease have failed. This could be due to diagnostic challenges of Alzheimer’s—either patients’ disease state is too advanced for effective treatment or the diagnosis of Alzheimer’s dementia is inaccurate and patients have another type of dementia. “Currently, the diagnosis of Alzheimer’s disease is incorrect about one-third of the time,” she said.
Early disease detection is not easy. Dr. Fekrat pointed out that in their recent study researchers did not see a difference between those who had intact cognition and those with mild cognitive impairment, which is thought to often represent the cognitive stage before Alzheimer’s. “We were surprised that we did not see a difference in retinal vessel density between the cognitively healthy controls and those with MCI,” she said. Dr. Grewal said it may be necessary to study a larger group of individuals to detect a difference in retinal imaging parameters between MCI and controls.
From a clinical perspective, additional data to help physicians improve Alzheimer’s diagnostics would be pivotal, Dr. Grewal said. “This helps to address the diagnostic problem because you now have additional data that clinicians can use to try to determine if someone has Alzheimer’s,” he said. Testing for something like blood vessel density could augment the rest of the neurological investigation, Dr. Grewal said.
While the eye is likely to play a key role in diagnostics, it’s too early to determine the role of ophthalmologists, Dr. Fekrat said. “Perhaps the equipment that we use to predict the likelihood of someone having Alzheimer’s can be stationed in a neurologist’s office for screening or as a diagnostic adjunct, or maybe it can be incorporated into the primary care physician’s exam as part of Medicare’s Annual Wellness Visit,” she said. Looking to the future, there is also the possibility that smartphone apps may evaluate patients’ self-acquired retinal images through an embedded algorithm that then provides a risk score, she said.
Dr. Grewal pointed out that such a risk score would be an additional data point for physicians to assess. “At this time, however, we cannot install retinal imaging machines in CVS, for example, so that anyone can get a scan and receive an output from the machine saying they have Alzheimer’s,” he said. “That’s currently not feasible. Much more work needs to be done and is underway.”
Still, testing and evaluating ocular structures have many advantages that cannot be ignored, Dr. Grewal stressed. “It’s easy to acquire, the recurring cost is much lower than having the patient undergo an MRI scan, PET imaging, or lumbar puncture every year, and it is an objective measure,” he said. “Once we have correlations with structural tests like MRIs and other accepted biomarkers, multimodal retinal imaging has the potential to serve as a surrogate marker.” As the population grows older, better tools are needed to be able to more efficiently screen and diagnose individuals with MCI or Alzheimer’s, with the reasonable cost that examining the eye can allow, he concluded.

About the doctors

Sharon Fekrat, MD
Professor of Ophthalmology
Duke University
School of Medicine
Durham, North Carolina

Dilraj Grewal, MD
Associate Professor
of Ophthalmology
Duke University
School of Medicine
Durham, North Carolina


1. Papadopoulos Z. Neovascular age-related macular degeneration and its association with Alzheimer’s disease. Curr Aging Sci. 2020. Online ahead of print.
2. Fawzi AA, et al. Retinal imaging in Alzheimer’s disease: In search of the holy grail. Ophthalmology. 2020;127:119–121.
3. Kwak DE, et al. Alterations of aqueous humor Aß levels in Aß-infused and transgenic mouse models of Alzheimer disease. PloS One. 2020;15:e0227618.
4. Yoon SP, et al. Retinal microvascular and neurodegenerative changes in Alzheimer’s disease and mild cognitive impairment compared with control participants. Ophthalmol Retina. 2019;3:489–499.
5. Yoon SP, et al. Correlation of OCTA and volumetric MRI in mild cognitive impairment and Alzheimer’s disease. Ophthalmic Surg Lasers Imaging Retina. 2019;50:709–718.

Relevant disclosures

Fekrat: None
Grewal: None


Fekrat: sharon.fekrat@duke.edu
Grewal: dilraj.grewal@duke.edu

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