Elucidating Alzheimer disease pathophysiology

As researchers look for ways to diagnose Alzheimer disease (AD) at a preclinical stage and gain better understanding of the pathophysiologic process, many have focused on the eye and particularly on the retina because it represents an extension of the brain that can be imaged noninvasively.

Changes in retinal vascular structure and blood flow are among the targets of studies that are investigating pathologic changes associated with AD in the retina. However, the true relevance of their findings is confounded by the fact that the retinal vasculature is also affected by aging and age-related comorbidities that are common in the AD patient population.

Now, in a study conducted in a unique group of patients with an inherited, early-onset form of AD and using cutting-edge OCT angiography methods, a multidisciplinary team led by ophthalmologist Amir H. Kashani, MD, PhD and neurologist John M. Ringman, MD, MS provide evidence that specifically implicates human capillary blood flow in the pathophysiology of AD.¹

“Our research group is interested in using OCT angiography to understand and identify changes in the retinal vasculature that reflect early stages of retinal vascular disease. Our working hypothesis in this study was that by using this technology, we would find changes in the retinal capillaries of patients with early onset AD before they developed symptoms of dementia and before any vascular pathology can be detected clinically,” Dr. Kashani told Ophthalmology Times.

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“Our findings suggest that the pathological process of AD affects blood flow regulation many years before symptoms develop and that blood flow changes can be measured during the presymptomatic stage of AD. These are exciting findings. However, because our study had a small sample size and was cross-sectional in design, the results need to be validated in larger studies and in studies with longitudinal follow-up.”

Giuseppe Querques, MD, PhD, who was not involved with the study, told Ophthalmology Times, “Because it is very hard to isolate AD pathology in subjects with late onset Alzheimer disease, these observations of abnormal blood flow in subjects who are genetically at risk for AD are very useful in understanding the vascular consequences of AD pathology.”

Dr. Querques, Associate Professor of Ophthalmology at University Vita-Salute, IRCCS Ospedale San Raffaele, Milan, Italy, continued, “These findings seem to corroborate the idea that retinal vascular function is impaired early in the Alzheimer disease process, likely even before detectable structural changes.”²

Study rationale

Dr. Kashani is Associate Professor of Ophthalmology, Wilmer Eye Institute, Johns Hopkins School of Medicine, Baltimore, MD, and has NIH funding to study retinal vascular changes in subjects with neurodegenerative disease. Dr. Ringman is Professor of Clinical Neurology, Keck School of Medicine of the University of Southern California, Los Angeles, CA, and has NIH funding to study families mainly originating from Jalisco, Mexico whose members have or are at-risk for autosomal dominant AD (ADAD).

Persons with ADAD account for approximately 1% of the AD population. This rare form of inherited AD is due to mutations in PSEN and APP, the same genes implicated in the pathophysiology of late-onset AD. Compared to late onset AD, ADAD shares similar clinical and pathological phenotypes except that the age of onset of ADAD can be reliably predicted based on the specific mutation variant of a carrier. For individuals with an F388 substitution in PSEN1, the expected age of dementia onset is 25 years, while it is ~42 years for persons carrying an A431E substitution in PSEN1 and 52 years for those with a V717I substitution in APP.

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“Findings from previous studies suggest that clinically evident retinopathy is associated with cognitive impairment or dementia in general.³ Because of the age at which individuals with ADAD develop dementia, this cohort afforded us the opportunity to see if they had retinal capillary abnormalities without confounding influence from other issues that are present in the older AD population, such as diabetes, hypertension and age-associated changes,” Dr. Ringman said.

Study design

The study enrolled subjects carrying ADAD mutations and healthy controls, including individuals from families of the at-risk group who were not mutation carriers. The mutation carriers were divided into early-stage (ES) and late-stage (LS) subgroups defined by whether they were ≥4 years or <4 years, respectively, before the predicted age of dementia diagnosis.

The study cohort was comprised of 39 control eyes from 21 subjects, 9 eyes from 5 ES mutation carriers, and 11 eyes from 8 LS mutation carriers. Analyses of the collected data showed that the ES AD subjects had significantly higher capillary blood flow compared to both normal controls and the LS AD subgroup. In addition, both the ES and LS subgroups had significantly higher capillary blood flow heterogeneity compared to the normal controls. In pairwise comparisons, there were no differences between any of the study groups in capillary density or capillary caliber.

Ruikang Wang, PhD, a co-author on the study, and Professor of Bioengineering and Ophthalmology at the University of Washington, Seattle says, “OCTA-derived measures have a great deal of potential in detecting very subtle changes in the retinal vasculature. In this study, we were able to derive a new measure of red blood cell movement called 'flux' that appears to be more sensitive than more widely used measures of capillary density.”

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Clinical translation

Dr. Ringman said the findings might be explained based on what is known about the pathophysiology of AD.

“We know that deposition of amyloid protein in and around capillaries can occur in AD, and associated dementias and we postulate that it may be the cause of blood flow changes early in the disease process,” he said. “If the findings of our study are validated in larger trials, they speak to the possibility that identifying changes in capillary blood flow may predict people at risk for pathologic progression and clinical onset of AD.”

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Looking ahead, the ability to identify patients at risk for developing AD while they are asymptomatic ultimately offers hope for altering the natural history of the disease through therapeutic modulation.

“Achieving that goal will take more research to validate these findings and also understand the contribution of other prevalent causes of dementia such as cerebrovascular disease to late onset forms of AD. For example, we are conducting additional studies aimed at quantifying retinal blood flow changes resulting from cerebral small vessel disease which will likely have different therapeutic implications⁴,” said Dr. Kashani.

References

1. Singer MB, Ringman JM, Chu Z, Zhou X, Jiang X, Shahidzadeh A, Wang RK, Kashani AH, Abnormal Retinal Capillary Blood Flow in Autosomal Dominant Alzheimer’s Disease Alzheimers Demen (Amst)2021 Mar 4;13(1):e12162

2. Querques G, Borreli E, Sacconi R, De Vitis L, Leocani L, Santangelo R, Magnani G, Comi G, Bandello F.Functional and morphological changes of the retinal vessels in Alzheimer’s disease and mild cognitive impairment. Scientific Reports 2019 9:63.

3. Kashani AH, Asanad S, Chen J, et al. Past, present and future role of retinal imaging in neurodegenerative disease. Prog Retin Eye Res. 2021 Jan 21. Online ahead of print.

4. Ashimatey BS, D’Orazio LM, Ma SJ, Jann K, Jiang X, Lu H, Wang DJ, Ringman J, Kashani AH.Lower retinal capillary density in minimal cognitive impairment among older Latinx Adults. Alzheimers Demen (Amst) 2020 Aug 25;12(1)e12071.

Amir Kashani, MD, PhD

E: akashani1@jhmi.edu

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