Retinal Imaging: A Noninvasive Approach to Identifying Early Signs of Alzheimer’s Disease

While the vast majority of individuals with Alzheimer’s disease (AD) have late-onset dementia, occurring at age 65 or older, there are families who carry genetic mutations which are associated with early onset of illness.  Although rare, these families with autosomal dominant mutations and early-onset AD provide a unique opportunity for studying the pathogenesis of this disease.  In the Familial Dementia Neuroimaging Lab and the Multicultural Alzheimer’s Prevention Program (MAPP), Yakeel Quiroz-Gaviria, PhD and colleagues have been studying individuals belonging to the world’s largest family with autosomal-dominant Alzheimer’s disease.  In this family, there is a single mutation in the gene coding for the amyloid precursor protein, presenilin 1 (PSEN-1), which results in early onset of AD. 

Using cognitive testing, brain imaging and genetics, Dr. Quiroz-Gaviria’s research has examined brain function and pathology in members of this family decades before they show any symptoms of the disease.  This research can help us to better understand the earliest stages of Alzheimer’s disease and can be used to identify biomarkers evident prior to the onset of cognitive decline.  Ultimately this sort of information can improve our ability to diagnose Alzheimer’s disease as early as possible and could help us to develop novel interventions which stop, or at least slow, the progression of the disease.  

Over the last few years, optical coherence tomography (OCT) has emerged as a potential noninvasive technique capable of identifying changes in the central nervous system (CNS) for biomarkers of Alzheimer’s disease.  In visualizing the retina, which is an extension of the CNS, with OCT, previous studies in older patients with AD have shown that the characteristic changes seen in the brains of patients with AD, specifically amyloid beta (Aβ) plaques and neurofibrillary tangles (NFTs), are also visible in the retina.  

In a recent study, OCT was used to examine whether carriers of the PSEN1 mutation associated with familial Alzheimer’s disease — before the onset of any cognitive changes– have retinal alterations which distinguish them from non-carrier family members.  This study included 10 carriers of the PSEN1 E280A mutation who were cognitively unimpaired (mean age 36.3 years) and 10 healthy non-carrier family members. 

Using OCT imaging, the researchers observed that PSEN1 mutation carriers, compared to non-carrier controls, had a generalized decrease in the thickness of the entire retina, as well as a thinning of specific retinal layers.  Age was a significant effect modifier of the association between PSEN1 mutation and amyloid β levels in cortical regions: however, age did not affect the association between PSEN1 mutation and retinal thickness. 

How Can This Information Help Us?

Most patients with Alzheimer’s disease present relatively late in the course of their illness, after cognitive changes have become evident.  At this point, interventions are unlikely to be beneficial.  Thus, there is a clear impetus to identify patients with AD very early in the course of illness, ideally before there are changes in cognitive functioning, so that interventions that limit the progression of AD can be initiated earlier.  

Optical coherence tomography is a noninvasive, relatively inexpensive technique that offers us a glimpse into what is going on in the brain.  Through analyzing the morphologic changes in the retina of  individuals with PSEN1-associated early-onset familial Alzheimer’s disease, we may be able to identify biomarkers that could be used to identify early Alzheimer’s disease in other populations who do not have this mutation. 

Armstrong GW, Kim LA, Vingopoulos F, Park JY, Garg I, Kasetty M, Silverman RF, Zeng R, Douglas VP, Lopera F, Baena A, Giraldo M, Norton D, Cronin-Golomb A, Arboleda-Velasquez JF, Quiroz YT, Miller JB.  Retinal Imaging Findings in Carriers With PSEN1-Associated Early-Onset Familial Alzheimer Disease Before Onset of Cognitive Symptoms.  JAMA Ophthalmol. 2021 Jan 1;139(1): 49-56.

Yakeel T. Quiroz-Gaviria, PhD is an Assistant Professor in the Departments of Psychiatry and Neurology at Massachusetts General Hospital.  She is a Clinical Neuropsychologist and Neuroimaging Researcher. Dr. Quiroz currently serves as the Director of the Familial Dementia Neuroimaging Lab, and the Multicultural Alzheimer’s Prevention Program (MAPP). She is also the Co-Director of the MUNDOS Neuropsychological Service at the Psychology Assessment Center, a clinical service that offers specialized cognitive testing to Spanish-speaking patients.