Because of a shared ontogenic origin, the retina displays similarities to the brain and spinal cord in terms of anatomy, functionality, response to insult, and immunology. Hence, the retina can be approached as an integral part of the central nervous system. The occurence of ocular manifestations in several neurodegenerative pathologies, such as Alzheimer's disease and Parkinson's disease, accentuates the strong relationship between eye and brain. Particularly retinal changes can present a substrate for cerebral changes in these disorders. Offering a 'window to the brain', the transparent eye enables non-invasive imaging of these changes in retinal structure and vasculature. In this project, the potential of retinal biomarkers for e.g. Alzheimer's will be explored with the aim to overcome some of the hurdles in the current management of these pathologies, mainly the lack of techniques for patient screening and early diagnosis. The aim of this clinical trial is to correlate the retinal biomarkers for Alzheimer's with neuro-imaging, and cognitive function. Integrating the results will yield non-invasive retinal biomarkers for clinical research, screening, and follow-up of disease progression in various neurodegenerative disorders.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of dementia worldwide. A growing number of people are surviving into their 80s-90s and the number of AD patients projected to nearly triple in the next three decades, affecting 80-90 million people worldwide by 2040. As such, AD will become the third cause of death for older people, just behind cardiovascular disease and cancer. In contrast to the latter, AD cannot be prevented, slowed or cured. AD represents an enormous socio-economic burden and has become a trillion dollar disease. Despite decades of intensive research, diagnosis and treatment remain challenging for AD. A string of recent failures in clinical trials for AD drugs has pointed out that our understanding of the disease is still far from complete. More in detail, three major reasons underlying this treatment gap have been identified:

i. The lack of techniques for patient screening and early diagnosis. ii. The incomplete understanding of the complex interplay of pathological processes that underlie AD.

iii. The many hurdles between drug discovery and approval.

With this study, the investigators propose a novel way to address these needs, by using the retina as a model organ to study the central nervous system (CNS). Many of the hallmark cerebral pathophysiological processes of AD have also been observed in the retina. Unlike the rest of the CNS, the retina can be visualized directly, with an imaging resolution up to 100x higher than PET and MRI scans. Using these high-resolution imaging tools such as Optical Coherence Tomography (OCT), studies have demonstrated microvascular changes and neuro-retinal thinning in AD patients. Pilot data show that retinal Aβ can be visualized non-invasively solely based on the intrinsic hyperspectral signature of aggregated amyloid deposits. Non-invasive retinal imaging (e.g., fundus photography, OCT, hyperspectral imaging (HSI)) - which are all available at affordable cost -, could therefore represent novel means for identifying patients at risk, for longitudinal follow-up of disease progression in AD patients, and for research in a quest for more effective treatments.

This is an open-label longitudinal biomarker study without investigational medicinal product in subjects in different stages of the AD spectrum.

The data that we will collect consist of amyloid imaging, MRI, blood, genetic, general health and cognitive data, as well as visual acuity, ocular biomicroscopy and funduscopy, fundus photographs, hyperspectral retinal images, Optical Coherence Tomography (OCT) retinal images and OCT angiography (OCT-A) retinal images. Subjects will be followed longitudinally. In the current study the investigators will primarily investigate the potential of non-invasive, multimodal retinal imaging for the early detection of Alzheimer's disease and for the evaluation of disease progression. This will be done in comparison with amyloid imaging and neuropsychological evaluations.

The investigators will build a longitudinal database of ocular, systemic, neuro-psychiatric, MRI and PET imaging parameters of Aβ-positive and Aβ-negative patients with different stages of cognitive impairment. This database will be used to provide proof-of-concept that retinal biomarkers provide an early, accurate and non-invasive tool for AD detection and follow-up. All data will be collected in a database for statistical analysis.

Inclusion Criteria:

• Between ≥ 50 and ≤ 85 years of age.
• In the opinion of the investigator, the patient is in stable medical condition and willing and able to perform study procedures.
• Patient is fluent in written and verbal Dutch.
• Patient is capable of giving informed consent.

Exclusion Criteria:

• Patient has a history or current evidence of a neurological disorder, which, in the opinion of the primary investigator, may contribute to the subject's cognitive impairment.
• Patient has a history of large-vessel stroke or evidence of a large-vessel infarction or other focal lesions on baseline MRI scan, which may contribute to the cause of the memory impairment in the opinion of the investigator. Vascular white matter lesions or other signs of microangiopathy will not be considered an exclusion.
• Patient has a history of malignancy ≤ 5 years prior to signing informed consent, except for patients who have undergone potentially curative therapy with no evidence of recurrence for 1 year, and who are deemed at low risk for recurrency by her/his treating physician.
• Patient is currently participating or has participated in a study with an investigational compound within 30 days of signing informed consent.
• Subject has any magnetizable metal prostheses, implants or foreign objects that could pose a hazard during MRI scans.
• Patient has a known history of ocular diseases other than the exception of cataract and/or wearing glasses/contact lenses.

Cfr. eligibility criteria