Alzheimer's disease pathophysiology in the Retina

Gaire, Bhakta Prasad; Koronyo, Yosef; Fuchs, Dieu-Trang; Shi, Haoshen; Rentsendorj, Altan; Danziger, Ron; Vit, Jean-Philippe; Mirzaei, Nazanin; Doustar, Jonah; Sheyn, Julia; Hampel, Harald; Vergallo, Andrea; Davis, Miyah R.; Jallow, Ousman; Baldacci, Filippo; Verdooner, Steven R.; Barron, Ernesto; Mirzaei, Mehdi; Gupta, Vivek K.; Graham, Stuart L.; Tayebi, Mourad; Carare, Roxana O.; Sadun, Alfredo A.; Miller, Carol A.; Dumitrascu, Oana M.; Lahiri, Shouri; Gao, Liang; Black, Keith L.; Koronyo-Hamaoui, Maya

doi:10.1016/j.preteyeres.2024.101273

Cited by 3 publications

(4 citation statements)

References 584 publications

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“…These tau forms are primarily found within neurons in the INL and GCL. Inconsistencies in previous observations likely stem from variations in the geometric regions that were analyzed, as well as tissue preservation, fixation, and staining protocols [ 3 , 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…However, this is speculative for the current study and merits future quantitative investigation of the spatiotemporal distribution of tau isoforms in different retinal quadrants and layers during disease stages to confirm these observations. In addition, given the inconsistencies in previous reports on retinal AD tauopathy—where several studies identified certain pathological tau forms in the AD retina [ 21 , 31 , 34 , 65 , 87 ] that two earlier reports could not detect [ 36 , 88 ] or could partially detect [ 20 , 70 ]—workshop groups focused on harmonizing the methodologies for analyzing retinal tauopathy will be useful in future research [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The retina, an extension of the brain and the only central nervous system (CNS) organ not shielded by bone [ 24 , 66 ], holds promise for revolutionizing AD screening. Current limitations in early diagnosis and monitoring of AD in the clinical settings [ 3 , 41 ], make retinal imaging a potential solution due to its accessibility for noninvasive, repeated, low-cost imaging at ultra-high spatial resolution [ 27 ]. Our group and others have demonstrated the manifestation of AD pathological features in the retinas of asymptomatic individuals, those with mild cognitive impairment (MCI), and AD dementia patients, including Aβ deposits, vascular Aβ 40 and Aβ 42 , various aberrant tau isoforms, inflammation, vascular damage, and neurodegeneration [ 4 , 6 – 8 , 13 , 17 , 20 – 23 , 27 , 31 , 33 – 35 , 43 – 45 , 47 , 50 , 51 , 56 , 59 , 63 , 65 , 67 , 70 , 71 , 73 , 74 , 79 , 87 , 89 ].…”

Section: Introductionmentioning

confidence: 99%

“…Current limitations in early diagnosis and monitoring of AD in the clinical settings [ 3 , 41 ], make retinal imaging a potential solution due to its accessibility for noninvasive, repeated, low-cost imaging at ultra-high spatial resolution [ 27 ]. Our group and others have demonstrated the manifestation of AD pathological features in the retinas of asymptomatic individuals, those with mild cognitive impairment (MCI), and AD dementia patients, including Aβ deposits, vascular Aβ 40 and Aβ 42 , various aberrant tau isoforms, inflammation, vascular damage, and neurodegeneration [ 4 , 6 – 8 , 13 , 17 , 20 – 23 , 27 , 31 , 33 – 35 , 43 – 45 , 47 , 50 , 51 , 56 , 59 , 63 , 65 , 67 , 70 , 71 , 73 , 74 , 79 , 87 , 89 ]. Some pathological changes associated with AD, such as Aβ deposits, tau isoforms, vascular damage, and atrophy, were more frequently detected or had a greater impact in the superior temporal (ST) or inferior temporal (IT) retinal regions of AD patients compared to controls [ 7 , 20 , 31 , 43 , 44 , 47 , 50 , 74 ].…”

Section: Introductionmentioning

confidence: 99%

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Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

Shi,

Mirzaei,

Koronyo

et al. 2024

Acta Neuropathol

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This study investigates various pathological tau isoforms in the retina of individuals with early and advanced Alzheimer’s disease (AD), exploring their connection with disease status. Retinal cross-sections from predefined superior-temporal and inferior-temporal subregions and corresponding brains from neuropathologically confirmed AD patients with a clinical diagnosis of either mild cognitive impairment (MCI) or dementia (n = 45) were compared with retinas from age- and sex-matched individuals with normal cognition (n = 30) and non-AD dementia (n = 4). Retinal tau isoforms, including tau tangles, paired helical filament of tau (PHF-tau), oligomeric-tau (Oligo-tau), hyperphosphorylated-tau (p-tau), and citrullinated-tau (Cit-tau), were stereologically analyzed by immunohistochemistry and Nanostring GeoMx digital spatial profiling, and correlated with clinical and neuropathological outcomes. Our data indicated significant increases in various AD-related pretangle tau isoforms, especially p-tau (AT8, 2.9-fold, pS396-tau, 2.6-fold), Cit-tau at arginine residue 209 (CitR209-tau; 4.1-fold), and Oligo-tau (T22+, 9.2-fold), as well as pretangle and mature tau tangle forms like MC-1-positive (1.8-fold) and PHF-tau (2.3-fold), in AD compared to control retinas. MCI retinas also exhibited substantial increases in Oligo-tau (5.2-fold), CitR209-tau (3.5-fold), and pS396-tau (2.2-fold). Nanostring GeoMx analysis confirmed elevated retinal p-tau at epitopes: Ser214 (2.3-fold), Ser396 (2.6-fold), Ser404 (2.4-fold), and Thr231 (1.8-fold), particularly in MCI patients. Strong associations were found between retinal tau isoforms versus brain pathology and cognitive status: a) retinal Oligo-tau vs. Braak stage, neurofibrillary tangles (NFTs), and CDR cognitive scores (ρ = 0.63–0.71), b) retinal PHF-tau vs. neuropil threads (NTs) and ABC scores (ρ = 0.69–0.71), and c) retinal pS396-tau vs. NTs, NFTs, and ABC scores (ρ = 0.67–0.74). Notably, retinal Oligo-tau strongly correlated with retinal Aβ42 and arterial Aβ40 forms (r = 0.76–0.86). Overall, this study identifies and quantifies diverse retinal tau isoforms in MCI and AD patients, underscoring their link to brain pathology and cognition. These findings advocate for further exploration of retinal tauopathy biomarkers to facilitate AD detection and monitoring via noninvasive retinal imaging.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

Shi,

Mirzaei,

Koronyo

et al. 2024

Acta Neuropathol

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Color Fundus Photography and Deep Learning Applications in Alzheimer’s Disease

Dumitrascu,

Li,

Zhu

et al. 2024

Mayo Clinic Proceedings: Digital Health

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Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer’s disease pathology in the eye clinic

Bader,

Groot,

Tan

et al. 2024

Alz Res Therapy

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Background Alzheimer’s disease (AD) is a common, complex and multifactorial disease that may require screening across multiple routes of referral to enable early detection and subsequent future implementation of tailored interventions. Blood- and eye-based biomarkers show promise as low-cost, scalable and patient-friendly tools for early AD detection given their ability to provide information on AD pathophysiological changes and manifestations in the retina, respectively. Eye clinics provide an intriguing real-world proof-of-concept setting to evaluate the performance of these potential AD screening tools given the intricate connections between the eye and brain, presumed enrichment for AD pathology in the aging population with eye disorders, and the potential for an accelerated diagnostic pathway for under-recognized patient groups. Methods The BeyeOMARKER study is a prospective, observational, longitudinal cohort study aiming to include individuals visiting an eye-clinic. Inclusion criteria entail being ≥ 50 years old and having no prior dementia diagnosis. Excluded eye-conditions include traumatic insults, superficial inflammation, and conditions in surrounding structures of the eye that are not engaged in vision. The BeyeOMARKER cohort (n = 700) will undergo blood collection to assess plasma p-tau217 levels and a brief cognitive screening at the eye clinic. All participants will subsequently be invited for annual longitudinal follow-up including remotely administered cognitive screening and questionnaires. The BeyeOMARKER + cohort (n = 150), consisting of 100 plasma p-tau217 positive participants and 50 matched negative controls selected from the BeyeOMARKER cohort, will additionally undergo Aβ-PET and tau-PET, MRI, retinal imaging including hyperspectral imaging (primary), widefield imaging, optical coherence tomography (OCT) and OCT-Angiography (secondary), and cognitive and cortical vision assessments. Results We aim to implement the current protocol between April 2024 until March 2027. Primary outcomes include the performance of plasma p-tau217 and hyperspectral retinal imaging to detect AD pathology (using Aβ- and tau-PET visual read as reference standard) and to detect cognitive decline. Initial follow-up is ~ 2 years but may be extended with additional funding. Conclusions We envision that the BeyeOMARKER study will demonstrate the feasibility of early AD detection based on blood- and eye-based biomarkers in alternative screening settings, and will improve our understanding of the eye-brain connection. Trial registration The BeyeOMARKER study (Eudamed CIV ID: CIV-NL-23–09-044086; registration date: 19th of March 2024) is approved by the ethical review board of the Amsterdam UMC.

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Alzheimer's disease pathophysiology in the Retina

Cited by 3 publications

References 584 publications

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

Identification of retinal oligomeric, citrullinated, and other tau isoforms in early and advanced AD and relations to disease status

Color Fundus Photography and Deep Learning Applications in Alzheimer’s Disease

Rationale and design of the BeyeOMARKER study: prospective evaluation of blood- and eye-based biomarkers for early detection of Alzheimer’s disease pathology in the eye clinic

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