Ocular Manifestations of Alzheimer Disease
Alzheimer disease (AD) is a primary progressive neurodegenerative disease affecting approximately 4.7% of individuals age 60 years. AD is typically characterized by deterioration of memory and other neurocognitive functions that ultimately interferes with daily life and is can be fatal. AD is the most common form of dementia, accounting for over 50% of cases. In the United States, 5.5 million people are affected and and up to 35 million worldwide have the disease. There is currently no cure for AD but there are treatments with variable and modest efficacy .
AD is believed to arise from the accumulation of misfolded proteins that induces oxidative and secondary inflammatory damage on the aging brain leading to cognitive decline. Specific pathological features of AD include β-amyloid (Aβ) peptide plaques and tau protein neurofibrillary tangles (NFT). According to the predominant ‘amyloid hypothesis,’ Aβ precipitates secondary to an imbalance between production and clearance such that there is an accumulation and aggregation of Aβ2. NFT are formed from the intracellular aggregation of abnormal tau proteins. The number of NFT correlates with disease severity. Secondary inflammation and oxidative stress may interfere with synaptic and neuronal activity, leading to neuronal loss and brain atrophy.
As visualization of Aβ and NFT via brain imaging is of limited specificity and resolution, AD diagnosis is primarily clinical with reliance on a range of testing modalities ranging from cognitive assessments and physical exam to brain imaging (MRI, CT, PET). Definitive diagnosis is only through postmortem histological exam with visualization of NFT and Aβ.
|Ocular Structures||Pathological Changes in AD|
|Retina||- Deposition of proteins tau, Aβ and pTAu- Impaired metabolism of amyloid β precursor protein (APP)|
|Retinal and choroidal vasculature||- Retinal and choroidal vascular β-amyloid deposits in transgenic mouse model of AD lead to retinal degeneration- Impaired vascularization|
|Retinal vascular blood flow||- Blood flow disturbances can lead to neurodegeneration|
|Optic nerve||- Axonal degeneration in the axonal segments- Loss of optic nerve thickness
- Papillary paleness due to axonal loss and perfusion alterations
|Lens||- Correlation between AD and supranuclear cataract- Presence of abnormal protein deposits|
|Tears||- Changes in the chemical barrier composition of tears|
|Cornea||- Reduced corneal sensitivity|
|Pupil||- Pupillary response, possible biomarker|
|Choroid||- Attenuation of choroidal thickness|
|Visual Function||Pathological Changes in AD|
|Visual fields||- Inferior hemifield loss|
|Visual acuity||- Decreased visual acuity in low luminance|
|Sensory perception||- Clinically important symptoms of visuospatial disorientation|
|Visual processing||- Deficits of visual motion perception|
|Contrast sensitivity||- Contrast sensitivity disturbances and motion perception|
|Color vision||- Color discrimination error inversely proportional with mini-mental state examination (MMSE) score|
|Stereopsis||- Reduced stereoscopic depth perception|
|Circadian rhythm||- Alterations in the circadian rhythm and β-amyloid deposits inside and surrounding degenerating mRGCs|
Of note, the visual variant of AD (VVAD), also known as posterior cortical atrophy (PCA), is characterized by prominent visual symptoms due to localized atrophy of the parieto-occipital lobe. VVAD is For more information, please see corresponding EyeWiki article.
Patients with PCA typically present with difficulty reading or problems with visuospatial and visual processing. A homonymous hemianopsia or cortical visual loss with a negative structural imaging study (e.g., MRI) or neuroimaging showing only posterior cortical atrophy may suggest the diagnosis of AD.
Previously, retinal OCT imaging in AD patients noted NFL layer atrophy and ganglion cell death . However, these findings were not specific to AD and were also reported in other neurodegenerative disorders (e.g., Parkinson disease). Reduced RNFL thickness on OCT has been associated with memory deficits. Recent studies have reported detection of hallmark Aβ plaques in the retina in AD patients via scanning laser ophthalmoscope using the natural fluorochrome curcumin that binds to the plaques . Fluorescence is quantified via an automated calculation of the retinal amyloid index (RAI). Compared to healthy controls, AD patients had a 2.1-fold increase in fluorescent intensity over baseline. Furthermore, the fluorescence pattern is consistent with histological data showing Aβ deposits clustered in the peripheral superior quadrant, often along blood vessels. Retinal vascular parameters (RVPs) may also serve as a tool for early AD diagnosis . The decreased retinal microvascular network density noted in AD patients suggests retinal vessel reaction to flicker stimulation, delayed in AD patients, could be another potential non-invasive biomarker.
Optical coherence tomography angiography (OCTA)
OCTA has also been used on AD patients to detect decreased retinal vasculature density as well as reduced retinal and choroidal flow rates . The metabolic hyperspectral retinal camera is another device currently being studied for its biomarker potential via measurement of regional retinal vessel oxygen saturation. This device utilizes 225 contiguous spectral bands collected at high speeds to localize biomolecules and structures based on their respective spectral signatures. Another study evaluating the association between type 2 diabetes and AD employs microperimetry to measure retinal neurodegeneration. Microperimetry assesses retinal sensitivity by measuring the minimum light intensity which the patients can perceive by stimulating specific areas of retina with spots of light.
Another target for AD detection is the pathologic hyperphosphorylated Tau protein (NFT), which has been detected in postmortem human retinas and AD human models in the absence of tau aggregation, suggesting a pre-symptomatic disease stage.
Studies have detected β-amyloid in the lens of human AD patients as well as correlation between cortical cataracts and AD degeneration. A clinical trial is currently evaluating the use of aftobetin hydrochloride, a topical amyloid-binding compound to detect β-amyloid in patients with mild cognitive impairment and mild AD (ClinicalTrials.gov Identifier: NCT02928211).
AD patients have been reported to have increased tear flow rate and protein levels. The presence of lipocalin-1, dermicidin, lysozyme C and lactritin had an 81% sensitivity and 77% specificity for AD35.
Pupillary Light Response and Eye Movement
Pupillary light reflex amplitude has been noted to be decreased in AD. There is also an ongoing study to track eye movements as an AD diagnostic tool, with previous studies showing delayed saccadic eye movement and smooth ocular pursuit (ClinicalTrials.gov Identifier: NCT01434940).
While still in development, this wide range of AD detection modalities are promising as a specific, early and noninvasive method of objective AD diagnosis, with potential for prognostication as well.
- Rauch K, Garg SJ, Seldomridge DL, Hazanchuk V. Alzheimer’s Disease, Dementia and the Eye. American Academy of Ophthalmology. EyeSmart® Eye health. https://www.aao.org/eye-health/diseases/alzheimers-disease-dementia-eye-list. Accessed November 17, 2022.
- Querfurth, H. W. & LaFerla, F. M. Alzheimer’s Disease. N. Engl. J. Med. 362, 329–344 (2010).
- Prince, M. et al. The global prevalence of dementia: A systematic review and metaanalysis. Alzheimers Dement. J.Alzheimers Assoc. 9, 63–75.e2 (2013).
- Weiner, M. W. et al. The Alzheimer’s Disease Neuroimaging Initiative: A review of papers published since its inception. Alzheimers Dement. J. Alzheimers Assoc. 8, S1-68 (2012).
- Heneka, M. T. et al. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 14, 388–405 (2015).
- Perl, D. P. Neuropathology of Alzheimer’s Disease. Mt. Sinai J. Med. N. Y. 77, 32–42 (2010).
- Javaid, F. Z., Brenton, J., Guo, L. & Cordeiro, M. F. Visual and Ocular Manifestations of Alzheimer’s Disease and Their Use as Biomarkers for Diagnosis and Progression. Front. Neurol. 7, (2016).
- Colligris, P., Perez de Lara, M. J., Colligris, B. & Pintor, J. Ocular Manifestations of Alzheimer’s and Other Neurodegenerative Diseases: The Prospect of the Eye as a Tool for the Early Diagnosis of Alzheimer’s Disease. J. Ophthalmol. 2018, (2018).
- Schön, C. et al.Long-term in vivo imaging of fibrillar tau in the retina of P301S transgenic mice. PloS One 7, e53547 (2012).
- Alexandrov, P. N., Pogue, A., Bhattacharjee, S. & Lukiw, W. J. Retinal amyloid peptides and complement factor H in transgenic models of Alzheimer’s disease. Neuroreport 22, 623–627 (2011).
- Koronyo, Y. et al. Retinal amyloid pathology and proof-of-concept imaging trial in Alzheimer’s disease. JCI Insight 2, (2017).
- Koronyo, Y., Salumbides, B. C., Black, K. L. & Koronyo-Hamaoui, M. Alzheimer’s disease in the retina: imaging retinal aβ plaques for early diagnosis and therapy assessment. Neurodegener. Dis. 10, 285–293 (2012).
- Gao, L. et al.Neuroprotective effect of memantine on the retinal ganglion cells of APPswe/PS
- Rusu, P. et al. Axonal accumulation of synaptic markers in APP transgenic Drosophila depends on the NPTY motif and is paralleled by defects in synaptic plasticity. Eur. J. Neurosci. 25, 1079–1086 (2007).
- Dutescu, R. M. et al. Amyloid precursor protein processing and retinal pathology in mouse models of Alzheimer’s disease. Graefes Arch. Clin. Exp. Ophthalmol. Albrecht Von Graefes Arch. Klin. Exp. Ophthalmol. 247, 1213–1221 (2009).
- Sadun, A. A. & Bassi, C. J. Optic nerve damage in Alzheimer’s disease. Ophthalmology 97, 9–17 (1990).
- Blanks, J. C., Hinton, D. R., Sadun, A. A. & Miller, C. A. Retinal ganglion cell degeneration in Alzheimer’s disease. Brain Res. 501, 364–372 (1989).
- Hinton, D. R., Sadun, A. A., Blanks, J. C. & Miller, C. A. Optic-nerve degeneration in Alzheimer’s disease. N. Engl. J. Med. 315, 485–487 (1986).
- Trebbastoni, A. et al. Retinal nerve fibre layer thickness changes in Alzheimer’s disease: R
- Parisi, V. et al. Morphological and functional retinal impairment in Alzheimer’s disease patients. Clin. Neurophysiol. Off. J. Int. Fed. Clin. Neurophysiol. 112, 1860–1867 (2001).
- Hedges, T. R. et al. Retinal nerve fiber layer abnormalities in Alzheimer’s disease. Acta Ophthalmol. Scand. 74, 271–275 (1996).
- Coppola, G. et al. Optical Coherence Tomography in Alzheimer’s Disease: A Meta-Analysis. PloS One 10, e0134750 (2015).
- Berisha, F., Feke, G. T., Trempe, C. L., McMeel, J. W. & Schepens, C. L. Retinal abnormalities in early Alzheimer’s disease. Invest. Ophthalmol. Vis. Sci. 48, 2285–2289 (2007).
- Burke, W. J. et al. Evidence for retrograde degeneration of epinephrine neurons in Alzheimer’s disease. Ann. Neurol. 24, 532–536 (1988).
- Mutlu, U. et al. Association of Retinal Neurodegeneration on Optical Coherence Tomography With Dementia: A Population-Based Study. JAMA Neurol. 75, 1256–1263 (2018).
- Swanson, A., Wolf, T., Sitzmann, A. & Willette, A. A. Neuroinflammation in Alzheimer’s disease: Pleiotropic roles for cytokines and neuronal pentraxins. Behav. Brain Res. 347, 49–56 (2018).
- Ning, A., Cui, J., To, E., Ashe, K. H. & Matsubara, J. Amyloid-beta deposits lead to retinal degeneration in a mouse model of Alzheimer disease. Invest. Ophthalmol. Vis. Sci. 49, 5136–5143 (2008).
- Paris, D. et al.Impaired angiogenesis in a transgenic mouse model of cerebral amyloidosis. Neurosci. Lett. 366, 80–85 (2004).
- Feke, G. T., Hyman, B. T., Stern, R. A. & Pasquale, L. R. Retinal blood flow in mild cognitive impairment and Alzheimer’s disease. Alzheimers Dement. Amst. Neth. 1, 144–151 (2015).
- Kesler, A., Vakhapova, V., Korczyn, A. D., Naftaliev, E. & Neudorfer, M. Retinal thickness in patients with mild cognitive impairment and Alzheimer’s disease. Clin. Neurol. Neurosurg. 113, 523–526 (2011).
- Tsai, C. S. et al. Optic nerve head and nerve fiber layer in Alzheimer’s disease. Arch. Ophthalmol. Chic. Ill 1960 109, 199–204 (1991).
- Bambo, M. P. et al. Analysis of optic disk color changes in Alzheimer’s disease: a potential new biomarker. Clin. Neurol. Neurosurg. 132, 68–73 (2015).
- Tian, T., Zhang, B., Jia, Y. & Li, Z. Promise and challenge: the lens model as a biomarker for early diagnosis of Alzheimer’s disease. Dis. Markers 2014, 826503 (2014).
- Liu, S. S. & Zhu, S. Q. [Correlation between Alzheimer disease and cataract]. Zhonghua Yan Ke Za Zhi Chin. J. Ophthalmol. 53, 314–316 (2017).
- Kerbage, C., Sadowsky, C. H., Jennings, D., Cagle, G. D. & Hartung, P. D. Alzheimer’s disease diagnosis by detecting exogenous fluorescent signal of ligand bound to Beta amyloid in the lens of human eye: an exploratory study. Front. Neurol. 4, 62 (2013).
- Kalló, G. et al. Changes in the Chemical Barrier Composition of Tears in Alzheimer’s Disease Reveal Potential Tear Diagnostic Biomarkers. PloS One 11, e0158000 (2016).
- Örnek, N., Dağ, E. & Örnek, K. Corneal sensitivity and tear function in neurodegenerative diseases. Curr. Eye Res. 40, 423–428 (2015).
- Granholm, E. L. et al. Pupillary Responses as a Biomarker of Early Risk for Alzheimer’s Disease. J. Alzheimers Dis. JAD 56, 1419–1428 (2017).
- Trebbastoni, A. et al. Attenuation of Choroidal Thickness in Patients With Alzheimer Disease: Evidence From an Italian Prospective Study. Alzheimer Dis. Assoc. Disord. 31, 128–134 (2017).
- Trick, G. L., Trick, L. R., Morris, P. & Wolf, M. Visual field loss in senile dementia of the Alzheimer’s type. Neurology 45, 68–74 (1995).
- Gilmore, G. C. & Levy, J. A. Spatial contrast sensitivity in Alzheimer’s disease: a comparison o
- Cormack, F. K., Tovee, M. & Ballard, C. Contrast sensitivity and visual acuity in patients with Alzheimer’s disease. Int. J. Geriatr. Psychiatry 15, 614–620 (2000).
- Lakshminarayanan, V., Lagrave, J., Kean, M. L., Dick, M. & Shankle, R. Vision in dementia: contrast effects. Neurol. Res. 18, 9–15 (1996).
- Polo, V. et al. Visual dysfunction and its correlation with retinal changes in patients with Alzheimer’s disease. Eye Lond. Engl. 31, 1034–1041 (2017).
- Thiyagesh, S. N. et al. The neural basis of visuospatial perception in Alzheimer’s disease and healthy elderly comparison subjects: an fMRI study. Psychiatry Res. 172, 109–116 (2009).
- Mapstone, M., Dickerson, K. & Duffy, C. J. Distinct mechanisms of impairment in cognitive ageing and Alzheimer’s disease. Brain J. Neurol. 131, 1618–1629 (2008).
- Rizzo, M. & Nawrot, M. Perception of movement and shape in Alzheimer’s disease. Brain J. Neurol. 121 ( Pt 12), 2259–2270 (1998).
- Gilmore, G. C., Wenk, H. E., Naylor, L. A. & Koss, E. Motion perception and Alzheimer’s disease. J. Gerontol. 49, P52-57 (1994).
- Salamone, G. et al. Color discrimination performance in patients with Alzheimer’s disease. Dement. Geriatr. Cogn. Disord. 27, 501–507 (2009).
- Mittenberg, W., Malloy, M., Petrick, J. & Knee, K. Impaired depth perception discriminates Alzheimer’s dementia from aging and major depression. Arch. Clin. Neuropsychol. 9, 71–79 (1994).
- Musiek, E. S., Xiong, D. D. & Holtzman, D. M. Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease. Exp. Mol. Med. 47, e148 (2015).
- La Morgia, C., Ross-Cisneros, F. N., Sadun, A. A. & Carelli, V. Retinal Ganglion Cells and Circadian Rhythms in Alzheimer’s Disease, Parkinson’s Disease, and Beyond. Front. Neurol. 8, 162 (2017).
- Feng, R., Li, L., Yu, H., Liu, M. & Zhao, W. Melanopsin retinal ganglion cell loss and circadian dysfunction in Alzheimer’s disease (Review). Mol. Med. Rep. 13, 3397–3400
- Jindahra, P., Hedges, T. R., Mendoza-Santiesteban, C. E. & Plant, G. T. Optical coherence tomography of the retina: applications in neurology. Curr. Opin. Neurol. 23, 16–23 (2010).
- La Morgia, C. et al. Melanopsin retinal ganglion cell loss in Alzheimer disease. Ann. Neurol. 79, 90–109 (2016).
- Méndez-Gómez, J. L. et al. Peripapillary Retinal Nerve Fiber Layer Thickness and the Evolution of Cognitive Performance in an Elderly Population. Front. Neurol. 8, 93 (2017).
- Jiang, J., Wang, H., Li, W., Cao, X. & Li, C. Amyloid Plaques in Retina for Diagnosis in Alzheimer’s Patients: a Meta-Analysis. Front. Aging Neurosci. 8, (2016).
- Koronyo-Hamaoui, M. et al. Identification of Amyloid Plaques in Retinas from Alzheimer’s Patients and Noninvasive In Vivo Optical Imaging of Retinal Plaques in a Mouse Model. NeuroImage 54S1, S204–S217 (2011).
- Frost, S. et al. Retinal vascular biomarkers for early detection and monitoring of Alzheimer’s disease. Transl. Psychiatry 3, e233 (2013).
- Kotliar, K. et al. Altered neurovascular coupling as measured by optical imaging: a biomarker for Alzheimer’s disease. Sci. Rep. 7, 12906 (2017).
- Jiang, H. et al. Altered Macular Microvasculature in Mild Cognitive Impairment and Alzheimer Disease. J. Neuro-Ophthalmol. Off. J. North Am. Neuro-Ophthalmol. Soc. 38, 292–298 (2018).
- Baumann, B. et al. Visualization of neuritic plaques in Alzheimer’s disease by polarization-sensitive optical coherence microscopy. Sci. Rep. 7, 43477 (2017).
- Bulut, M. et al. Evaluation of optical coherence tomography angiographic findings in Alzheimer’s type dementia. Br. J. Ophthalmol. 102, 233–237 (2018).
- Shahidi, A. M., Patel, S. R., Flanagan, J. G. & Hudson, C. Regional variation in human retinal vessel oxygen saturation. Exp. Eye Res. 113, 143–147 (2013).
- Mordant, D. J. et al. Oxygen saturation measurements of the retinal vasculature in treated asymmetrical primary open-angle glaucoma using hyperspectral imaging. Eye Lond. Engl. 28, 1190–1200 (2014).
- Ciudin, A. et al. Retinal Microperimetry: A New Tool for Identifying Patients With Type 2 Diabetes at Risk for Developing Alzheimer Disease. Diabetes 66, 3098–3104 (2017).
- Spires-Jones, T. L., Stoothoff, W. H., de Calignon, A., Jones, P. B. & Hyman, B. T. Tau pathophysiology in neurodegeneration: a tangled issue. Trends Neurosci. 32, 150–159 (2009).
- Chiasseu, M. et al. Tau accumulation in the retina promotes early neuronal dysfunction and precedes brain pathology in a mouse model of Alzheimer’s disease. Mol. Neurodegener. 12, 58 (2017).
- Tales, A. et al. The pupillary light reflex in aging and Alzheimer’s disease. Aging Milan Italy 13, 473–478 (2001).
- Sadun, A. A., Borchert, M., DeVita, E., Hinton, D. R. & Bassi, C. J. Assessment of visual impairment in patients with Alzheimer’s disease. Am. J. Ophthalmol. 104, 113–120 (1987).
- Fletcher, W. A. & Sharpe, J. A. Smooth pursuit dysfunction in Alzheimer’s disease. Neurology 38, 272–277 (1988).