Atlas of Retinal Imaging in Alzheimer's Study

Inclusion Criteria (ALL PARTICIPANTS):

• · Individuals between the ages of 55 and 80 years old (inclusive).

• Permitted medications stable for at least 1 month prior to screening. Inparticular:

• Participants may take stable doses of antidepressants lacking significantanticholinergic side effects (if they are not currently depressed and do nothave a history of major depression within the past year).

• Adequate visual and auditory acuity to allow neuropsychological testing, asdetermined by the eye exam and the neuropsychologist's judgment. Hearingaugmentation by hearing aids is allowed.

• Good general health or without any clinically significant abnormalities (seeexclusion criteria) that would be expected to interfere with participation inthe study.

• Participants must be willing and able to provide written informed consent.

• Participants must have a study partner (i.e., family member, close friend, orcaregiver) who can attend study appointments with them and report on theirlevel of daily functioning.

• As this is entirely an observational study, without treatment intervention, wewill allow concurrent enrollment in other clinical trials for mild cognitiveimpairment (MCI) or AD, including those that involved the use ofinvestigational drugs. Relevant information about other studies in whichparticipants are participating (e.g., study name, sponsor) will be collectedand considered as a potential statistical covariate in the statistical analysisplan (SAP).

Additional Inclusion Criteria - Healthy Control Participants

• Montreal Cognitive Assessment (MoCA) total score > 26 at screening

• Clinical Dementia Rating (CDR) 0 at screening

• An absence of substantial subjective memory complaints or worry

• No first degree relative with either diagnosed AD or suspicion of AD

• A screening genotype result showing non-carrier status for APOE ε4 allele

Additional Inclusion Criteria - High-Risk for Preclinical AD Participants

• MoCA total score > 26 at screening

• CDR 0 at screening

• No clinical diagnosis of MCI or dementia of any type

• Must have all of the following three risk factors for AD:

• Subjective memory complaints as ascertained on a standardized questionnaire (i.e.,ECOG).

• A positive (suspected) first-degree family history for the disease.

• A screening genotype result showing carrier status for at least one APOE ε4 geneallele Additional Inclusion Criteria - Patients with Mild Cognitive Impairment

• MoCA total score > 19 at screening

• CDR 0.5 at screening

• A clinical diagnosis of MCI (amnestic type, but may include multiple domains) fromqualified specialist or from a memory disorders clinic or center

• Score of less than or equal to 85 (1.5 SD below age and education adjusted normativedata) on the RBANS Delayed Memory Index (DMI)

• Positive prior biomarker evidence of Alzheimer's disease (PET imaging or CSF study),if available

Additional Inclusion Criteria - Patients with Mild Alzheimer's Disease

• MoCA total score > 15 and < 26 at screening

• CDR 1 at screening

• A clinical diagnosis of mild AD from qualified specialist or from a memory disordersclinic or center

• Score of less than or equal to 85 (1.5 SD below age and education adjusted normativedata) on the RBANS Delayed Memory Index (DMI)

• Positive prior biomarker evidence of Alzheimer's disease (PET imaging or CSF study),if available

• Informed consent provided from partner, caregiver or immediate family member, withverbal assent provided by individual patient.

Exclusion Criteria:

• · Patients with histories of other ocular or neurologic disease that could affectthe results, such as unusually high refractive errors ( > or < 5.0 diopters nativespherical equivalent), age related macular degeneration, diabetic retinopathy,hypertensive retinopathy, retinal vascular disease, glaucoma, optic nerve disease,cystic macular edema, large cataracts or corneal disease that may precludevisualization of the retinal fundus, substantial ocular media opacity, and/orintraocular surgery within 90 days of any study visit will be excluded.

• History of severe brain injury or other known neurologic disease or insult,which, as described by medical records, and/or as determined by the PI'sclinical judgment, has resulted in lasting cognitive sequelae that wouldconfound the assessment and staging of potential neurodegenerative disease.

• Geriatric Depression Scale Short Form (GDS-S 15 Items) score > 6.

• Poorly controlled major depression or another psychiatric disorder within thepast year.

• History of alcohol or substance abuse and/or dependence within the past 2 years (DSM-V criteria).

• History of schizophrenia or a history of psychotic features, agitation orbehavioral problems within the last 3 months, which could lead to difficultycomplying with the protocol.

• Participants who, in the investigator's opinion, will not comply with studyprocedures.

• Any significant systemic illness or unstable medical condition which could leadto difficulty complying with the protocol including:

• History of systemic cancer within the past 5 years (non-metastatic skin cancersare acceptable).

• History of clinically significant liver disease, coagulopathy, or vitamin Kdeficiency within the past 2 years.

• History of myocardial infarction within the past six (6) months or unstable orsevere cardiovascular disease including angina or congestive heart failure (CHF) with symptoms at rest.

• History of stroke(s) with lasting impairment to vision or the visual system,coagulopathy, uncontrolled hypertension (i.e., systolic BP > 170 or diastolicBP > 100) and uncontrolled or insulin requiring diabetes. Blood pressure willbe recorded on the day of each examination.

• Evidence of enlarged ventricles and/or normal pressure hydrocephalus on reviewof medical records or inspection of CT/MRI of the brain based on previousclinical diagnosis (MRI) as noted in their neurological history

• History of Parkinson's disease, Parkinsonism due to multiple system atrophy (MSA), progressive supranuclear palsy (PSP), Shy Drager Syndrome (SDS) or otherneuro-degenerative dementias

• History of symptoms of narrow-angle glaucoma (warning signs include eye pain,restricted vision, blurred vision)

• History of elevated intraocular pressure, or medical record evidence ofintraocular pressure > 20 mm Hg

• Regular (daily) use of narcotics or antipsychotic medications.

• New use of anti-Parkinsonian medications (e.g., sinemet, amantaine,bromocriptine, pergolide and selegiline) within 2 months prior to screening.

• New use of anti-convulsants (e.g., phenytoin, phenobarbital, carbamazepine)within 2 months prior to screening.

• New use of centrally active beta-blockers, narcotics, methyldopa and clonidinewithin 4 weeks prior to screening.

• New use of neuroleptics or narcotic analgesics within 4 weeks prior toscreening.

• New and chronic use of long-acting benzodiazepines or barbiturates within 4weeks prior to screening.

• Use of short-acting anxiolytics or sedative-hypnotics more frequently than 2times per week within 4 weeks prior to screening (note: sedative agents shouldnot be used within 72 hours of the baseline and follow-up visits).

• Initiation or change in dose of an antidepressant lacking significantcholinergic side effects within the 4 weeks prior to screening (use of stabledoses of antidepressants for at least 4 weeks prior to screening is acceptable)

• An anticholinergic burden score of >3 on the Anticholinergic Cognitive BurdenScale (see appendix item 9.19).

• Known hypersensitivity to anticholinergic medications, including tropicamideeye drops.