Psilocybin for Depression in People With Mild Cognitive Impairment or Early Alzheimer's Disease

Inclusion Criteria:

* Must meet either A) Diagnostic and Statistical Manual of Mental Disorders 5 (DSM-5) criteria for Mild Neurocognitive Disorder due to AD or Major Neurocognitive Disorder due to AD with Mild severity (including probable), or B) meet criteria for MCI including a subjective memory complaint relative to previous functioning and confirmed by Clinical Dementia Rating (CDR) Memory score at screening of \>0.5
* Have Mini-Mental State Examination scores \>18
* Have a Montreal Cognitive Assessment score \<26.
* Have Cornell Scale for Depression in Dementia (CSDD) patient score \>/= 6, or Geriatric Depression Scale-Short Form score ≥ 5, indicating at minimum a mild to moderate degree of distress.
* Acetylcholinesterase inhibitors are allowed so long as the dose has been stable for \> 6 weeks.
* Concurrent pharmacotherapy with selective serotonin reuptake inhibitors (SSRI), serotonin and norepinephrine reuptake inhibitors (SNRI), and/or bupropion is allowed if the type and frequency of the therapy has been stable for at least two months prior to screening. Allowable bupropion doses for participants will be ≤300mg/day.
* Have a close friend or family member willing and able to serve the role of community observer / informant for data collection procedures

Exclusion Criteria:

* Individuals 86 years of age or older will be excluded.
* Currently taking antipsychotics, monoamine oxidase (MAO) inhibitors, or antidepressant medications other than SSRIs, SNRIs, or bupropion. Allowable bupropion doses for participants will be ≤300mg/day.
* Long-acting opioid pain medications (e.g. oxycodone sustained release, morphine sustained release - which are usually taken at 12 hour intervals) will be allowed if the last dose occurred at least 2 hours before psilocybin administration and the next dose was not scheduled until at least 8 hours after psilocybin administration.
* Participants must agree not to take sildenafil, tadalafil, or similar medications within 72 hours of each psilocybin administration, as these medications may potentiate hypotensive reactions to psilocybin
* Cardiovascular conditions: angina, a clinically significant ECG abnormality (e.g. atrial fibrillation or heart-rate corrected QT interval (QTc) \>450msec), Transient Ischemic Attack (TIA) in the last 6 months, stroke, artificial heart valves, or uncontrolled hypertension with resting blood pressure systolic \>150 or diastolic \>95
* Minimum acceptable heartrate at screening is 50 bpm unless the individual is cleared for participation by a cardiologist, in accord with the American College of Cardiology's 2018 guidelines for bradycardia
* Seizure disorder
* Insulin dependent diabetes mellitus
* Renal disease (creatinine clearance \< 40 ml/min using the Cockcroft and Gault equation)
* Baseline liver enzyme elevation \>2x the upper limit of normal
* Current or past history of meeting DSM-5 criteria for Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), or Bipolar I Disorder
* Family (i.e., 1st degree relative) history of Schizophrenia, Psychotic Disorder (unless substance-induced or due to a medical condition), or Bipolar I Disorder
* Past-year hallucinogen use.