Neuroplasticity Enhancement From Cognitive Training Reinforced by Psilocybin

* INCLUSION CRITERIA:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

* Capacity to provide informed consent.
* Stated willingness to comply with all study procedures and availability for the duration of the study.
* Male or female, age \>= 65 years old.
* Cognitive Status:

  * Early-stage AD population: Meets the 2024 Alzheimer s Association Workgroup revised criteria for diagnosis and staging of AD (symptomatic cognitive impairment consistent with amnestic MCI or mild AD dementia) with a CDR score of 0.5-1 (including 0.5 for the memory box) and a Montreal Cognitive Assessment (MoCA) score of 20-25.
  * Cognitively normal population: No cognitive impairment based on history and examination, with a CDR score of 0 and MoCA score \>= 26.
* For participants with early-stage AD, evidence of underlying AD pathology by the only FDA-approved blood-based test, Lumipulse G p217-Tau/Abeta42 ratio \>= 0.00738. Alternatively, participants who previously underwent amyloid PET or CSF testing for diagnosis of AD (to qualify for treatment with anti-amyloid monoclonal antibodies or for any other reason) may provide report of the amyloid PET scan or results of CSF analysis compatible with underlying AD pathophysiology; Lumipulse G p217-Tau/Abeta42 will still be measured to maintain consistency in study assessments, but values \< 0.00738 will not disqualify them.
* Absence of serious neuropsychiatric symptoms, defined as a score of 0 on Delusions and Hallucinations items and a score \<= 2 on Anxiety, Aggression, Irritability, and Disinhibition items of the Neuropsychiatric Inventory Questionnaire (NPI-Q).
* Acetylcholinesterase inhibitors and/or memantine are permitted (alone or in combination) provided the dose(s) have been stable for (Bullet) 6 weeks prior to screening and remain stable through the psilocybin dosing period and primary outcome assessments, unless a change is medically necessary.
* Concurrent pharmacotherapy with a single selective serotonin reuptake inhibitor (SSRI), serotonin and norepinephrine reuptake inhibitor (SNRI), tricyclic anti-depressant (TCA) or monoamine oxidase inhibitor (MAOI) is allowed if the participant is willing and able to taper off this medication after Visit 1 (Screening) and stay off it for a washout period of at least 7 +/- 2 days prior to Visit 2 (Baseline) and at least 14 +/- 2 days prior to Visit 3 (for the Psilocybin + Cognitive Training group) or Visit 4 (for the Cognitive Training alone group). Bupropion (\<= 300 mg/day) is permitted without taper or washout if the dose has been stable for \>= 6 weeks before screening.
* Absence of active suicidal ideation with plan/intent and no suicidal behavior within the past 6 months, as defined by Columbia-Suicide Severity Rating Scale (C-SSRS) of 0 or 1. Participants with passive ideation (severity 1) may be included only if risk is judged low, a safety plan is documented, and there is no suicidal behavior in the prior 6 months.
* For the early-stage AD population, participation of a study partner who is willing and able to serve as a medical history informant, accompany participants during visits, and provide psychological support following psilocybin sessions. For the cognitively normal population, participation of a study partner will be encouraged, but not mandated as eligibility criterion.
* Ability to take oral medication.
* Pregnancy prevention:

  * Participants of childbearing potential must have a negative urine pregnancy test at screening and prior to psilocybin on Visits 3 and 7, and agree to use highly effective birth control beginning at least 14 days before any psilocybin dosing day and continuing through 30 days after the last psilocybin dose.
  * Male participants with partners of childbearing potential must agree to use condoms and to ensure their partner uses a highly effective contraceptive method during the same window. Sperm donation is not permitted during the study and for 30 days after the last psilocybin dose.

EXCLUSION CRITERIA:

An individual who meets any of the following criteria will be excluded from participation in this study:

-Medical history

--Neurological disorders (besides AD): Brain disorders, either previously diagnosed or revealed through screening exams or baseline neuroimaging, including:

* Stroke (except single asymptomatic old lacune)
* Transient Ischemic Attack (TIA) within the past year, unless work-up shows no ongoing risk
* Extensive microvascular pathology or microbleeds
* Multiple sclerosis or demyelinating disorders
* Parkinson s disease or movement disorders (e.g., Multiple Systems Atrophy, Progressive Supranuclear Palsy)
* Brain tumors
* History of meningitis or encephalitis
* History of moderate/severe traumatic brain injury (Glasgow Coma Scale \<= 12)
* Other dementias
* Epilepsy

Stable, mild neurological conditions (e.g., migraine, essential tremor, peripheral neuropathy) may be allowed at the discretion of the medically responsible investigator.

--Psychiatric disorders:

* Current or past moderate-to-severe mood disorders
* History of psychotic disorders unless remote, short-lived, and directly attributable to medication misuse or overdose
* Active suicidal ideation (C-SSRS severity 2-5) within the past 1 month or any suicidal behavior within the past 6 months; or current elevated acute risk in the opinion of the medically responsible investigator
* Severe PTSD, defined as a Primary Care PTSD Screen for DSM-5 (PC-PTSD-5) score \>= 4 in men or \>= 3 in women
* Anxiety or personality disorders, if moderate to severe, as determined by the medically responsible investigator.

Mild depression and/or anxiety may be permitted if successfully treated with psychotherapy and/or single anti-depressant. Participants taking a single SSRI, SNRI, TCA, or MAOI may still be eligible only if they are willing and able to taper off this medication after Visit 1 (Screening) and complete a washout period of at least 7 +/- 2 days prior to Visit 2 (Baseline) and at least 14 +/- 2 days prior to Visit 3 (for the Psilocybin + Cognitive Training group) or Visit 4 (for the Cognitive Training alone group). Tapering requires participant agreement, prescribing-clinician agreement, and investigator determination of no elevated risk. A written taper/monitoring plan and point of contact must be documented. Weekly safety check-ins will assess discontinuation symptoms, mood/anxiety, sleep, and suicidality. If clinically significant worsening occurs, taper may be slowed, paused, stopped, or the participant excluded for safety.

* Cardiovascular conditions:

  * Any history of coronary artery disease
  * Clinically significant electrocardiographic (EKG) abnormalities (e.g., atrial fibrillation/flutter, QTc \> 450 ms, evidence of myocardial infarct history, high-grade conduction disease, or other rhythm/conduction abnormalities). For EKG abnormalities other than QTc \> 450 ms, clinical significance may be corroborated by transthoracic echocardiogram (TTE).
  * Uncontrolled hypertension (systolic blood pressure (SBP) \> 150 mmHg or diastolic blood pressure (DBP) \> 95 mmHg) confirmed after \>=5 minutes seated rest using 3 readings averaged.
  * Resting heart rate (HR) \<= 55 bpm or \> 100 bpm or clinically significant arrythmia: HR will be assessed concurrently with the blood pressure protocol above.
  * Clinically significant cardiomyopathy (e.g., hypertrophic, dilated, restrictive) or heart failure
  * Moderate to severe valvular heart disease (valvulopathy) or pulmonary hypertension
* Metabolic disorders:

  * Insulin-dependent diabetes mellitus
  * Renal impairment (eGFR \< 60 ml/min/1.73 m2)
  * Liver function tests \> 2x upper limit of normal
* Infectious \& Hematologic Conditions:

  * Positive HIV, HBV, or HCV status
  * Anemia (HGB \< 12 g/dL in men, \< 11 g/dl in women)
* Poor venous access

  -Medications Exclusions
* Absolute

  * Typical \& atypical antipsychotics
  * Multiple antidepressants medications (i.e., combinations of SSRIs, SNRIs, MAOIs, TCAs and bupropion). Bupropion (\<= 300 mg/day) is permitted without taper or washout if the dose has been stable for \>= 6 weeks before screening.
* Relative

  * Benzodiazepines and non-benzodiazepine sedative-hypnotics (e.g., zolpidem, eszopiclone):

    * Regular use: participants must be willing and able to taper off and remain off for at least 14 +/- 2 days prior to Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group), due to potential confounding effects on EEG recordings and sleep architecture and potential attenuation of the acute psilocybin experience. Because benzodiazepine withdrawal can cause clinically significant symptoms (and, rarely, seizures), tapering must be gradual. Discontinuation schedule will be directed by the medically responsible investigator in coordination with the prescribing clinician per participant wishes; participants with evidence of physiologic dependence or for whom safe tapering is not feasible within the study timeline will not be eligible for further study participation.
    * Intermittent PRN use: participants may be eligible if they can hold these medications for at least 72 hours prior to each psilocybin dosing session (for the psilocybin + cognitive training group) and avoid use during the overnight EEG recording window.
  * Sleep-inducing medications (e.g., trazodone, sedative-hypnotics) should not be taken for at least 14 +/- 2 days before Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group) (due to potential confounding effects on EEG recordings and sleep architecture)
  * Melatonin (and similar over-the-counter sleep aids) should not be taken for at least 72 hours prior to Visit 3 (for the psilocybin + cognitive training group) or Visit 4 (for the cognitive training alone group), due to potential confounding effects on EEG recordings
  * Mood stabilizers (e.g., lithium), long-acting opioids (unless they are willing and able to taper off after Visit 1 (Screening) and have stayed off for a washout period of at least 7 +/- 2 days prior to Visit 2 (Baseline) and at least 14 +/- 2 days prior to Visit 3 (for the psilocybin + cognitive training group)). Participants taking lithium will be eligible only if (i) lithium is being used for a condition where supervised discontinuation is clinically appropriate (e.g., augmentation for unipolar depression or another non-bipolar indication), (ii) there is no history of bipolar disorder/mania, and (iii) the prescribing clinician confirms that a gradual taper and washout can be completed safely before baseline/dosing. During any lithium taper/washout, participants will be monitored for symptom recurrence and safety concerns; if relapse risk is unacceptable, participants will be excluded from further study participation.
  * Sildenafil, tadalafil, or similar medications should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
  * UGT1A10 and 1A9 inhibitors (e.g., diclofenac, probenecid) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
  * Alkaline phosphatase inhibitors (e.g., cinacalcet) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
  * Serotonin agonists (e.g., migraine medications like triptans) should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)
  * Serotonergic supplements, such as St. John s Wort, should not be taken within 72 hours of psilocybin administration (for the psilocybin + cognitive training group)

For the purposes of these medication criteria, regular use means scheduled/daily use or PRN use on \>= 3 days per week over the prior 4 weeks. Intermittent PRN use means \<= 1 day per week on average over the prior 4 weeks (and no evidence of physiologic dependence, in the judgment of the medically responsible investigator).

* Substance Use History

  * Psychedelic substance use within the past year by self-report. This criterion aims to minimize potential confounding effects of recent psilocybin exposure on study outcomes.
  * Positive urine drug screen for substances of use, including cannabis (THC), cocaine, amphetamines, methamphetamines, MDMA (ecstasy), opioids, phencyclidine (PCP), barbiturates, and benzodiazepines.
  * Participants with a positive urine screen for benzodiazepines may be eligible only if they hold a valid prescription and the participant s use pattern meets the protocol s benzodiazepine criteria (intermittent PRN use). Eligibility will be determined based on prescription verification and medication history, and participants must comply with required holds/tapers (e.g., intermittent PRN users must hold benzodiazepines for \>= 72 hours prior to each psilocybin dosing session and avoid use during overnight EEG recording windows; regular users must complete a taper and be off benzodiazepines for at least 14 +/- 2 days prior to required visits). Because benzodiazepine metabolites may remain detectable after discontinuation, a positive screen alone will not be grounds for exclusion or discontinuation from the study.
  * Participants testing positive for cannabis (THC) may be eligible for re-screening after a 4-8-week washout period.
* Anti-Amyloid Monoclonal Antibodies

  * Participants actively receiving FDA-approved IV or SC anti-amyloid monoclonal antibodies (including lecanemab, donanemab, or aducanumab) will be excluded.
  * Participants who previously received any anti-...