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 antid