Inclusion criteria (patients):
• Age 50-99
• English speaking
• Diagnosis of dementia or cognitive impairment or memory loss
• Clinical Dementia Rating (CDR) scale score between 0.5 and 2.0
• Actively involved caregiver
• Resides at home, assisted living facility, or long-term care facility Inclusion criteria (caregivers)
• English speaking
• Age 18 and older
• Contact with patient at least 1 time a week
• Has access to a working telephone Exclusion criteria (patients):
• Dementia due to cerebrovascular disease as primary cause
• History of head and neck cancer or other structural deformity that can affect swallowing
• Allergy to barium
• Currently breastfeed or pregnant or planning to become pregnant Exclusion criteria (caregivers):
• Lacks ability to give consent

• Female, post-menopausal
• Probable AD or MCI due to AD according to NIA-AA criteria
• Taking a stable dose of a cholinesterase inhibitor such as donepezil/Aricept and dosage likely to remain stable throughout the trial
• MOCA > 11 or blind MOCA > 8 (inclusive) at screening visit
• Hachinski score <5 supporting clinical judgment that dementia is not of vascular origin
• Fluent in English
• has a study partner / caregiver who interacts with the subject for at least 5 hours per week on average and can participate in evaluations
• Presence based on exam, history or MRI of significant brain disease other than AD such as schizophrenia, epilepsy, Parkinson's disease or large territory stroke
• Current substance abuse in accord with DSM V criteria
• Significantly depressed (Geriatric Depression Scale > 10)
• Physical or psychological MRI contraindications, or likely unable to tolerate neuroimaging
• Taking other medications known to affect serum sex hormone or gonadotropin concentrations such as estrogen and/or progesterone for hormone replacement therapy, goserelin or danazol
• Presence of significant systemic illness likely to interfere with participation in or completion of the study or to affect study results such as cancer within 5 years (other than non-melanoma skin cancer), autoimmune disease, recent myocardial infarction, signs/symptoms of organ failure based on history, ECG, screening laboratory and/or physical exams
• Receiving other investigational drugs within 30 days or 5 half-lives prior to randomization, whichever is longer
• Ever treated with active or passive immunization for AD (e.g. Lecanemab) due to unknown alterations in systemic and brain inflammation, which may confound results

• 40-75 years of age (inclusive)
• Free of chronic disease
• Comprehension of the protocol as indicated by an ability to respond to questions about the study after reading the consent form.
• Able to use and be contacted by telephone.
• Able to speak, read, and understand English, and complete a questionnaire in English
• Independently mobile
• Pregnancy
• Heart disease (history, abnormal ECG, abnormal stress ECG)
• Cerebrovascular disease (history)
• Cancer (history)
• Chronic respiratory disease (history, forced expiratory volume at one second/forced vital capacity [FEV1/FVC] < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, alanine transaminase [ALT] > 52 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, oral glucose tolerance test [OGTT] ≥ 200 mg/dl at 2 hrs)
• Impaired kidney function (eGFR ,45 mL/min)
• B12 lab values outside of normal range (<193 or >982 pg/mL)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine > 1.4)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Those on glucose lowering drugs
• Those planning to have imaging that requires intravenous contrast dye (within 6 weeks) or are on any of the following medications since they are contraindicated with the use of metformin: Dofetilide, Lamotrigine, Pegvisomant, Somatropin, Trimethoprim, Trospium, Gatifloxacin, Cephalexin, Cimetidine, Dalfampridine
• Tobacco use
• Allergies to lidocaine or metformin

Inclusion criteria: Participants must meet all of the following criteria to be included in this study: 1. Male or female, age 55 to 80 years inclusive at the time of informed consent, with a plasma biomarker result that is predictive of intermediate or elevated brain amyloid at Screening or known before Screening to have elevated or intermediate amyloid according to previous PET, cerebrospinal fluid (CSF), or plasma testing • Those 55 to 64 must have 1 of the following additional risk factors, given the relatively low rates of amyloid positivity less than (<) 65 years, before screening:
• First degree relative diagnosed with dementia onset before age 75, or
• Known to possess at least 1 apolipoprotein E4 variant (APOE4) allele, or
• Known before screening to have elevated brain amyloid according to previous plasma biomarker results, PET imaging, or CSF testing 2. Global Clinical Dementia Rating (CDR) score of 0 at screening 3. Mini Mental State Examination score greater than or equal to (>=) 27 (with educational adjustments) at screening. 4. Wechsler Memory Scale-Revised Logical Memory subscale II (WMS-R LM II) score at screening of >=6 5. A45 Trial: Elevated brain amyloid pathology by amyloid PET: defined as approximately greater than (>) 40 Centiloids on screening scan A3 Trial: Intermediate levels of brain amyloid pathology by amyloid PET: defined as approximately 20 to 40 Centiloids on screening scan 6. Has a study partner that is willing to participate as a source of information and has approximately weekly contact with the participant (contact can be in-person, via telephone or electronic communication). The study partner must have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily function 7. Provide written (or electronic, if allowed per country-specific regulations) informed consent 8. Willing and able to comply with all aspects of the protocol For extension phase : 1. Completed the Core Study, or meet the following progression criteria during the Core Study:
• Two consecutive CDR visits with Global Scores > zero when measured at least 6 months apart within the Core Study
• The principal investigator's confirmation that the participant has clinically declined consistent progression to EAD 2. Must continue to have a study partner who is willing and able to provide follow-up information on the participant throughout the course of the Extension Phase. The study partner must provide separate written informed consent for the Extension Phase. Study partners must continue to have sufficient contact such that the investigator feels the study partner can provide meaningful information about the participant's daily functions 3. Provide written informed consent for the Extension Phase. If a participant lacks capacity to consent in the investigator's opinion, the participant's assent should be obtained, if required and in accordance with local laws, regulations, and customs, plus the written informed consent of a legal representative (capacity to consent and the definition of a legal representative should be determined in accordance with applicable local laws and regulations). In countries where local laws, regulations, and customs do not permit participants who lack capacity to consent to participate in this study (example, Spain), they will not be enrolled 4. Willing and able to comply with all aspects of the protocol Exclusion criteria: Participants who meet any of the following criteria will be excluded from this study: 1. Females who are breastfeeding or pregnant at screening or baseline 2. Females of childbearing potential who: • Within 28 days before study entry, did not use a highly effective method of contraception For sites outside of Europe, it is permissible that if a highly effective method of contraception is not appropriate or acceptable to the participant, then the participant must agree to use a medically acceptable method of contraception 3. History of transient ischemic attacks (TIA), stroke, or seizures within 12 months of screening 4. Current or history within the past 2 years of psychiatric diagnosis or symptoms that, in the opinion of the investigator, could interfere with study procedures 5. Contraindications to 3 Tesla magnetic resonance imaging (MRI) scanning, including cardiac pacemaker/defibrillator, ferromagnetic metal implants (example, in-skull and cardiac devices other than those approved as safe for use in MRI scanners), or exhibit other significant pathological findings on brain MRI at Screening 6. Hypersensitivity to any monoclonal antibody treatment 7. Any immunological disease which is not adequately controlled, or which requires treatment with immunoglobulins, systemic monoclonal antibodies (or derivatives of monoclonal antibodies), systemic immunosuppressants, or plasmapheresis during the study 8. Bleeding disorder that is not under adequate control (including a platelet count <50,000 or international normalized ratio [INR] >1.5) at screening 9. Results of laboratory tests conducted during screening that are outside the following limits:
• Thyroid stimulating hormone (TSH) above normal range
• Abnormally low (below lower limit of normal [LLN]) serum vitamin B12 levels for the testing laboratory (if participant is taking vitamin B12 injections, level should be at or above the LLN for the testing laboratory). A low vitamin B12 is exclusionary, unless the required follow-up labs (homocysteine and methylmalonic acid [MMA]) indicate that it is not physiologically significant 10. Known to be human immunodeficiency virus (HIV) positive 11. Any other clinically significant abnormalities that in the opinion of the investigator require further investigation or treatment or may interfere with study procedures or safety 12. Malignant neoplasms within 3 years of screening (except for basal or squamous cell carcinoma in situ of the skin, or localized prostate cancer in male participants with treatment cycles completed at least 6 months before screening). Participants who had malignant neoplasms but who have had at least 3 years of documented uninterrupted remission before screening need not be excluded 13. Answer "yes" to Columbia-Suicide Severity Rating Scale (C-SSRS) suicidal ideation Type 4 or 5, or any suicidal behavior assessment within 6 months before screening, at screening, or at baseline, or has been hospitalized or treated for suicidal behavior in the past 5 years before screening 14. Known or suspected history of drug or alcohol abuse or dependence within 2 years before screening or a positive urine drug test at screening. Participants who test positive for benzodiazepines, opioids, or tetrahydrocannabinol (THC) in urine drug testing need not be excluded unless in the clinical opinion of the investigator this is due to potential drug abuse 15. Taking prohibited medications 16. Participation in a clinical study involving:
• Any anti-amyloid plaque lowering immunotherapy (example, therapeutic monoclonal antibody or active anti-amyloid vaccine) at any time, unless it can be documented that the participant was randomized to placebo or never received study drug
• Any immunoglobulin therapy, or vaccine within 6 months before Screening, unless it can be documented that the participant was randomized to placebo or never received study drug
• Lecanemab
• Any new chemical entities or investigational drug for AD within 6 months before randomization unless it can be documented that the participant received only placebo
• Any other investigational medication or device study in the 8 weeks or 5 half-lives (whichever is longer) of the medication before randomization unless it can be documented that the participant was in a placebo treatment arm 17. Planned surgery during the pre-randomization phase or within 3 months of randomization, which requires general anesthesia For extension phase: 1. Discontinued from the Core Study or from study treatment 2. Under study drug interruption due to ARIA or other AE at the time of transition to the extension phase

Inclusion Criteria 1. Subject has given written informed consent 2. Male or female, at least 18 years of age 3. Diagnosis and treatment of HF (regardless of left ventricular ejection fraction (LVEF)) for ≥ 3 months and NYHA Class III HF at time of Screening 4. Subjects should be on stable, optimally titrated medical therapy for at least 30 days, as recommended according to current American Heart Association (AHA)/American College of Cardiology (ACC) guidelines as standard-of-care for HF therapy in the United States, or current European Society of Cardiology (ESC) guidelines for HF treatment in Europe, with any intolerance documented. 5. HF related hospitalization, HF treatment in a hospital day-care setting, or urgent outpatient clinic HF visit for IV diuretics within 12 month (last hospitalization should be 30 days before Screening/Enrollment) and/or N-terminal pro B-type Natriuretic Peptide (NT proBNP) at time of Screening/ Enrollment defined as: 1. Subjects with LVEF ≤ 50%: NT-proBNP ≥ 1500 pg/mL. 2. Subjects with LVEF > 50%: NT-proBNP ≥ 800 pg/mL . Thresholds for NT-proBNP (for both LVEF ≤ 50% and LVEF > 50%) will be corrected for body mass index (BMI) using a 4% reduction per BMI unit over 25 kg/m2 6. Subjects should be on diuretic therapy 7. Subjects who are physically able to hold the myCordella™ Patient Reader unit (approximate weight 1.3lb) against the ventral thoracic surface for up to 2 minutes per day while in a seated position, as well as dock and undock the myCordella™ Patient Reader 8. Subjects with sufficient eyesight, hearing, and mental capacity to respond to the myCordella™ Patient Reader's audio/visual cues and operate the myCordella™ Patient Reader 9. Subject has sufficient Cellular and/ or Wi- Fi Internet coverage at home 10. Subject agrees to return to the treating Investigator for all scheduled follow up visits and can return to the hospital for follow up Exclusion Criteria 1. Intolerance to all neuro-hormonal antagonists (i.e., intolerance to ACE-I, ARB, ARNI, and beta-blockers) due to hypotension or renal dysfunction 2. ACC/AHA Stage D refractory HF (including having received or currently receiving pharmacologic circulatory support with inotropes) 3. Subjects with history of recurrent pulmonary embolism ( ≥2 episodes within 5 years prior to Screening Visit) and/or deep vein thrombosis (< 3 month prior to Screening Visit) 4. Subjects who have had a major cardiovascular (CV) event (e.g. myocardial infarction, stroke) within 3 months of the Screening Visit 5. Unrepaired severe valvular disease 6. Subjects with significant congenital heart disease that has not been repaired and would prevent implantation of the Cordella PA sensor or mechanical/tissue right heart valve(s) 7. Subjects with known coagulation disorders 8. Subjects with a hypersensitivity or allergy to platelet aggregation inhibitors including aspirin, clopidogrel, prasugrel, and ticagrelor; or patients unable to take dual antiplatelet or anticoagulants for one-month post implant 9. Known history of life threatening allergy to contrast dye 10. Subjects whereby RHC is contraindicated 11. Subjects with an active infection at the Sensor Implant Visit 12. Subjects with a Glomerular Filtration Rate (GFR) <25 ml/min or who are on chronic renal dialysis 13. Implanted with Cardiac Resynchronization Therapy (CRT)-Pacemaker (CRT-P) or CRT-Defibrillator (CRT-D) for less than 90 days prior to screening visit 14. Received or are likely to receive an advanced therapy (e.g. mechanical circulatory support or lung or heart transplant) in the next 12 months 15. Subjects who are pregnant or breastfeeding 16. Subjects who are unwilling or deemed by the Investigator to be unwilling to comply with the study protocol, or subjects with a history of non-compliance 17. Severe illness, other than heart disease, which would limit survival to <1 year 18. Subjects whose clinical condition, in the opinion of the Investigator, makes them an unsuitable candidate for the study 19. Subjects enrolled in another investigational trial with an active treatment arm 20. Subject who is in custody by order of an authority or a court of law

• 65 years of age or older
• Ability to provide informed consent or the presence of a legally authorized representative (LAR) who can consent on behalf of the patient
• Post-menopausal (female participants)
• Not pregnant
• Allergy to barium
• Prior surgery to the head and neck region affecting swallowing-related structures
• Prior chemotherapy or radiation treatment to the head and neck region
• Prior cerebral vascular accident with resulting persistent dysphagia
• Non-English speaking

• For women of childbearing potential, agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception, during the study for at least 28 days after the last fluorescein injection for the fluorescein angiography (FA) administration
• Study eye: High-risk intermediate AMD
• Macular disease in either eye with subretinal deposits not typical of AMD
• Pigmentary abnormalities of the retina in either eye not typical of AMD
• Atrophy in either eye due to causes other than AMD
• Study eye: Any concurrent or history of ocular or intraocular condition
• Study eye: Intraocular surgery, including cataract surgery, within 3 months prior to Day 1
• Study eye: Retinal tears or peripheral retinal breaks within 3 months prior to Day 1
• Study eye: Concurrent or history of retinal laser photocoagulation or anti-vascular endothelial growth factor (anti-VEGF) treatment for exudative MNV, diabetic macular edema, retinal vein occlusion, or proliferative diabetic retinopathy
• Study eye: Presence of choroidal nevus with overlying drusen in the circle with a radius 3600 micrometer centered on the fovea
• Study eye: Previous participation in interventional clinical trials for GA or early stages of AMD, except for vitamins and minerals, regardless of the route of administration within the last 6 months, except for sham-arm participants
• Study eye: History of glaucoma surgery, corneal transplant, retinal pigment epithelium tear, retinal tear that involves the macula, retinal detachment
• Either eye: Uncontrolled progressive glaucoma
• Either eye: Moderate or severe non-proliferative diabetic retinopathy or proliferative diabetic retinopathy
• Either eye: History of recurrent infectious or inflammatory ocular disease
• Any concurrent or history of taking medications that can induce retinal toxicity

Adults aged 55-80 years old
• Free of overt chronic disease
• Willing to provide informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Able to use and be contacted by the telephone
• Ability to take oral medication
• Insulin Resistant defined by HOMA-IR greater than or equal to 1.5 or prediabetic defined as:
• impaired fasting glucose (100-125 mg/dL)
• HbA1c (5.7-6.4 percent)
• glucose 2 hours after a 75 gram oral glucose tolerance test (140-199 mg/dL)
• previous diagnosis of prediabetes in the past year
• Not planning to change diet or physical activity status
• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), clinical chemistry and urinalysis
• Females of childbearing potential must have a negative urine pregnancy test before DEXA and before the oral glucose tolerance test (OGTT). A female of child-bearing potential is any woman (regardless of sexual orientation, having undergone a tubal ligation, or remaining celibate by choice) who meets the following criteria:
• Has not undergone a hysterectomy or bilateral oophorectomy; or
• Has not been naturally postmenopausal for at least 12 consecutive months (i.e., has had menses at any time in the preceding 12 consecutive months)
• Women of childbearing potential in sexual relationships with men must use an acceptable method of contraception from 30 days prior to enrollment until 4 weeks after completing study visits. Males must agree to avoid impregnation of women during and for four weeks after completing study visits through use of an acceptable method of contraception.
• Note: Includes, but is not limited to, barrier with additional spermicidal foam or jelly, intrauterine device, hormonal contraception (started at least 30 days prior to study enrollment), intercourse with men who underwent vasectomy. Younger Adults aged 18-35 (No intervention)
• Free overt chronic disease
• Pregnancy or breastfeeding
• Heart disease
• Cerebrovascular disease
• Cancer or less than 5 years in remission
• Chronic respiratory disease
• Chronic liver disease
• Diabetes
• Alzheimer's
• Chronic kidney disease
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors
• Taking strong CYP3A4 activators
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, and other foods that are known to inhibit cytochrome P450 and PgP activity and may increase everolimus exposures and should be avoided during treatment
• Subjects who are not willing to restrict the use of St. John's Wort (Hypericum perforatum) because it may decrease everolimus exposure unpredictably
• Subjects who are not willing to avoid blood donations 8 weeks prior to the first visit and 8 weeks after the last visit
• Contraindications with MRI which could include metal on your body
• Low white-blood cell count (<4,000 cell/µL)
• History of stomatitis or ulcers in the mouth
• Those on glucose lowering drugs
• Participating in intensive exercise training program (high to moderate intensity exercise greater than 150 minutes per week) or planning to start new exercise program during study period
• Tobacco use
• Allergies to lidocaine or everolimus
• Subjects currently enrolled in other clinical trials. Subjects may be eligible after a washout period that will be reviewed on a case by case basis.
• Individuals with limited English proficiency

• Middle-age adults free of overt chronic disease
• Willing to provide informed consent
• Willing to comply with all study procedures and be available for the duration of the study
• Able to use and be contacted by telephone
• Ability to take oral medication
• Not planning to change diet or physical activity status
• Adequate organ function as indicated by standard laboratory tests: hematology (complete blood count), and clinical chemistry
• Males must agree to avoid impregnation of women during and for four weeks after completing study visits through use of an acceptable method of contraception
• Heart disease (history, abnormal ECG)
• Cerebrovascular disease (history)
• Cancer or less than 5 years in remission (history)
• Chronic respiratory disease (history, FEV1/FVC < 70, FEV1 < 80% predicted)
• Chronic liver disease (history, abnormal blood liver panel, ALT >104 IU/L, AST >80 IU/L)
• Diabetes (history, HbA1C ≥ 6.5, fasting blood glucose≥126 mg/dl, OGTT ≥ 200 mg/dl at 2 hrs.)
• Alzheimer's (history)
• Chronic kidney disease (history, abnormal blood kidney panel including serum creatinine>1.4, eGFR≤60 ml/min/1.73m2)
• Problems with bleeding, on medication that prolongs bleeding time (if subject cannot safely stop prior to biopsy)
• Taking azathioprine (Imuran), cyclosporine (Gengraf, Neoral, Sandimmune), dexamethasone (Decadron, Dexpak), methotrexate (Rheumatrex, Trexall), prednisolone (Orapred, Pediapred, Prelone), prednisone (Sterapred), sirolimus (Rapamune), and tacrolimus (Prograf) or other medications proposed to lower the immune system
• Taking strong or moderate CYP3A4 and/or P-glycoprotein (PgP) inhibitors such as ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole, amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem
• Taking strong CYP3A4 activators such as phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital
• Subjects who are not willing to restrict the use of grapefruit, grapefruit juice, cannabidiol (CBD) and other foods/substances that are known to inhibit cytochrome P450 and PgP activity and may increase everolimus exposures and should be avoided during treatment
• Subjects who are not willing to restrict the use of St. John's Wort (Hypericum perforatum) because it may decrease everolimus exposure unpredictably.
• Subjects who are not willing to avoid blood donations 8 weeks prior to the first visit and 8 weeks after the last visit
• Low white-blood cell count (<4,000 cell/µL)
• History of stomatitis or ulcers in the mouth
• Those on glucose lowering drugs
• Participating in intensive exercise training program (high to moderate intensity exercise greater than 150 minutes per week) or planning to start new exercise program during study period
• Tobacco use
• Allergies to lidocaine, sirolimus, or everolimus
• Subjects currently enrolled in other clinical trials. Subjects may be eligible after a washout period that will be reviewed on a case-by-case basis.
• Individuals with limited English proficiency
• Subjects who are planning to have elective surgery 12 weeks prior to or during the intervention