Repurposing a Combination Antiretroviral Drug Therapy to Target Retrotransposons and Treat Early Alzheimer's Disease

Prior treatment

• Excluded medications: Antipsychotic medications; antidepressant medications with anticholinergic side effects. Washout from psychoactive medications for at least 8 weeks before screening.

Other illness

• Neurologic diseases: Neurologic disease other than AD such as Parkinson's disease, vascular dementia, dementia with Lewy bodies, frontotemporal dementia, normal pressure hydrocephalus, corticobasal syndrome, malignant brain tumor (within the last 1 year), multiple sclerosis, or significant head trauma (e.g. with loss of consciousness for 30 minutes or more) followed by persistent neurologic deficits, or significant structural brain abnormalities.
• Neuroimaging: Magnetic resonance imaging (MRI) scan evidence of cortical stroke or macrohemorrhage (\>1 cm), strategically located lacunar stroke, or severe small vessel disease.
• Alcohol or substance use disorder or dependence (Diagnostic and Statistical Manual of Mental Disorders version 5 \[DSM 5\] criteria) within the last 2 years.
• Untreated major depressive disorder (within the last 1 year), bipolar disorder, schizophrenia (DSM 5 criteria), or current major psychotic symptoms or behavioral problems.
• Any systemic illness or unstable medical conditions, which could affect valid cognitive and self-report assessments.
• Conditions which, in the opinion of the investigator, would jeopardize safety or impact the validity of the study results.
• Person who is positive for HBV Surface Antigen.
• Person with a history of osteoporosis or osteomalacia.
• Person taking FTC-TDF for pre-exposure prophylaxis or treatment of HIV.

Lab values

• Laboratory abnormalities: AST or ALT \> 3 times the upper limit of normal; creatinine clearance \<60 mL/min; HbA1C \> 8.5%.

Other

• Participation in an investigational trial within the past 3 months or 5 half-lives, whichever is shorter

• Meets National Institute on Aging-Alzheimer's Association clinical diagnostic criteria for mild cognitive impairment (MCI) or AD dementia.
• Has evidence of AD assessed by plasma p-tau217. Prior cerebrospinal fluid (CSF) or positron emission tomography (PET) amyloid testing (obtained clinically or through previous research) from the past 2 years may be used for eligibility with approval from study investigators.
• Clinical Dementia Rating (CDR) global score of 0.5 or 1.
• Mini-Mental State Exam (MMSE) score of 18 to 30 (inclusive).
• 15-item Geriatric Depression Scale (GDS) score of \< 6.
• Impaired memory performance below an education adjusted cut-off score on the Logical Memory II subscale delayed paragraph recall of Wechsler Memory Scale-Revised (WMS-R) (≥16 years: ≤8; 8-15 years: ≤4; 0-7 years: ≤2).
• May take FDA approved medications for the treatment of AD dementia, but if taking such medications, they must be stable for at least 8 weeks before screening (for cholinesterase inhibitors and/or memantine) or 6 months (for lecanemab or donanemab).
• Has adequate visual and auditory acuity to participate in neuropsychological testing and other study outcomes.
• Has availability of a study partner who has regular contact with the participant and knows him/her well.
• Is willing and able to participate in all assessments in English.
• Is capable of providing written informed consent