Recent studies have identified an association between Alzheimer's Disease (AD) and an expansion of DNA content in the brain (prefrontal cortex). This additional DNA content appears to be derived from reverse transcriptase (RT) activity that incorporates genomic cDNAs (gencDNAs) into chromosomes, resulting in multiple copies of full length and shorter cDNAs involving many genes - including the causal AD gene amyloid precursor protein (APP). Accumulation of these APP gencDNAs is associated with AD.

This identifies RT as a promising therapeutic target for the attenuation of AD progression through existing reverse transcriptase inhibitors (RTi's) that have been widely used for treating HIV and hepatitis B. Since this class of drugs has been in the clinic for over 3 decades, there are significant data supporting their post-approval safety for long-term use. However, this has not been specifically addressed in the target population - patients with mild cognitive impairment (MCI), particularly women - who are underrepresented in HIV datasets.

This proposed Phase I safety trial will perform a Special Population Study in a cohort of MCI patients who may benefit from the intervention.

This study aims to (1) evaluate the safety and tolerability of standard dose FTC or Descovy for 3 months in MCI patients; (2) as secondary aims, collect preliminary data on clinical effects of standard dose FTC or Descovy compared to placebo for 3 months on cogntiive function in MCI patients; and (3) collect preliminary data on clinical effects of standard dose FTC or Descovy compared with placebo on AD-associated inflammatory markers.

Participants will be randomized into either Descovy or FTC arms in equal numbers, and receive either active drug or placebo. Participants will orally ingest 1 capsule or tablet (depending on drug arm) daily for the 3 month participation period.

The investigators hypothesise that MCI are not at increased risk of adverse effects due to administration of standard dose FTC or Descovy.

Inclusion Criteria:

• MMSE score of 24 or above.
• CDR-GS of 0 or 0.5 (calculated by the QDRS)
• Diagnosed with MCI, determined by impairment in at least one domain of the neuropsychological test battery without significant dysfunction in activities of daily living OR MCI consistent with the NIA/AA diagnostic criteria.
• Does not have any medical condition (e.g. cardiac, respiratory, gastrointestinal, renal disease) which are not stably and adequately controlled, or which in the opinion of the investigator(s) could affect the subject's safety or interfere with the study assessments.
• Willingness to provide blood sample and neuropsychological testing for the study.
• Ability for the patient to provide informed consent.

Exclusion Criteria:

• Patient who is receiving a prescription of acetylcholinesterase inhibitor (AChEI) and/or Memantine at screening or baseline.
• Patients with a history of HIV or HBV infection, or that test positive for HIV or HBV on screening.
• Pre-existing comorbidities such as Hepatits, cardiovascular disease, or renal insufficiency.
• History of Moderate to severe hepatic impairment indicated by screening AST or ALT > 3x the upper limit of normal (ULN) or total bilirubin > 2x ULN.
• Patients with severe renal impairment, or creatinine clearance ≤ 30 mL/min (calculated by Cockcroft-Gault formulae at screening).
• Co administration of nephrotoxic drugs.
• Current or previous RTi use within the last 2 years.
• Malignant neoplasm, and are undergoing active treatment.
• Participating in other interventional clinical trials during the course of the study.
• Documented history of lactic acidosis and severe hepatomegaly with steatosis.
• Documented history of osteoporosis.

Sensitive health information will be collected as part of this study. Only de-indentified data will be used for study purposes.