NRTIs for Alzheimer's Disease: Targeting Type-I Interferon-Driven Neuroinflammation (NCT04500847)

ClinicalTrials.gov Identifier: [NCT04500847](https://clinicaltrials.gov/study/NCT04500847)

Trial Overview

| Attribute | Details |
|-----------|---------|
| Phase | Phase 1 |
| Status | Completed |
| Sponsor | Butler Hospital (Providence, Rhode Island) |
| Intervention | Emtriva (emtricitabine) and lamivudine (Nucleoside Reverse Transcriptase Inhibitors) |
| Indication | Alzheimer's Disease |
| Study Design | Single-arm, open-label |
| Enrollment | 35 participants |
| Location | Butler Hospital, Providence, Rhode Island |

Study Title

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) as a Novel Therapeutic Approach for Alzheimer's Disease

Mechanism of Action

NRTIs and the Viral Reservoir Theory

This clinical trial investigates the repurposing of FDA-approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs) — specifically emtricitabine (Emtriva) and lamivudine — for the treatment of Alzheimer's disease. The rationale is grounded in the viral reservoir hypothesis and emerging evidence linking type-I interferon signaling to neurodegeneration[@brouwers2020].

Endogenous Retrovirus Theory

The viral reservoir theory proposes that:

ClinicalTrials.gov Identifier: [NCT04500847](https://clinicaltrials.gov/study/NCT04500847)

Trial Overview

| Attribute | Details |
|-----------|---------|
| Phase | Phase 1 |
| Status | Completed |
| Sponsor | Butler Hospital (Providence, Rhode Island) |
| Intervention | Emtriva (emtricitabine) and lamivudine (Nucleoside Reverse Transcriptase Inhibitors) |
| Indication | Alzheimer's Disease |
| Study Design | Single-arm, open-label |
| Enrollment | 35 participants |
| Location | Butler Hospital, Providence, Rhode Island |

Study Title

Nucleoside Reverse Transcriptase Inhibitors (NRTIs) as a Novel Therapeutic Approach for Alzheimer's Disease

Mechanism of Action

NRTIs and the Viral Reservoir Theory

This clinical trial investigates the repurposing of FDA-approved Nucleoside Reverse Transcriptase Inhibitors (NRTIs) — specifically emtricitabine (Emtriva) and lamivudine — for the treatment of Alzheimer's disease. The rationale is grounded in the viral reservoir hypothesis and emerging evidence linking type-I interferon signaling to neurodegeneration[@brouwers2020].

Endogenous Retrovirus Theory

The viral reservoir theory proposes that:

Type-I Interferon Pathway Dysregulation

The type-I interferon response is a critical component of the innate immune system and has emerged as a key pathway in AD pathogenesis[@main2020]:

Innate Immunity Connection

The innate immune system plays a dual role in Alzheimer's disease:

| Innate Immune Component | Role in AD | NRTI Mechanism |
|------------------------|------------|----------------|
| Microglia | Chronic activation drives neuroinflammation | Reduced interferon signaling may shift microglia to homeostatic state |
| Astrocytes | Reactive astrogliosis contributes to pathology | Decreased inflammatory triggers |
| Complement system | C1q, C3 involved in synaptic pruning | Potential reduction in complement activation |
| Toll-like receptors (TLRs) | Recognize viral RNA/DNA analogs | Reduced TLR stimulation from HERV products |

Study Design

Interventional Arms

| Arm | Intervention | Dosing |
|-----|--------------|--------|
| Single Arm | Emtricitabine (200mg) + Lamivudine (150mg) | Daily oral |

Rationale for Dose Selection

The trial uses standard HIV doses of NRTIs. These doses have established safety profiles from decades of use in HIV patients. The hypothesis is that antiviral doses — not sub-toxic doses — are needed to suppress HERV reverse transcriptase activity effectively.

Outcome Measures

Primary Outcomes

Secondary Outcomes

Clinical Context

Repurposing Antiretrovirals for Neurodegeneration

This trial represents a novel therapeutic approach that draws on:

• HIV-associated neurocognitive disorders (HAND) — Research on how antiretroviral therapy affects brain function in HIV patients
• HERV biology — Growing understanding of endogenous retrovirus reactivation in neurodegeneration
• Innate immune modulation — Recognition that type-I interferon dysregulation is common to multiple neurodegenerative conditions

Comparison to Other Immunomodulatory Approaches

| Trial | Target | Phase | Approach |
|-------|--------|-------|----------|
| NCT04500847 (NRTIs) | HERVs, type-I interferon | Phase 1 | Reverse transcriptase inhibition |
| NCT06384378 (IL-2) | Treg expansion | Phase 2 | Immunomodulation |
| NCT05318998 (AL002) | TREM2 | Phase 2 | Microglial activation |
| NCT01796964 | Cannabinoid receptor | Phase 2 | Anti-inflammatory |

Butler Hospital

Butler Hospital in Providence, Rhode Island is a leading site for Alzheimer's disease clinical research, particularly known for studies investigating the intersection of infection, immunity, and neurodegeneration.

Eligibility Criteria

Inclusion Criteria

• Age 50-85 years
• Diagnosis of probable Alzheimer's disease (NIA-AA criteria)
• MMSE score 18-26 (mild to moderate dementia)
• Stable on cholinesterase inhibitor and/or memantine for 3+ months
• Able to undergo MRI and PET imaging

Exclusion Criteria

• Active HIV infection
• History of hepatitis B or C
• Significant hepatic or renal impairment
• Current antiretroviral therapy
• Active malignancy
• Significant cardiovascular disease
• [Alzheimer's Disease](/diseases/alzheimers-disease)
• [Neuroinflammation in Alzheimer's Disease](/mechanisms/neuroinflammation)
• [Type-I Interferon Signaling Pathway](/genes/fer)
• [Innate Immune Response in Neurodegeneration](/diseases/neurodegeneration)
• [Human Endogenous Retroviruses](/genes/ret)
• [Microglia in Neurodegeneration](/diseases/neurodegeneration)
• [NRTIs (Antiretroviral Drugs](/genes/ret)
• Butler Hospital
• [Alzheimer's Disease Clinical Trials](/diseases/amyotrophic-lateral-sclerosis)

External Links

• [ClinicalTrials.gov: NCT04500847](https://clinicaltrials.gov/study/NCT04500847)
• [Butler Hospital Memory and Aging Program](https://www.butler.org/memory)
• [HERV Database](https://herv.img.cas.cz/)

References