Alzheimer Disease Gene Therapy Provides Restoration of Entorhinal Cortex FDG-PET Activity in Phase 1 Trial

This article originally appeared on our sister site, NeurologyLive®.

An adeno-associated virus serotype 2 (AAV2)-brain derived neurotrophic factor (BDNF) gene therapy demonstrated potential for preventing neuronal loss, activating neuronal function, and restoring synapses in patients with mild Alzheimer disease (AD) and mild cognitive impairment (MCI) in the context of a small-scale, phase 1 clinical trial (NCT05040217).¹ The data were presented at the 2025 Alzheimer’s Association International Conference (AAIC), held July 27-31, in Toronto, Canada.

In the trial, 12 patients underwent an MRI-guided injection of AAV2-BDNF into the entorhinal cortex and were followed for over 2 years. FDG PET scans in the 3 patients with 6 months or more of follow up time displayed increases in cortical metabolism in entorhinal regions that received AAV2-BDNF. This finding stands in contrast to the pattern of decline normally seen in AD.

Of the 12 participants included in the trial, 6 have been treated with the gene therapy as of yet, and treatment for the MCI cohort is slated to start soon. Time of treatment on the gene therapy to date ranges from 1 to 18 months. Thus far, no serious adverse events related to the study procedure have been reported in the trial, which is being led by Mark H. Tuszynski, MD, PhD, a neurologist at the University of California, San Diego Health. According to the investigators, the gene therapy has demonstrated the ability to restore FDG-PET activity in the treated entorhinal cortex region and has been safe so far.

Treatments specifically focused on BDNF are currently rare in the therapeutic pipeline for AD. BDNF gene therapy is infused into the entorhinal cortex, the location in which BDNF protein is produced and transported to the hippocampus. In the hippocampus BDNF protein serves to safeguard brain cells, promote connections between cells, and bolster memory. Being carried out at the University of California, San Diego, this first-in-human trial received clearance from the FDA and the UC San Diego Human Subjects Safety Committee.

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The phase 1 study comprised individuals aged 50 to 80 years with either mild AD (MMSE, 22-28) or MCI due to AD (MMSE, 24-29). Coming into the study, patients were required to show no significant cerebrovascular disease, have stable permitted medications, and demonstrate no depression per GDS-30. EEGs must have been free of epileptiform activity, and recent brain imaging should have been free of significant lesions.²

Exclusion criteria included any significant neurological condition aside from early AD, major psychiatric illness within the past 2 years, substance abuse, recent cancer, or unstable systemic diseases that could interfere with participation. Specific medication restrictions apply, including recent use of neuroleptics, corticosteroids, long-acting sedatives, antiParkinsonian agents, and centrally acting beta-blockers. Participants cannot have undergone prior gene therapy, received anti-amyloid monoclonal antibodies within one month of treatment, or used investigational drugs within 30 days. Those with MRI contraindications or who are unlikely to comply with the protocol are also excluded.

AAV2-BDNF gene therapy represents a neurorestorative approach to AD–focusing not on amyloid or tau, but on repairing neuronal networks and preserving cognitive function by restoring a critical growth factor. To date, preclinical studies in rodent and primate models have shown improved memory, reduced neurodegeneration, and increased synaptic markers following AAV2-BDNF treatment.

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REFERENCES
1. Tuszynski MH, Scharre DW, Leger GC, et al. A Phase I Clinical Trial of AAV2-BDNF Gene Therapy for Alzheimer's Disease: Findings. Presented at: AAIC 2025; July 27-31; ABSTRACT 101305
2. A Clinical Trial of AAV2-BDNF Gene Therapy in Early Alzheimer's Disease and Mild Cognitive Impairment. ClinicalTrials.gov. Updated April 27, 2025. Accessed July 29, 2025. https://www.clinicaltrials.gov/study/NCT05040217