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Gene Therapy for Alzheimer’s Disease: Understanding the Research

April 28, 2022Neelem Sheikh

Countless failed Alzheimer’s disease clinical trials and a lack of effective therapies have resulted in the development of many novel therapies for Alzheimer’s disease, and more recently, gene therapy.

Gene therapy represents a promising area of research for neurodegenerative diseases, like Alzheimer’s and Parkinson’s disease. One of the biggest challenges of drug delivery for Alzheimer’s is the blood-brain barrier (BBB), as it prevents large molecules from reaching the brain. Gene therapy for Alzheimer’s disease is unique in that it can essentially circumvent the BBB by delivering genes directly via delivery systems, like viral vectors. Additionally, due to the persistent nature of gene expression, only a single administration of the therapy is theoretically required.

Below, we take a closer look at gene therapy for Alzheimer’s disease, including identified targets for genetic therapies for Alzheimer’s, associated clinical research, and insight into what is needed to accelerate and improve clinical research in this space.

Gene Therapy for Alzheimer’s Disease

Over the years, several targets for genetic therapies have been researched and assessed in pre-clinical trials. These targets include but are not limited to the following:

  • Amyloid pathway intermediates and enzyme modulation
  • Tau protein downregulation
  • APOE4 downregulation and APOE2 upregulation
  • Neurotrophin expression (nerve growth factor [NGF] and brain-derived neurotrophic factor [BDNF])
  • Inflammatory cytokine alteration

Below, we take a closer look into clinical research surrounding BDNF and APOE2.

AAV2-BDNF Treatment

BDNF, also known as abrineurin, is a protein that is encoded by the BDNF gene and is found in the central nervous system. This protein is part of a family of growth factors and is responsible for promoting the survival of neurons via its role in the growth, differentiation, and maintenance of new neurons and synapses.

BDNF is produced in the entorhinal cortex, an important region of the brain for memory that is typically affected by Alzheimer’s early in the disease continuum. In individuals with Alzheimer’s disease, the levels of BDNF are reduced.

Animal studies, including those involving aged rats, aged monkeys, and amyloid mice, found that delivering BDNF to the entorhinal cortex and hippocampus via a modified viral vector, adeno-associated virus (AAV2), was a promising approach. When compared to non-treated animals, the animals treated with this approach showed notable improvement in learning and memory assessments, while the brains of treated animals showed restored BDNF gene expression and activation of function in neurons that would have otherwise degenerated.

Following promising animal studies, in 2021, researchers at the University of California San Diego School of Medicine launched a first-in-human Phase I clinical trial to investigate the safety and potential therapeutic benefits of the AAV2-BDNF gene therapy for Alzheimer’s disease. 

AAVrh.10-APOE2 Treatment

The most common and widely researched gene associated with late-onset Alzheimer’s disease is APOE, which has been identified as a risk gene. APOE is responsible for creating a protein that helps carry cholesterol and other fats in the bloodstream. 

Genetic variants on the APOE gene on chromosome 19 are known to increase the risk of developing Alzheimer’s. APOE comes in several forms, or alleles: APOE2, APOE3, and APOE4. Individuals inherit two APOE alleles—one from each biological parent.

APOE Allele

Genetic Significance


APOE2 is relatively rare and may provide individuals with some level of protection against Alzheimer’s disease. Experts estimate that carrying two APOE2 alleles (or one APOE2 and one APOE3) may reduce the risk of developing Alzheimer’s by up to 40%. Typically, if an individual with this allele does develop Alzheimer’s, the development of the disease occurs later in life compared to an individual with the APOE4 allele.


APOE3 is the most common APOE allele and is currently believed to play no role in increasing or decreasing the risk of developing Alzheimer’s disease.


APOE4 is believed to increase the risk of developing Alzheimer’s disease and is associated with an earlier onset of the disease. Approximately 25% of people carry a single copy of APOE4, and 2% to 3% of people carry two copies. Individuals with one copy have an increased risk of developing Alzheimer’s. The presence of two copies is a stronger indicator that an individual may develop the disease. More specifically, carrying one copy of APOE4 may increase Alzheimer’s risk by two to three times, while carrying two copies may increase risk by up to 12 times.

Because of the significant risk associated with carrying two copies of APOE4, researchers began investigating the potential of treating APOE4 homozygotes (with Mild Cognitive Impairment [MCI], mild dementia, and moderate dementia due to Alzheimer’s) via intrathecal administration of AAVrh.10hAPOE2 (serotype rh.10 adeno-associated virus gene transfer vector expressing cDNA coding for human APOE2) directly to the central nervous system/cerebrospinal fluid. The goal of this approach is to increase the expression of APOE2 and overcome the harmful effects of APOE4.

In preclinical research, AAVrh.10hAPOE2 was tested with mice expressing human APP, PS1, and APOE4. Intracerebral delivery resulted in widespread brain expression of APOE2 as well as decreased beta-amyloid levels and amyloid deposition. Widespread expression of APOE2 was also observed in nonhuman primates two months after intraparenchymal, intracisternal, or intraventricular delivery of AAVrh.10hAPOE2.

In 2019, Weill Medical College of Cornell University began a Phase 1 trial, set to end in January 2024, evaluating LX1001 (AAVrh.10hAPOE2) in 15 volunteers who carry two APOE4 alleles, confirmed amyloid deposition, and a clinical diagnosis of MCI to moderate dementia. In March 2022, the FDA granted LX1001 Fast Track designation.

Improving and Accelerating Clinical Trials Assessing Gene Therapy for Alzheimer’s Disease

It is clear that gene therapy for Alzheimer’s disease is a promising area of clinical research, and advancements in neurosurgical techniques now enable reliable delivery of therapeutic vectors with real-time verification—yet several issues, such as the following, are hindering the ability to bring therapies to market quickly and help Alzheimer’s disease patients:  

  • Costly and time-consuming subject screening and selection
  • Unreliable tools for longitudinal cognitive assessment of trial subjects
  • Lack of tools to support decentralized clinical trials and remote subject monitoring

Altoida’s mission is to accelerate and improve drug development, neurological disease research, and patient care. To learn more about our precision-neurology platform and app-based medical device, contact us!

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