Converging on 9 Areas of Focus

Genes to Therapies™ / Drug Screening

The Genes to Therapies program seeks to:

  • Elucidate the mechanisms of action of the Alzheimer’s risk-impacting genes identified by Whole Genome Sequencing, and 
  • Identify targets within those mechanisms for potential drug or other therapeutic interventions. 


Of the already identified Alzheimer’s genes and candidate genes, more than 60 are being screened for mutations/functional variants in the Whole Genome Sequencing project. Of these, more than 20 variants currently are prioritized based on three important criteria for immediate and thorough investigation: 

1. High genetic impact or ranking in Alzheimer’s pathology;

2. “Druggable,” as defined by being in known biological systems and producing proteins that appear to be most readily accessed and modified by typically successful therapeutic agents, such as small molecules or biologicals, e.g., antibodies; and

3. Affect the most obvious intervention points, which include Abeta/plaque production and clearance, tangle formation/spreading and neuroinflammation.


Additionally, 3-D drug screening is being used to identify and characterize novel AD drugs and drug targets. This project utilizes high-throughput drug screening in combination with an innovative 3-D human cellular model that recapitulates both beta-amyloid and tau pathologies.



Project Description Researchers
Molecular and Cellular Mechanisms of ACE1 Variant in Alzheimer’s Disease

Alzheimer’s disease (AD) is a complex genetic disorder that is the leading cause of dementia in the elderly. Dr. Rudolph Tanzi and the Cure Alzheimer’s Fund Alzheimer’s Genome Project™ have identified a new mutation in a gene called ACE1 that is associated with increased risk for AD. How the ACE1 gene causes AD is completely unknown. The goal of this project is to study the role of the ACE1 gene in the disease process in genetically engineered mice.

ABCA7 in Brain Homeostasis and Alzheimer's Disease

Genetic and environmental factors influence the risk of late-onset Alzheimer's disease; genetic studies have identified novel risk genes for the disease. ABCA7 is the gene encoding ATP-binding cassette sub-family A member 7; variants of ABCA7, which shares a homology with ABCA1, have shown a strong association with increased risk for late-onset Alzheimer’s disease. Importantly, loss-of-function variants in ABCA7 also have been demonstrated to significantly increase Alzheimer’s disease risk.

The Role of PICALM Mutations in Alzheimer’s Disease

The search for biological understanding of Alzheimer’s disease (AD) has expanded to include new risk factors, particularly genes. Thanks to breakthroughs in human genetics and high-throughput genome sequencing, PICALM, the gene encoding phosphatidylinositol binding clathrin assembly protein, has been identified as a new risk gene for AD. As a key player in clathrin-mediated endocytosis and intracellular trafficking, PICALM critically regulates amyloid beta brain metabolism and neuronal toxicity.

Role of ATXN1 in Regulating BACE1 Activity

A recent genetic study from our research group revealed that the Ataxin-1 gene (ATXN1) is genetically associated with Alzheimer's disease. ATXN1 encodes a nuclear protein, Ataxin-1, and DNA mutations that increase the CAG trinucleotide repeat in ATXN1 are known to cause spinocerebellar ataxia type 1 (SCA1). SCA1 is a neurodegenerative disease that primarily impairs coordinated movement and later deteriorates the cognitive function of patients. In a preliminary study with mouse models, we found the deletion of ATXN1 elevates BACE1 expression in the brain.

Alzheimer’s Genome Project™

The goal of this project is to evaluate our new Alzheimer’s disease gene candidates for effects on Alzheimer’s pathology and related biological pathways, including APP processing, amyloid beta protein generation, tangle formation and cell death. These studies are being carried out as part of Phase II of the Alzheimer’s Genome Project (AGP) and entail functional analyses of the Alzheimer’s gene candidates identified in Phase I of the AGP.

Discovery of CK1 Activators for Inducing the Autophagic Degradation of APP Beta-CTF

Alzheimer’s disease (AD) is a neurodegenerative disorder that affects more than 5 million people in the United States. One of the hallmarks of AD is the accumulation of amyloid plaques in the brain of patients. The amyloid plaque is composed of beta amyloid (Abeta) peptide, which originates from an amyloid precursor protein (APP).

3-D Neural Core/High-Throughput Drug Screening for Alzheimer’s Disease Using 3-D Human Neural Culture Systems

The “beta-amyloid cascade hypothesis” of Alzheimer's disease (AD) has provided a major framework for AD drug discovery and has led to many current clinical trials. However, to date, no single in vitro or in vivo AD model has been able to recapitulate the presumed patient pathophysiology: beta-amyloid deposition directly leads to tangles and neurodegeneration. Recently, we created a novel three­ dimensional (3-D) human neural cell culture model of AD using genetically engineered human neural stem cells.

Microglial Core/CD33 and Alzheimer’s Disease: From Biology to Therapy

Our current inability to prevent or delay Alzheimer’s disease (AD) and the expected increase in the prevalence of AD are predicted to give rise to a global AD pandemic. We recently have identified a novel pathway for amyloid beta (Abeta) clearance in the aging brain that is highly relevant to AD pathogenesis. In a very large family-based, genome-wide association study, we identified CD33 as a novel late-onset AD risk factor. CD33 encodes a transmembrane sialic acid-binding immunoglobulin-like lectin that regulates innate immunity.

G2T Research Models and Materials
Taconic Biosciences GMBH, a global provider of genetically modified mouse models and associated services, is providing customized mouse models (transgenic, conventional/conditional knock out, conventional/conditional knock in) for each specific gene and type of mutation that will be studied in the Genes to Therapies™ project.
PICALM Gene Therapy and Drug Screening for Abeta Clearance

Our novel theory regarding PICALM, published last year in Nature Neuroscience, is that its genome-wide association study (GWAS)-linked impact on lower Alzheimer’s disease (AD) risk is due to its role internalizing Abeta into brain endothelial cells and then out into the bloodstream, effectively increasing amyloid clearance across the blood-brain barrier.

Role of Blood-Brain Barrier Function in Alzheimer’s Disease Pathogenesis Investigated Using a 3-D Microfluidic Platform

Alzheimer’s disease (AD) is the most common form of dementia among older people. The blood-brain barrier (BBB) is a highly selective permeable barrier that separates the brain from circulating blood. It is formed by brain endothelial cells and prevents harmful materials from the blood from entering the brain. Evidence identifying BBB dysfunction in AD or patients at risk (i.e., those with mild cognitive impairment) continues to escalate.

The Biological Impact of TREM Locus Mutations in Alzheimer’s Disease

Whole Genome Sequencing has identified certain polymorphisms affecting genes encoding triggering receptors expressed on myeloid cells (TREMs) with increased risk of non-familial (sporadic) Alzheimer's disease. TREM signaling is known to be important in the innate immune response, particularly in the inflammatory response. However, the relationship between the function of TREM receptors and Alzheimer's disease pathology is largely unresolved.

Studying the Functional Consequences of Alzheimer’s Disease Risk Variants in the CLU and ABCA7 Genes Using Both Human and Mouse Models

The vast majority of people with Alzheimer’s disease (AD) suffer from the sporadic (late-onset) form, whose causes remain completely unknown. From studies involving thousands of people, researchers have identified a number of genetic variants that may increase one’s risk for sporadic AD (sAD). However, little is understood regarding how carrying these variants impacts one’s sAD risk.

Genes to Therapies (G2T) Centralized Research Core Oversight

Wilma Wasco, Ph.D., is responsible for the day-to-day organization of the Genes to Therapies™ (G2T) Centralized Research Core. She meets routinely with Dr. Tanzi as well as the members of the G2T Steering Committee and Meg Smith of Cure Alzheimer’s Fund to outline and discuss progress with timelines and investigations as well as reagent generation and budgets. She will be responsible for determining what reagents are available from investigators or commercial sources while investigators are being recruited.

A 3-D Human Neural Cell Culture System for Studying Neuron-Microglia Interaction in Alzheimer’s Disease

In this proposal, we aim to dramatically improve the current microglial chemotactic model into a hybrid brain model that recapitulates pathological cascades of Alzheimer’s disease, including beta-amyloid deposits, microglial recruitment/clearance of beta-amyloid, neurofibrillary tangles and possibly neuronal death. To do this, we have been collaborating closely with Drs. Doo Yeon Kim and Rudolph E. Tanzi (Massachusetts General Hospital) to combine their novel “three-dimensional Alzheimer’s in a dish” model with our microglial chemotactic model. Drs.

Use of High-Content Drug Screening and Systems Biology Modeling on a Novel 3-D Cell Model to Repurpose Known Drugs for Alzheimer’s Disease

Taking advantage of recent research progress, we propose to carry out a compound screen to find potential drugs to treat Alzheimer’s disease (AD). The screen will use a revolutionary 3-D stem cell model, recently developed by Drs. Rudy Tanzi and Doo Yeon Kim at Massachusetts General Hospital, which for the first time faithfully recapitulated major pathological hallmarks of AD in a dish. The screen also will use the previously developed neuronal image processing software packages, which are able to automatically and accurately assess the cell phenotype to evaluate the compound effect.

BIN1 in Alzheimer’s Disease Neuropathology

The goal of this proposal is to investigate how one of the recently identified late-onset Alzheimer’s disease risk genes, namely BIN1, contributes to neuropathology. BIN1 is an adaptor protein that regulates membrane dynamics in a variety of cellular contexts. Only limited information is available on BIN1 expression and function in the brain. As such, there is much to be learned about the precise biological and mechanistic connection between BIN1 and Alzheimer’s disease.

3DDS: Alzheimer's Disease Drug Discovery in 3-D

We propose to examine biological fluids from cells treated with individual drugs that have been approved previously by the U.S. Food and Drug Administration for the treatment of numerous diseases and disorders. We will determine whether these drugs reduce the levels of the toxic proteins known to cause Alzheimer’s disease. Newly identified drugs or similar modified compounds will be developed as Alzheimer’s therapeutics.

Extracellular Vesicle-Based Targeting of CD33-Mediated Pathology for Alzheimer’s Disease Therapy

Alzheimer’s disease (AD) is a devastating disease for patient and family alike. Unfortunately, there is no effective treatment and conventional, drug based therapies have failed. Our lab has developed a therapeutic virus vector that the body’s immune defenses will tolerate and that efficiently delivers nucleic acid-based material into cells. In this case, the material is a gene therapy specifically tailored to manipulate the expression of CD33, a gene seen in mouse models to slow beta amyloid clearance and thus contribute to Alzheimer’s disease pathology.

In Vitro and In Vivo Analysis of APP Variants

It is widely accepted that Abeta peptides, the principal component of senile plaques, play a causative role in the pathogenesis of Alzheimer’s disease (AD). Abeta is derived from larger beta-amyloid precursor proteins (APP). Early-onset, familial AD (FAD) is caused by inheritance of mutations in genes encoding APP or presenilin (PS1 or PS2) variants. Mutations in APP lead to the production of elevated levels of Abeta or the ratio of Abeta42/40 peptides. Importantly, all of the known APP mutations reside proximal to, or within, the Abeta peptide sequence.

Alzheimer Disease-Associated Mutations in Protein Kinase C

This proposal addresses whether a key protein that is turned off in cancer, a disease characterized by uncontrolled cellular growth and survival, is excessively active in Alzheimer’s disease, a degenerative disease. This protein, called protein kinase C, is an information processor, or “signal transducer,” that regulates cellular activities. Its activity needs to be precisely balanced to maintain normal cellular function. Reduced function promotes cell survival, a hallmark of cancer.

Investigating the Mechanism of Entorhinal Cortex Hypermetabolism in APOE4 Targeted Replacement Mice

Carriers of the APOE4 gene are at significantly increased risk for developing Alzheimer’s disease. We have discovered that aging mice that express the APOE4 gene possess increased activity in a region of the brain that is implicated in the development of Alzheimer’s disease, and we think this increased activity may be an important link between APOE4 and Alzheimer’s disease pathology. In order to understand the cause of this increased brain activity, we will utilize sophisticated techniques to measure important genes and proteins known to increase brain activity.

Therapeutic Modulation of TREM2 Activity

There is strong evidence that inflammation occurs in different stages of Alzheimer’s disease (AD). Understanding this process can help us to design new therapeutic approaches. TREM2 is a protein directly related to the inflammation process that occurs in the brain of patients with AD. Mutations in this protein increase the risk to develop AD up to threefold. A fragment of this protein, namely soluble TREM2 (sTREM2), increases at very early stages of AD, and this increase occurs in parallel to an increase of biomarkers for neuronal cell death.

SORLA Attenuates Abeta Toxicity Through Interactions With EphA4

SORLA is a genetic risk factor in Alzheimer’s disease (AD), but it is unclear how changes in SORLA abundance can trigger the onset of AD in the elderly. So far, studies have shown that SORLA can limit the amount of neurotoxic Abeta generated in the brain. However, since high levels of Abeta also are seen in aged individuals without symptoms of dementia or cognitive decline, neuroprotective mechanisms are likely in place to protect neurons from Abeta damage.

Characterization of Certain Human APOE Targeted Gene Replacement Mice

APOE4 is the strongest identified genetic risk factor for late-onset Alzheimer’s disease. Strong evidence from Abeta-deposition mouse models and humans indicate that APOE4 influences the metabolism of Abeta within the brain, which promotes Abeta plaque pathology. The precise mechanism(s) by which APOE isoforms influence Abeta are not completely clear, although numerous in vivo and in vitro studies suggest that APOE4 slows the clearance of Abeta from the brain and facilitates the aggregation of monomeric Abeta.

PKC Mutations and Alzheimer's Disease

The goal of this project is to analyze how Alzheimer’s disease (AD)-associated mutations in a key signaling molecule, protein kinase C α (PKCα), contribute to disease pathogenesis. PKCα plays a pivotal role in tuning the signaling output of cells and, as such, is frequently mutated in human cancers. The Alzheimer’s Genome Project™ led by Tanzi and colleagues has identified unique mutations in PKCα that co-segregate with AD in families with the disease.

Functional Characterization of GGA3 Mutations Associated with Alzheimer’s Disease

Neurons, highly organized brain cells, are characterized by specialized projections called dendrites and axons. The axon is the longest neuronal projection where proteins move like along a highway, in two different directions and at different speeds. Scientists demonstrated that in the brain of subjects affected by Alzheimer’s disease (AD), a disorder characterized by memory loss, this coordinate traffic doesn’t work properly, so neurons start to be unhealthy and die.

The Putative Role of Red Blood Cell CR1 Levels in Amyloid-Beta Clearance and Alzheimer’s Disease Pathogenesis

The immune system uses complement proteins and receptors to “coat and clear” pathogens and proteins from the body. Complement Receptor 1 (CR1/CD35) is found on the surface of red blood cells in humans and helps shuttle cellular debris to the liver for degradation. Recently, specific genetic variations, called polymorphisms, in the CR1gene were found to be associated with an increased risk of late-onset Alzheimer’s disease.

TREM2 Function and Dysfunction in Alzheimer's Disease

There is strong evidence that inflammation occurs in different stages of Alzheimer’s disease (AD), and understanding this process can help us to design new therapeutic approaches. TREM2 is a protein that is directly related to the inflammation process that occurs in the brain of patients with AD; mutations in this protein increase the risk to develop AD up to threefold. A fragment of this protein, namely soluble TREM2 (sTREM2), can be detected in biological fluids like the cerebrospinal fluid (CSF). The function of sTREM2 in health and disease currently is not known.

The Role of the KIBRA Gene in Abeta Regulation of AMPAR Trafficking

Modulation of AMPA receptors (AMPARs), the major excitatory receptors in the brain, is thought to underlie learning and memory, as aberrant AMPAR regulation contributes to impaired memory and cognition. Several studies suggests that dysregulation of AMPAR modulation plays a central role in Alzheimer’s disease (AD). We recently identified a protein implicated in human memory performance, KIBRA, and its binding partner PICK1 as critical modulators of synaptic regulation of AMPARs.