Alzheimer's Disease (AD), the most common form of dementia in the elderly, affects over 5 million Americans. There are no treatments to slow progression or prevent AD. This reflects limitations in knowledge of mechanisms underlying AD, and in tools and models for early development and testing of treatment. Genetic breakthroughs related to early onset AD led to initial treatment targets related to a protein called amyloid, but clinical trials have been negative. Extensive research links genetic risk to AD, even when the age at onset is after the age of 65. AD affects the brain alone, therefore studying authentic nerve cells in the laboratory should provide the clearest insights into mechanisms and targets for treatment. This has recently become feasible due to advances in programming skin cells into stem cells and then growing (differentiating) them into nerve cells. In this project we will obtain skin biopsies from a total of 220 people with AD and 120 controls, who are extensively studied at the [REDACTED] AD Research Center. These studies include detailed genetic (DNA) analysis, which will allow genetic risks to be mapped onto reprogrammed cells. These derived cells that preserve the genetic background of the person who donated the skin biopsy will be made available to the research community, and have the promise to accelerate studies of mechanisms of disease, understanding genetic risk, new treatment targets, and screening of new treatments for this devastating brain disorder.
The proposed project will provide a unique and valuable research resource, which will be stored and managed in California. This resource will consist of skin cells or similar biological samples, suitable for reprogramming, obtained from well-characterized patients with Alzheimer's Disease and cognitively healthy elderly controls. Its immediate impact will be to benefit CIRM-funded researchers as well as the greater research community, by providing them access to critical tools to study, namely nerve cells that can be grown in a dish (cultured) that retain the genetic background of the skin cell donors. This technology to develop and reprogram cells into nerve cells or other cell types results from breakthroughs in stem cell research, many of which were developed using CIRM funding. Alzheimer's Disease affects over 600,000 Californians, and lacks effective treatment. Research into mechanisms of disease, identifying treatment targets, and screening novel drugs will be greatly improved and accelerated through the availability of the resources developed by this project, which could have a major impact on the heath of Californians. California is home to world class academic and private research institutes, Biotechnology and Pharmaceutical Companies, many of whom are already engaged in AD research. This project could provide them with tools to make research breakthroughs and pioneer the development of novel treatments for AD.
In this proposal, the applicant aims to collect skin biopsies from controls and patients with sporadic Alzheimer's Disease (AD). Sporadic AD has a range of causes associated with age, polygenic risk factors and environmental risk factors. The applicant proposes to recruit 220 people with AD and 120 controls. For all subjects, the applicant will collect patient data including cognitive characterization, family and clinical histories and for many patients and control subjects, genetic analysis will also be available. The applicant will match controls subjects to AD patients with respect to risk genotype(s), age and gender.
Impact and Significance
- The impact and significance of the proposal is very high. AD represents an enormous health-care burden, which will increase greatly in our ageing population.
- The proposal makes an excellent case that the new iPS models will complement existing animal models, which have proven inadequate to predict clinical responses.
- The investigators’ in life AD diagnosis accuracy is impressive and it strengthens the impact of the collection as samples are collected and banked in life.
- The rationale for patient selection and incorporation of genetic risk assessment is very good. The close age matching with controls will help increase the value of an excellent resource.
- Having a strong genetic component to the collection increases confidence that the lines can model cellular aspects of disease.
- AD has reproducibly proven suitable for hiPSC based disease modeling, strengthening the rationale for the proposed collection and study.
- It was noted that the selected cohort lacks ethnic diversity.
Quality of the Proposed Protocols
- The scope of relevant data to be collected from all subjects is excellent, and the management of all confidential patient data is well described.
- Consent allows patients to be re-contacted, the consent form requests no limitation on use of tissue and the sample size collected is justified and reasonable.
- The availability of information derived from genotyping for an allele that is a major risk factor for the disease and of genome wide association studies (GWAS) data for many of the samples strengthens the proposal. A reviewer encouraged access to this and all other relevant patient data for those researchers who acquire the hiPSC lines through the repository.
- The proposal is excellent in this regard. The applicant leads a relevant center with a strong history of patient recruitment, comprehensive infrastructure and standards to facilitate the sample collection for this proposal.
- An IRB approval to collect fibroblasts is already in place and the group has already successfully collected patient fibroblasts although some reviewers expressed concern that skin biopsy may make the recruitment goal more challenging.
- Reviewers noted that a particular rare patient cohort maybe difficult to recruit and would have appreciated more discussion on this topic.
- The reviewers considered the budget to be reasonable.
Qualifications of the Principal Investigator (PI) and Team Members, Resources
- The team is highly experienced very well placed to undertake the work.
- The team’s participation in broader AD efforts further strengthens the proposal