"Roadmap" is a popular term in scientific research today, and one we believe well-chosen. The concept implies direction, purpose, and an endpoint. Please join us to review our roadmap.

How will we achieve our mission?

The Cure Alzheimer's Fund Research Consortium has developed this Research Roadmap, beginning with its history and purpose, to clarify our path to slowing, stopping or reversing Alzheimer's disease.

History and Purpose

Alzheimer's disease (AD), a progressive neurodegenerative disorder affecting all aspects of cognition, is the most common form of dementia in the elderly. Already affecting over four million people in the US, the number of Alzheimer's disease cases in the US will total over 14 million by 2040 if unchecked. If effective therapeutic strategies for prevention and treatment are not developed soon, AD carries the potential to bankrupt federal and state healthcare systems.

Epidemiological and genetic studies over the past three decades have documented a strong genetic component in the etiology of Alzheimer's disease. To date, four different genes have been firmly established to play a role in the etiology and pathogenesis of AD. These include three genes that can contain mutations that cause with certainty the rare "early-onset" familial forms of AD in approximately 5 % of AD patients (onset < 60 years). A common genetic variant of a fourth gene was identified as a frequent risk factor for late-onset AD which affects the large majority of AD patients.

Over the past two decades, it has become increasingly clear that our best chance for beating this disease requires identification of all genes associated with AD, including those with strong, moderate, and modest effects on risk. Since Dr. Alois Alzheimer first described the disease in 1906, physiological causes of AD could only be guessed at until AD genes were identified, beginning in the late-1980's. Identification and characterization of AD genes has already provided an unprecedented window into the biological underpinnings of AD. Every new AD gene has furnished novel targets for drug discovery and unique opportunities to design innovative therapies to treat and prevent AD. Ultimate elucidation of all AD genes will also enable more accurate prediction and diagnosis of the disease.

Therefore, the overarching goal of AD genetic research is to one day conquer this dreadful disease by enabling reliable, legally protected genetic testing, to identify those who are at greatest risk for AD, and then to prevent AD at its earliest stages with novel therapies made possible by the knowledge gained from genetic discoveries. We call this strategy early prediction-early prevention.

One of the major findings to come out of previous AD genetics studies regards the AD-related brain lesions known as senile plaques, composed of a sticky and toxic substance called β-amyloid, present in both early and late onset AD victims. The chief component of β-amyloid is a small protein (peptide) called Aβ, particularly a form called Aβ42. Numerous lines of evidence point to accumulation of Aβ42, a peptide found in great abundance in plaques, as a causative agent of the disease.

Recently, studies indicate that Aβ42 mainly wreaks havoc on synapses, which are the connections made by nerve cells that allow them to communicate to establish associative learning and memory. In an analogy to heart disease, accumulation of Aβ in the brain is akin to the accumulation of cholesterol in blood vessels. The most effective heart disease therapies lower cholesterol production or enhance clearance and diminish toxicity. Likewise, our genetic studies of AD have taught us that the most effective AD therapies must be aimed at either lowering production of Aβ42 or enhancing its clearance and breakdown, especially from nerve synapses required for normal cognitive function. Our best chance at achieving this pharmacological outcome comes from knowledge gained in studying the known AD genes.

The Road Map

The initial goal of the road map to beating AD begins with experiments aimed at identifying all gene mutations and common genetic variants in the human genome that either cause AD or predispose one to the increased risk of developing AD with advancing age. Just as four known AD genes have begun to serve as the principle guide for drug design and development, identification by power simulations on hundreds of families of the several dozen suspected AD genes that remain unknown will serve as the starting point for a roadmap that will not only enable the accurate diagnosis and early prediction AD, but also provide critical clues for the design and development of novel therapies aimed at effectively treating and preventing AD.

Specifically, the steps involved in this road map are as follows: 

 Foundational Research

1. Identify all gene mutations and genetics variants in the human genome that either cause/increase risk or confer protection against AD.

2. Use this genetic information to reliably predict, early in life, those at greatest risk for AD (with legal safeguards and genetic and psychological counseling).

Translational Research

1. Determine how inherited defects in AD genes lead to changes at molecular and biochemical levels and serve to cause or increase susceptibility to AD, by studying genes in cell culture and animal models.

2. Use knowledge gained from molecular and biochemical analyses of AD genes to elucidate exact biological pathways that are detrimentally impacted.

3. Prioritize known and novel AD genes for follow-up studies, placing a strong emphasis on “drugable” targets.

4. Determine exact points in genetically-disrupted biological pathways where one could pharmacologically intervene to treat or prevent AD.

Crossover Research

1. Search for known drugs that have been approved or already shown to be safe in humans and test them for the ability to intervene at appropriate step in the genetically disrupted biological pathway elucidated above.

2. Screen tens of thousands of small molecule compounds and existing drugs, both approved and unapproved for their ability to intervene at the appropriate step in the genetically disrupted biological pathway.

Facilitative Research

1. Optimize active compounds using medicinal chemistry and high-throughput organic synthesis to maximize potency.

2. Advance promising compounds to preclinical testing in mouse models of AD, based on the identified genes, for efficacy and safety.

3. Initiate human clinical trials in partnership with drug companies.

4. Work with drug companies to bring the drug to market.

5. Use the novel drugs to not only treat AD but to prevent AD in those at greatest risk based on genetic testing: Early Prediction --- Early Prevention.