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A GIVING SMARTER GUIDE TO ACCELERATEDEVELOPMENT OF NEW THERAPIES

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CONTENTS

Executive Summary ................................................................................................................ 5

Overview ................................................................................................................................ 6

Imperative to Advance Alzheimer’s Research ................................................................................................... 6

Population Burden ............................................................................................................................................... 6

Economic Burden ................................................................................................................................................. 7

AD Awareness Falls Behind Compared to Other Diseases ................................................................................. 8

Public Policies Adressing AD Unmet Needs .............................................................................. 9

National Alzheimer's Project Act ...................................................................................................................... 9

Alzheimer’s Accountability Act ....................................................................................................................... 10

Risk, Diagnosis, and Progression ........................................................................................... 11

Risk Factors .................................................................................................................................................... 11

Three Stages of Alzheimer’s disease ............................................................................................................... 11

Preclinical AD ..................................................................................................................................................... 12

Mild Cognitive Impairment Due to AD ............................................................................................................... 12

Dementia Due to AD .......................................................................................................................................... 12

Measuring Cognitive Impairment for Diagnosis .............................................................................................. 13

Disease Biology .................................................................................................................... 14

Beta Amyloid Protein Build-‐Up in the Brain Leads to Plaques ......................................................................... 14

Tau Protein Build-‐Up in the Brain Leads to Tangles ........................................................................................ 15

Neurotransmitter Dysfunction ....................................................................................................................... 16

Treatments ........................................................................................................................... 17

Clinical Trials and Investigational Therapies ......................................................................... 18

Clinical Trials -‐ Overview ................................................................................................................................ 18

Investigational Therapies ............................................................................................................................... 18

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Amyloid-‐Targeting Therapies ............................................................................................................................. 19

Tau-‐Targeting Therapies .................................................................................................................................... 19

Neurotransmitter Targeting Therapies .............................................................................................................. 20

Immunotherapy ................................................................................................................................................. 21

Stem Cells ........................................................................................................................................................... 22

Nutraceuticals .................................................................................................................................................... 22

Challenges Impeding AD Research and Key Philanthropic Opportunities ............................... 24

Lack of Reliable Biomarkers ........................................................................................................................... 24

The Problem ....................................................................................................................................................... 24

Potential Solutions ............................................................................................................................................. 24

Examples of Corresponding Philanthropic Opportunities .................................................................................. 25

Inadequate Preclinical Models ....................................................................................................................... 25

The Problem ....................................................................................................................................................... 25



Identifying New Druggable Molecular Targets ................................................................................................ 26

The Problem ....................................................................................................................................................... 26



AD Research Is Conducted in Silos .................................................................................................................. 26

The Problem ....................................................................................................................................................... 26



Key Stakeholders in the Alzheimer’s Community ................................................................... 28

Research Grantmaking Organizations ............................................................................................................. 28

Alzheimer’s Association ..................................................................................................................................... 28

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Alzheimer’s Drug Discovery Foundation ............................................................................................................ 29

BrightFocus Foundation ..................................................................................................................................... 29

Cure Alzheimer’s Fund ....................................................................................................................................... 29

New York Stem Cell Foundation ......................................................................................................................... 29

Key Initiatives and Strategic Partnerships ....................................................................................................... 30

Alzheimer’s Disease International ...................................................................................................................... 30

Dementia Discovery Fund .................................................................................................................................. 30

Global Alzheimer’s and Dementia Action Alliance ............................................................................................. 30

Global CEO Initiative on Alzheimer’s .................................................................................................................. 30

US Against Alzheimer’s ....................................................................................................................................... 31

World Dementia Council .................................................................................................................................... 31

Academic Consortia ....................................................................................................................................... 31

Alzheimer’s Disease Neuroimaging Initiative ..................................................................................................... 31

Cohorts for Alzheimer’s Prevention Action ........................................................................................................ 32

Global Alzheimer’s Association Interactive Network ......................................................................................... 32

Global Biomarker Standardization Consortium ................................................................................................. 32

Alzheimer's Disease Cooperative Study ............................................................................................................. 32

Glossary ............................................................................................................................... 34

References ............................................................................................................................ 36

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EXECUTIVE SUMMARY

Alzheimer’s disease (AD) is the sixth leading cause of death in the United States and claims the lives of more than 500,000 people in the United States alone each year. Currently, more than 5 million Americans are living with this disease. The economic impact of AD is significant, costing the United States $214 billion in 2014 and on pace to escalate to more than $1 trillion over the next four decades.

Despite significant attention and investment from government and industry, progress in the areas of clinical research and integrated care has been modest at best. Our society remains at the mercy of this disease as a result of:

• poor understanding of disease onset and progression, • gaps in funding to support high-‐risk research efforts, • insufficient research tools and companion resources, • lack of disease-‐modifying treatment options, and • limited public awareness of the societal impact of this disease.

It is imperative that we significantly improve upon the aforementioned deficiencies to avoid the economic and social catastrophe that accompanies AD. Strategic focus on funding high-‐impact research and critical infrastructure to support both AD research and patients will be essential to reaching this goal.

The FasterCures Philanthropy Advisory Service has developed this Giving Smarter Guide for Alzheimer’s disease with the specific aim of empowering patients, supporters, and stakeholders to make strategic and informed decisions with respect to directing their philanthropic investments and energy into research and development efforts. Readers will be able to use this guide ultimately to pinpoint research solutions aligned with their interests.

The guide will help to answer the following questions:

• Why is it important to invest in AD research? • What key things should I know about the disease? • What is the current state of care? • What is the state of research? • What are the barriers to progress? • How can philanthropy advance new therapies for AD?

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OVERVIEW

AD is a neurodegenerative disease that severely impairs memory, cognition, and a person’s ability to conduct common daily activities. As the nerve cells of an AD patient become diseased and ultimately die, communication among the cells that direct memory, speech, and executive function (motor skills, speech, swallowing, etc.) is lost, ultimately leading to the death of the patient.

AD most commonly occurs in people aged 65 or older; however, some individuals, especially those with a familial gene for Alzheimer’s, experience symptoms before the age of 65. This is commonly referred to as early onset Alzheimer’s disease.

Because age is one of the most important risk factors for AD, the burden of AD will increase with longer life expectancies and the aging of baby boomers. It is estimated that by 2050, nearly 15 million people will suffer from the disease in the United States, which will lead to significant population and economic burdens.

IMPERATIVE TO ADVANCE ALZHEIMER’S RESEARCH

POPULATION BURDEN

In 2014, the Alzheimer’s Association estimated that there are 5.2 million AD patients in the United States. It is estimated that one in three people (33 percent) age 85 and older have Alzheimer’s, and one in nine people (11 percent) age 65 and older is stricken with this disease. By 2025, the number of people age 65 and older with AD is expected to more than triple from 5 million to nearly 16 million if there are no significant medical breakthroughs to slow, prevent, or cure the disease.

Alzheimer’s is the sixth leading cause of death in the United States, claiming the lives of more than 500,000 people each year. According to the Alzheimer’s Association, deaths attributed to AD increased dramatically between 2000 and 2010, increasing by 68 percent, while deaths from other major diseases decreased during this decade. Among the top 10 leading causes of death in the United States, AD is the only disease that cannot be prevented, slowed, or cured.

Subjectively, it is without question that the overall burden of AD is catastrophic; however, objective evaluation of disease burden based on disability-‐adjusted life years (DALYs) underscores the magnitude of this burden and highlights the steep upward trajectory of continued burden in the coming decades.

Figure 1: Proportion of people with AD in the United States according to age. Source: Alzheimer’s Association, 2014 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia, Volume 10, Issue 2.

4% 15%

38%

43%

Alzheimer's Pa`ent Popula`on Breakdown by Age

Under 65 65-‐74 75-‐84 85+

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DALYs are the sum of the number of years of life lost due to premature mortality and the number of years lived with disability. According to an article published in the Journal of the American Medical Association by the U.S. Burden of Disease Collaborators, AD was ranked as the 25th most burdensome disease in the United States in 1990. In 2010, the ranking of AD rose to the 12th most burdensome disease. It is important to note that no other disease or condition has increased in rank that much within a 10-‐year time span. When the same study exclusively evaluated years of life lost due to premature mortality, the data showed that the AD ranking rose from 32nd to 9th, the largest increase for any disease. Overall, these data punctuate the point that AD is not only taking the lives of an increasing number of Americans, but it is also attributing to increased incidence and prevalence of poor health and disability in the Unites States.

ECONOMIC BURDEN

Alzheimer’s disease is the most costly disease to the American healthcare system. The National Institutes of Health (NIH) estimated the direct annual cost of AD during the 1990s to be more than $100 billion. Today the annual cost of AD has more than doubled to $214 billion and is on track to surge to $1.2 trillion (today’s dollars) by 2050 if we cannot find a suitable intervention to prevent, slow, or cure this disease.

Given that this disease primarily affects the elderly, more than half of the $214 billion cost is borne by the Centers for Medicare & Medicaid Services through Medicare and Medicaid reimbursements (Figure 2). According to the Alzheimer’s Association, the average per-‐person Medicare spending for those with Alzheimer's and other dementias is three times higher than for those without these conditions. The average per-‐person Medicaid spending for seniors with Alzheimer's and other dementias is 19 times higher than average per-‐person Medicaid spending for all other seniors.

It is important to remember that AD significantly impacts both the patient and caregivers. Given the physical, mental, and emotional strain of caring for someone with Alzheimer’s, the health of caregivers often declines steadily throughout the duration of care. In addition to suffering from physical illness, caregivers are more likely to experience depression and abuse substances. These physical manifestations on the health of caregivers add to the cost of AD to our healthcare system and our overall economy.

Furthermore, due to the intense level of care that many AD patients require, caregivers must often reduce working hours, take less demanding jobs, or discontinue work altogether. While this often creates financial hardship for the caregiver, employers are also impacted. According to the Alzheimer’s Association, businesses lose more than $61 billion per year as a result of costs related to caregiver absenteeism, employee replacement, related productivity loss, and employee assistance programs.

Figure 2: Impact of Alzheimer’s disease on the U.S. healthcare system. Source: Alzheimer’s Association, 2014 Alzheimer’s Disease Facts and Figures, Alzheimer’s & Dementia, Volume 10, Issue 2.

Medicaid 17%

Medicare 53%

Out-‐of-‐pocket 17%

Other 13%

Breakdown of Alzheimer's $214 Billion Impact on the US Healthcare System

Medicaid Medicare Out-‐of-‐pocket Other

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AD AWARENESS FALLS BEHIND COMPARED TO OTHER DISEASES

People are often under the misconception that AD is a disease that only affects older people, and that dementia in general is a normal part of the aging process. We now know that dementia is caused by specific neurodegenerative diseases and is thus not a normal part of aging. In addition, while it is true that this disease predominantly affects the elderly population, the societal and economic consequences of the disease affects all generations. The emotional and financial strain that this disease places on the families of loved ones with Alzheimer’s in addition to the economic strain placed on our healthcare system will cripple our society if we cannot cure or prevent this disease in the near term. By raising awareness among individuals not yet affected by Alzheimer’s and educating those who are, the community can better mobilize the masses to:

• advocate to policymakers for additional resources to boost research efforts and improve infrastructures to support AD patients and families;

• participate in healthy brain aging studies to help researchers better understand factors that may either protect against AD and other forms of dementia, or increase susceptibility to these disorders; and

• participate in clinical research studies aimed at preventing and/or curing AD.

In order to attenuate the massive threat that AD poses to global health and the global economy, commitment of focused resources aimed at raising awareness, supporting research, and encouraging citizen participation in clinical research studies is imperative.

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“We spend one penny on research for every dollar the federal government spends on care for patients with Alzheimer’s. That just doesn’t make sense. We really need to step up the investment.” –Senator Susan Collins (R-‐Maine), National Alzheimer’s Project Act co-‐sponsor

OUR DOLLARS MUST MAKE SENSE

PUBLIC POLICIES ADRESSING AD UNMET NEEDS

To face the growing problem that is AD, public policies are needed to address the systemic issues that impede research progress. Core challenges that make Alzheimer’s research especially difficult to study include large-‐scale funding of research, regulatory issues, and improving care for patients. Despite the growing understanding of the burden of AD, there are major impediments to progress toward effective treatment. First, AD necessitates massive large-‐scale, long-‐term studies that are coordinated nationally to identify the best molecular targets for the disease and ultimately treatments and interventions that will be successful. Second, the ability to properly diagnose and study targets and progress toward successes has proven extremely difficult using the traditional clinical trial framework. Finally, barring a dramatic shift in the trajectory of this disease, combined with an aging population, the growing burden of this disease will vastly outpace the care.

A number of policy solutions that seek to address some of these issues have recently been signed into law in the United States. Those that are notable include the National Alzheimer's Project Act (NAPA) and the Alzheimer’s Accountability Act.

NATIONAL ALZHEIMER'S PROJECT ACT

NAPA was signed into law in 2011 after unanimous passage by both houses of Congress. The law mandates the creation of a national strategic plan to address the Alzheimer’s crisis with the specific goal of preventing and/or effectively treating AD by 2025. This act created the opportunity to improve, leverage, and coordinate existing U.S. Department of Health and Human Services programs and other federal efforts with the aim of changing the trajectory of AD. The law calls for a National Plan for AD with input from a public-‐private Advisory Council on Alzheimer's Research, Care and Services. This plan, first completed in 2012 and revised annually, presents a recurring opportunity for Congress to assess the efforts to combat AD.

Unfortunately, Congress has not mandated funding to support activities outlined in the NAPA strategic plan. Alzheimer’s advocacy groups, such as the Alzheimer’s Association, has recommended to Congress that NAPA include at least a $2 billion annual increase to Alzheimer’s research funding, in order to have the desired impact on AD; however, this recommendation has gone largely unsupported by lawmakers, to the detriment of taxpayers and the U.S. economy.

To jumpstart the plan, the Obama administration’s fiscal year 2014 budget proposal included $100 million in additional funding for research, awareness, education, outreach, and caregiver support. While the investment falls far short of what is necessary for actual impact, the inclusion in the budget helped to refocus attention on this very important problem and the strategic framework poised to potentially provide solutions.

To learn more about NAPA, please visit http://aspe.hhs.gov/daltcp/napa/.

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ALZHEIMER’S ACCOUNTABILITY ACT

Building on the coordinated goals of NAPA, the Alzheimer’s Accountability Act, signed into law at the end of 2014, requires the director of the NIH to submit to the President for review and transmittal to Congress an annual budget estimate for the NIH initiatives under NAPA. The secretary of Health and Human Services and the Advisory Council on Alzheimer's Research, Care and Services are provided an opportunity to comment on the budget but cannot change the content. The Alzheimer’s Accountability Act creates a formal process for NAPA recommendations to directly impact government funding allocation for AD each year until 2025. Again it is important to note that this provision does not increase funding to the recommended level of an additional $2 billion annually, but it does help to strategically reallocate resources toward the strategic plan put forth by NAPA.

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RISK, DIAGNOSIS, AND PROGRESSION

RISK FACTORS

While the cause of Alzheimer’s disease is not well understood, research has shown that there are both general and genetic factors that increase the risk of developing AD.

General risk factors include the following:

• Age – The risk of developing AD doubles every five years starting at age 65.

• Education – Lower educational attainment has been linked with higher risk of developing AD.

• Medical conditions – Medical conditions such as head trauma, diabetes, depression, high cholesterol, and cardiovascular diseases (including stroke) are associated with a higher risk of developing AD.

There are also genetic risk factors that have been shown to play a role in the development of AD. Based on our understanding of AD to date, researchers have found that there are two primary forms of Alzheimer’s that can be categorized based on age of onset and genetic mutations.

• Early onset / familial AD – affects people under the age of 65. Mutations in the following genes are strongly associated with this form of AD:

§ Amyloid precursor protein (APP) § Presenilin 1 (PSEN1) § Presenilin 2 (PSEN2)

• Late onset AD / sporadic AD – affects people over the age of 65 and is the most common form of AD. There are currently two genetic alleles (regions of DNA) shown to be strongly associated with this form of AD:

§ ApoE epsilon 4 (ApoE4)

The genes listed above are only a subset of genes thought to be involved in the development of AD. Researchers are continuously identifying new genes through the use of cutting-‐edge sequencing technologies that enable mapping of genetic mutations to clinical manifestations of AD.

THREE STAGES OF ALZHEIMER’S DISEASE

In 2011, Alzheimer’s diagnostic guidelines were updated for the first time in nearly 30 years. The previous guidelines published in 1984 were the first official criteria to outline diagnosis; however, the guidelines defined AD as a single-‐stage disease that only included dementia. In addition, diagnostic criteria were based solely on clinical symptoms, and diagnosis could only be confirmed upon autopsy of the brain.

As a result of modern research, we now know that AD is a multi-‐stage disease that may cause changes in the brain a decade or more before the display of clinical symptoms; however, these symptoms do not always relate to abnormal changes in the brain caused by AD. The updated guidelines cover the full spectrum of the disease, outlining diagnostic criteria for dementia due to AD, mild cognitive impairment due to AD, and preclinical AD. The guidelines also now address the use of imaging and biomarkers (biochemical and genetic characteristics that can

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• Age-‐Associated Memory Impairment/Cognitive Decline

• Parkinson’s Disease • Lewy Body Dementia • Cerebrovascular Disease • Frontotemporal Lobar Degeneration

OTHER CAUSES OF MCI

be used to track disease-‐related changes) in blood and spinal fluid. Additional descriptions of each of the three stages of AD are provided in the sections below.

PRECLINICAL AD

Preclinical is the earliest stage of AD. This stage refers to instances where AD-‐related changes in the brain are underway but clinical symptoms, such as memory impairment or behavioral alterations, are not yet evident. While the guidelines identify these preclinical changes as an Alzheimer's stage, they do not currently establish diagnostic criteria that doctors can use to categorize patients. Instead these guidelines apply only in a research setting.

The key challenge faced by the AD community is that it is clear that early intervention will be essential to optimally preserving cognition. The amendment of the guidelines to address this issue is helpful to the research community as it presents a framework for additional research on biomarkers to determine which ones can be used to track AD-‐related changes in the brain and how best to measure them.

MILD COGNITIVE IMPAIRMENT DUE TO AD

Patients suspected of having mild cognitive impairment (MCI) due to AD generally experience mild changes in memory and thinking that are enough to be noticed and measured using mental status tests, but are not severe enough to compromise personal independence or overall executive function in daily life. People with MCI may or may not progress to Alzheimer’s dementia.

It is important to note that MCI may be attributed to one or more etiologies (causes) outside of AD (see Figure 3); however AD accounts for 60 to 80 percent of all dementia cases. Clinicians may incorporate the use of biomarkers to help identify with more certainty whether or not a patient is experiencing MCI due to AD or other disorders that can lead to MCI.

DEMENTIA DUE TO AD

Dementia due to Alzheimer’s refers to the final stage of the disease. In this stage, impairments in memory, thinking, and behavior decrease a person's ability to function independently in everyday life. At this stage, biomarker test results may be used in some cases to increase or decrease the level of certainty about a diagnosis of Alzheimer’s dementia; however, these biomarker tests are primarily used as a complementary tool for clinicians rather than an official diagnostic.

Figure 3: Alternative causes of mild cognitive impairment

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MEASURING COGNITIVE IMPAIRMENT FOR DIAGNOSIS

Multiple clinical tests have been developed to measure mental decline by asking patients to memorize and associate words, complete simple mathematical calculations, or draw an object that can simultaneously enable the evaluation of multiple brain functions.

Such tests include but are not limited to the following:

• The Mini Mental State Examination (MMSE) • Clock Drawing Test and Mini-‐Cog Test • Montreal Cognitive Assessment

Once mental decline is confirmed, standard medical tests are conducted to dismiss other potential causes of dementia, such as stroke, Parkinson’s disease, or tumors. Such tests include blood tests and neuro-‐diagnostic tests such as brain screening.

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DISEASE BIOLOGY

Alzheimer’s is a form of dementia, which is an umbrella term used to describe a state in which there is a loss in cognitive function – thinking, reasoning, memory, etc. – and behavioral abilities to the extent where these losses interfere with routine daily activities. There are a number of disorders categorized as forms of dementia (Figure 4); however, AD is the most common, accounting for 60 to 80 percent of all cases of dementia.

AD is caused by irreversible loss of neurons. Neurons are nerve cells responsible for processing and transmitting information through electrical and chemical signals. These signals can be transmitted from neuron to neuron by traveling through cellular appendages called axons and exiting through synapses. Transmission of neuronal signals is essential to all processes involving the central nervous system.

While the cause of AD is unclear, there are some key pathological features of the disease that scientists strongly believe can lead to Alzheimer’s. These hallmark features of Alzheimer’s include the following:

• Build-‐up of beta-‐amyloid protein in the brain • Abnormal modification of tau protein in the brain

These events can lead to disruption in neuronal communication and/or neuronal death, which ultimately brings about the clinical symptoms of Alzheimer’s – memory impairment, cognitive decline, and behavioral problems that impair or prohibit independent living. Detailed descriptions of each of the aforementioned hallmarks are provided below.

BETA AMYLOID PROTEIN BUILD-‐UP IN THE BRAIN LEADS TO PLAQUES

Beta-‐amyloid protein is derived from a larger protein called amyloid precursor protein (APP), which is found in the synapses of neurons. The role of APP is not altogether clear; however, various research studies suggest that it plays a role in regulating synapse formation, neural plasticity, and iron export. Beta-‐amyloid protein is generated when APP is severed in the cell by other proteins called enzymes. Cleavage of APP into the truncated beta-‐amyloid form encourages the protein to assume a new three-‐dimensional structure that allows the surfaces of beta-‐amyloid to attract to other beta-‐amyloid molecules, forming a sticky aggregate that clumps together to form what is commonly referred to as amyloid plaques (Figure 5). We now know that beta-‐amyloid, which deposits in senile plaques, can promote formation of neurofibrillary tangles and inflammation, leading to neuronal cell death. Clumps of beta-‐amyloid called oligomers can also impair transmission of signals across neuronal synapses.

Figure 4: Select forms of dementia

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Figure 5: Amyloid precursor protein (APP) being snipped by enzymes to form beta-‐amyloid proteins that stick together to form beta-‐amyloid plaques. Source: National Institute on Aging, National Institutes of Health.

TAU PROTEIN BUILD-‐UP IN THE BRAIN LEADS TO TANGLES

Tau proteins are essential to stabilizing microtubules – the scaffolding structure of neurons (Figure 6). The abnormal modification of tau (namely the addition of phosphorous group) leads to a structural change that impedes the ability of tau to stabilize microtubules, leading to structural collapse of the neuron. This collapse prohibits the delivery of nutrients to the neuron, ultimately leading to neuronal death. In addition, the abnormal tau proteins aggregate such that they tangle together to form what is referred to as neurofibrillary tangles (Figure 7).

Figure 6: Healthy neurons – Microtubule scaffold of the neuron is stabilized by tau protein molecules. Source: Alzheimer’s Disease Education and Referral Center, National Institute on Aging.

Figure 7: Diseased neurons in AD – Tau proteins are modified with phosphate groups, which change the structure of tau and compromises its ability to stabilize microtubules leading to neuron collapse and the formation of tangled fibers. Source: Alzheimer’s Disease Education and Referral Center, National Institute on Aging.

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NEUROTRANSMITTER DYSFUNCTION

In addition to amyloid-‐beta and tau build-‐up in the brain, neurotransmitter deficiency is also an important pathological feature of AD. Neurotransmitters are responsible for carrying information from one cell to another. In AD, the processes by which neurotransmitters are produced and/or function are disrupted. Studies show that neurotransmitter deficiency over time leads to memory and cognition deficits commonly observed in AD.

Treatment strategies to date have focused on targeting the following neurotransmitters:

• Acetylcholine • Glutamate • Serotonin

As shown in Table 1, all currently U.S. Food and Drug Administration (FDA)-‐approved therapies for the treatment of AD target either acetylcholine or glutamate. New drugs targeting serotonin are currently in late-‐stage clinical trials.

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TREATMENTS

There is no cure for AD, and currently approved therapies by the FDA treat only the symptoms of AD rather than modifying the disease to cure or slow it down. Consequently one of the largest unmet needs for AD patients is access to effective disease-‐modifying therapies.

Currently, there are four FDA-‐approved drugs for the treatment of AD (Table 1). Three of these agents – donepezil, galantamine, and rivastigmine – target the process by which the neurotransmitter, acetylcholine, is broken down by an enzyme called cholinesterase. The hypothesis behind the use of this agent is that the inhibition of the breakdown of acetylcholine will consequently slow down mental degradation that leads to impaired learning, memory, and/or judgment. Cholinesterase inhibitors are believed to delay the disease process by 6 to 12 months, but the symptoms eventually worsen with additional destruction of neurons through other AD pathological pathways, such as amyloid-‐beta and tau buildup.

Memantine differs from the other agents in that it inhibits glutamate, a neurotransmitter that controls communication among neurons by regulating calcium ion levels in the cells. Excess glutamate can lead to an imbalance in calcium ions in neurons, ultimately resulting in their death. This effect is called excitotoxicity. By interfering with the action of glutamate, memantine reduces this toxic effect of calcium ion imbalance.

As mentioned previously, the efficacy and benefits of all of the current FDA-‐approved treatment options for AD are marginal at best and work only to alleviate the symptoms. New and effective AD treatment options are desperately needed.

Table 1: FDA-‐approved treatments for Alzheimer’s disease

Stage of Disease Treated

Drug Name Mechanism of Action

Mild Moderate Severe

Donepezil Cholinesterase Inhibitor

X X X

Galantamine Cholinesterase Inhibitor

X X

Rivastigmine Cholinesterase Inhibitor

X X X

Memantine Glutamate receptor antagonist

X X

* Tacrine, a cholinesterase inhibitor, was previously approved for AD, but was withdrawn from the U.S. market in May 2012

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CLINICAL TRIALS AND INVESTIGATIONAL THERAPIES

CLINICAL TRIALS -‐ OVERVIEW

Clinical research is research in human subjects aiming toward approved products for use in patients. Clinical trials determine whether a particular product is as effective in people as it is in the laboratory or in animal models, which often fail to adequately mimic human responses. Further, clinical trials provide information on potential adverse reactions or side effects that need to be weighed against the potential benefits.

Clinical research for drugs and vaccines is broken into four key phases. Each phase is described in Table 2.

Table 2: Phases of clinical development

Clinical Phase

Description Number of Patients

Phase I Examines the safety of the product in a very small group of healthy volunteers or patients afflicted with a specific disease. Also used to determine appropriate dose ranges.

20-‐80

Phase II Evaluates the safety and efficacy of the product at a pre-‐determined dose in comparison to the current standard of care treatment (commercially available therapies commonly used to treat the same disorder or disease).

100-‐300

Phase III Evaluates the product compared to the standard of care in a large diverse population to determine broader efficacy and develop usage guidelines.

1,000-‐3,000

Phase IV Evaluates the long-‐term effects of a drug post-‐FDA approval for public use.

All patients prescribed the drug by a treating physician

INVESTIGATIONAL THERAPIES

As of March 2015, there were 115 products in clinical development for AD. Figure 8 illustrates the distribution of these trials by phase of clinical development.

In the sections below we discuss key therapeutic strategies that are being explored in AD clinical trials.

Figure 8: Agents in research and clinical development for AD.

48

3

46

3 15

Phase I Phase I/II Phase II Phase II/III Phase III

AD Drug Development Pipeline

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AMYLOID-‐TARGETING THERAPIES

There are a number of drugs in development for AD that specifically target beta-‐amyloid proteins. The goal of this therapeutic strategy is to clear beta-‐amyloid build-‐up in the brain to deter plaque formation by either:

• decreasing the production of beta-‐amyloid protein, or • increasing removal of beta-‐amyloid protein from the brain.

As mentioned previously, the cleavage of amyloid precursor protein (APP) gives rise to a short toxic form of the protein – beta-‐amyloid. There are three enzymes that are primarily responsible for cleaving APP to form beta-‐amyloid:

• beta-‐secretase, • gamma-‐secretase, and • alpha-‐secretase.

These proteins have been key targets in AD drug development because of their role in regulating the production of beta-‐amyloid and ultimately plaque formation. Table 3 outlines the type of therapeutic required for impact on beta-‐amyloid production and drug class descriptors commonly used by the research and drug development communities.

Table 3: AD drug classes targeting specific proteins critical to the production of beta-‐amyloid

Protein name Function with respect to beta-‐amyloid production

Type of targeted therapeutic required for impact on beta-‐

amyloid

Drug class descriptor

Beta-‐secretase Increases production of beta-‐amyloid Inhibitor of beta-‐secretase BACE1 inhibitors

Gamma-‐secretase Increases production of beta-‐amyloid Inhibitor of gamma-‐secretase GSI and GSM

Alpha-‐secretase Decreases production of beta-‐amyloid Activator of alpha-‐secretase Alpha secretase activators

Challenges

While a number of drugs targeting beta-‐amyloid have been evaluated in AD clinical trials, there is not yet any clear indication that these drugs can improve Alzheimer’s symptoms or protect brain cells.

TAU-‐TARGETING THERAPIES

As mentioned previously, tau proteins play a key role in stabilizing the walls of neurons. The abnormal modification of tau, primarily phosphorylation (deposit of phosphorous and oxygen groups onto a protein by molecules called kinases – see Figure 9), leads to the collapse of the neuronal wall, neuronal dysfunction and/or death, and neurotransmitter deficits. In addition, the accumulation of abnormal tau protein leads to neurofibrillary tangles that are also toxic to neurons and is a key hallmark of AD.

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Tau-‐targeting therapies prevent tau aggregation or dissolve existing aggregates to interfere with the aforementioned pathological consequences of abnormal tau. Given the key role that kinases play in tau pathology, a number of tau-‐targeting therapies aim to modulate the process by which kinases phosphorylate tau. There are many types of kinases; however, research studies have shown that GSK3-‐beta (GSK3β) and cyclin dependent kinase 5 (cdk5) play key roles in tau phosphorylation and tangle formation. Tau antibodies (also referred to as tau immunotherapy) have the potential to target synaptic tau and interfere with the spread of tau among neurons.

The development of tau antibodies and drugs that inhibit the aforementioned kinase targets have been of intense focus in Alzheimer’s research and are currently in clinical development.

Challenges

The development of kinase inhibitors is an approach riddled with inherent challenges. As mentioned previously, there are numerous variations of kinases, many of which play a redundant role in targeting and phosphorylating various proteins such as tau. Because kinases interact with many different proteins, inhibition of these molecules will invariably inhibit kinase interactions necessary for normal cellular functions throughout the body. This inhibition of normal function leads to unintentional and potentially severe side effects.

The redundant roles of kinases also add to the challenge, that is, the inhibition of one kinase that phosphorylates tau does not necessarily lead to the inhibition of another kinase that also phosphorylates tau. Researchers have attempted to circumvent this challenge by developing drugs that can target more than one kinase. The multi-‐targeting approach has been to chemically link together two drugs that target different kinases. The outcome of this type of approach has been poor to date, primarily because this technique leads to large drugs with high molecular weights, which are less than optimal for penetrating the blood-‐brain barrier.

While protein kinases are promising drug targets, more work needs to be done to develop kinase inhibitors that have the following properties:

• can target multiple kinases, • low molecular weight so the drug can efficiently enter the brain, and • focused targeting of specific kinases to minimize cellular toxicity as a result of off-‐target effects.

NEUROTRANSMITTER TARGETING THERAPIES

As mentioned previously, the processes by which neurotransmitters are produced, released, and/or used are disrupted in AD. Many of the key neurotransmitters affected by AD pathology are critical to learning, memory, and cognition.

It is debated that acetylcholine is perhaps the most critical neurotransmitter affected by AD pathology. The vital neurotransmitter is of particular importance to AD as it is the primary neurotransmitter utilized by memory systems of the hippocampus, a key structure affected in AD. The emphasis on acetylcholine does not completely overshadow the role of the other aforementioned neurotransmitters – glutamate and serotonin –as many of them are also involved in the overall metabolism (production, use, and breakdown) of acetylcholine. To strengthen the

Figure 9: Proteins called kinases deposit phosphorous groups onto tau. Structural modification of tau with phosphoryl groups compromises tau’s ability to hold together neuronal walls.

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argument that acetylcholine metabolism is central to AD progression, multiple research studies strongly link acetylcholine deficiency to loss of brain volume and the severity of dementia.

Challenges

While FDA-‐approved AD treatments to date exclusively target neurotransmitter deficiencies, these drugs have proven to be ineffective in modifying the disease or significantly slowing progression. While an identified link between neurotransmitter deficiency and AD progression provides strong evidence that the research is on the right track, real-‐world clinical experience demonstrating limited efficacy of these agents suggests that they may need to be used in combination with other treatment strategies.

IMMUNOTHERAPY

As mentioned previously, much of the focus of Alzheimer’s research has been figuring out ways to prevent and/or slow down the process by which amyloid beta and tau build up in the brain. In addition to exploring small molecule drugs to serve this purpose, researchers have also identified ways to activate the immune system to target amyloid beta and tau. These strategies, referred to as immunotherapy, work by soliciting either an active or passive immune response. Active immunotherapy involves the administration of a substance (drug, vaccine, etc.) into the body that induces an immune response leading to the natural production of antibodies against the target (i.e., amyloid beta or tau). Passive immunotherapy differs in that the desired antibodies against the target are manufactured outside of the body and administered as a drug.

While immunotherapy strategies targeting amyloid beta have been extensively studied, tau-‐directed immunotherapies are not as advanced. Despite encouraging pre-‐clinical and early-‐stage data demonstrating that this approach can successfully clear amyloid beta build-‐up in mice, success in human trials has been moderate at best. A key challenge to this approach is managing the immune response such that the immune system does not over-‐react to the treatment. This can lead to excessive brain inflammation, brain hemorrhaging, and other severe side effects.

In addition to these challenges, it is also unclear when patients should be treated to fully benefit from these treatments. Data from two late-‐stage trials of passive immunotherapies that failed to meet their goals of improving cognition in patients with mild to moderate AD underscore the common belief that the pathology (amyloid or tau buildup) may be too far advanced for significant clinical benefit at this stage. Much of the data generated thus far suggest that patients should be treated well before they display clinical symptoms. However, identifying high-‐risk AD patients with reasonable confidence that they will develop AD and determining when to treat is a highly complicated, long-‐term undertaking.

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STEM CELLS

Scientists are currently exploring the use of stem cells to study the molecular features of Alzheimer’s and as a potential treatment option for patients.

Using Stem Cells to Model AD and Screen New Therapies

Research has shown that the pathological, molecular, and genetic features of AD can vary significantly among patients, and it is important to study the mechanisms driving the heterogeneity of the disease in order to find a cure. The tremendous progress in stem cell research – including breakthrough work on three-‐dimensional cell culture systems that can recapitulate Alzheimer’s – has enabled researchers to use this technology to create patient-‐specific models of AD in a petri dish. This is done by taking skin cells from an Alzheimer’s patient (donor) and reprogramming them to make a type of stem cell called induced pluripotent stem (iPS) cells. These iPS cells can be programmed to become all different types of cells in the body, but for the purpose of AD research, they are reprogrammed to become neurons. Because the cells are derived directly from a patient, despite being grown in petri dishes, they display the same molecular and pathological features as identified in the donor patient. The coupling of the patient’s clinical symptoms to the biology and behavior of the stem cells could provide new insights into the key mechanisms of Alzheimer’s.

These iPS cells can also be used to test new drugs. The use of iPS cells to screen drugs that may be effective against AD provides an additional method to validate results observed in animals studies. This is important because a major impediment to Alzheimer’s research is the poor translation of animal results to humans. This occurs because the biology of mice and other small animals is different from that of humans, thus positive results observed in animal models often cannot be recapitulated in humans.

Using Stem Cells to Treat Alzheimer’s

Stem cells are not currently used to treat AD, but researchers are pursuing this possibility. Treatment with neuronal stem cells could theoretically replace brain cells damaged by AD and encourage the generation of new healthy neurons. While the technology holds great promise, there are significant challenges that must be overcome before this type of treatment can become a reality. The first challenge is that AD affects many different types of neurons in various parts of the brain. Therefore, the stem cells would not only need to be able to generate a wide variety of neurons, but would also have to travel specifically to regions of the brain damaged by AD. In addition, the new neurons would need to integrate effectively into the complex network of the brain in order to complete synaptic circuits that control communication between neurons in the brain. Finally, there has not yet been a safe protocol developed for conducting these types of neural stem cell transplants.

NUTRACEUTICALS

There is evidence that suggests that properties of certain foods may provide protection against neurodegenerative disorders such as Alzheimer’s. These foods or food components are commonly referred to as nutraceuticals. Key nutraceuticals that have been studied for their neuroprotective effects against AD include the following:

• Flavonoids are a group of compounds commonly found in fruits, vegetables, and several types of tea, cocoa, and wine. These compounds have been shown to modulate several neurological processes including inducing changes in cerebral blood flow, increasing antioxidants involved in synaptic plasticity

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and neuronal repair, and inhibiting neuro-‐pathological processes in brain regions typically involved in AD pathogenesis.

• Resveratrol is a compound found in seeds and fruit skins. Evidence has shown that resveratrol can increase activity of serotonin, reduce inflammation, and protect neurons from death.

• Curcumin is the most active element of turmeric and has antioxidant and anti-‐inflammatory properties. It has been shown to reduce amyloid-‐beta cerebral burden and inflammation in AD mouse models.

• B vitamins (B6 and B12) have been shown to be essential for maintaining the integrity of the nervous and hematopoietic systems and are involved in the regulation of mental function and mood. Some studies suggest that the metabolite homocysteine is a risk factor for dementia or cognitive impairment and that supplementation with B vitamins can reduce homocysteine levels in the blood.

While there is significant interest in the neuroprotective properties of nutraceuticals, evidence supporting their use to prevent or delay Alzheimer’s remains inconclusive. There is very little standardization among clinical trials evaluating the effect of these dietary agents on cognitive impairment, which makes it very difficult to meaningfully analyze and compare results across trials. While the potential for nutraceutical development is promising, more work needs to be done to improve clinical trial design and make it uniform.

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CHALLENGES IMPEDING AD RESEARCH AND KEY PHILANTHROPIC OPPORTUNITIES

There are a number of challenges and unmet needs that stand in the way of desperately needed progress in Alzheimer’s research. In January 2015, FasterCures convened 12 world-‐renowned Alzheimer’s experts to discuss the state of science relevant to AD and the challenges currently impeding research progress. Below we present the key issues that were prioritized by the group and recommendations to address these challenges with strategic philanthropic investments.

It is important to note that the list below is in no way exhaustive, and the philanthropic opportunities presented here should be considered carefully with respect to your philanthropic goals and discussed in detail with a philanthropic advisor.

LACK OF RELIABLE BIOMARKERS

THE PROBLEM

The AD community is in desperate need of biomarkers that will:

• help clinicians diagnose and measure AD progression,

• determine whether drugs are engaging intended molecular targets to better predict side effects and inform dosing strategies, and

• enable accurate monitoring of treatment responses.

At this time there is not a single biomarker that can be used confidently for these purposes. Current methods used to track AD pathology (primarily brain imaging along with amyloid beta and tau biomarkers found in the cerebral spinal fluid, or CSF), are compromised by variability. These challenges significantly impede both standard of care and clinical development in that we do not have a reliable way to track disease progression in patients, nor do we have the tools necessary to effectively evaluate behavior and performance of drug candidates in pre-‐clinical models. The inherent limitations of the preclinical data due to lack of biomarkers have partially led to the large number of failed clinical trials.

POTENTIAL SOLUTIONS

Biomarker validation and standardization – A concerted effort to both validate and standardize current imaging and CSF biomarkers to raise confidence levels and mitigate variability will be key to addressing this challenge.

Identification of new biomarkers – There is a need for a strategic clinical program that would incentivize the collection of fluids (blood, plasma, serum, platelets, CSF, saliva, urine) as a standard to enable researchers to rationally explore various protocols that may unveil not only new biomarkers, but also new ways to quantify current biomarkers.

Studies correlating genotype, phenotype, and biomarkers – Collection of the various types of fluids mentioned above would enable an integrated research program that would allow researchers to correlate the relationship between an individual patient’s genes (genotype), clinical display of AD symptoms (phenotype), disease stage, and various biomarkers. This will improve clinicians’ understanding of AD patient subpopulations with the aim of

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elucidating which groups of patients may respond better or worse to various treatments. This method will also help to unveil biomarkers that can be used to diagnose and monitor progression and/or treatment response.

EXAMPLES OF CORRESPONDING PHILANTHROPIC OPPORTUNITIES:

• Support initiatives that focus on standardizing imaging parameters and CSF biomarkers.

• Support researchers who are willing to validate old and new biomarkers by attempting to replicate the original data and publishing the results, whether they are positive or negative.

• Support a team of researchers that proposes the best plan for conducting a large-‐scale genotype-‐biomarker-‐phenotype correlation study in various patient populations, stratified by stage of disease, using fluid and imaging samples.

INADEQUATE PRECLINICAL MODELS

THE PROBLEM

Both cellular and animal models used to test agents before entering clinical trials do not adequately recapitulate AD pathology. Part of the reason is that it is very difficult to mimic the complexity of the brain in laboratory models. As a result, drugs that seemingly modify the disease in animals or conventional cell lines do not have the same effect in humans, and a large number these agents fail in clinical trials.

POTENTIAL SOLUTIONS

Humanized cells as an alternative to animal models – In this approach, induced pluripotent stem cells are made from skin cells and reprogrammed to become neurons. These neuronal-‐like cells can be used to study genetic variants of AD that are specific to individual patients. These patient-‐ and disease-‐specific human iPS cells can be used as a drug discovery platform that will ultimately enable a personalized medicine approach for AD and potentially shave years off of the drug development timeline. While this approach is exciting and considered to be a major breakthrough, more work needs to be done to validate the likeness of these cells to human tissue.

EXAMPLES OF CORRESPONDING PHILANTHROPIC OPPORTUNITIES

• Support studies that validate iPS cells as models of in vivo human cells by comparing the transcriptional profile (the pattern by which the cells make DNA) of cells from human tissue samples with that of differentiated iPS cell transcriptional profiles.

• Support a personalized medicine study using iPS cells from a specific patient, enabling researchers to recreate the patient’s specific disease pathology in a petri dish and allow for testing of experimental and/or repurposed drugs.

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IDENTIFYING NEW DRUGGABLE MOLECULAR TARGETS

THE PROBLEM

The identification of new molecular targets is critical to the development of new agents for AD. Historically, AD drug discovery has primarily focused on amyloid beta and tau proteins as key drug targets. While there is evidence that drugs targeting amyloid beta and tau can successfully engage these molecules, they demonstrate very little efficacy with respect to mitigating the clinical manifestations of AD. As a result, these drugs have largely failed in clinical trials.

POTENTIAL SOLUTIONS

Rather than continuing to explore the same avenues of AD pathology that have led to no treatment breakthroughs, other processes suspected of playing a role in AD pathology must be studied in greater detail. These processes include but are not limited to synaptic interaction, vascular changes in the brain, the role of inflammation, and the study of genetic mutations that protect against Alzheimer’s.


• Support studies that evaluate the role of synaptic biology in healthy and AD-‐affected brains using optogenetics and other cutting-‐edge technologies.

• Support studies that explore the role of vascular changes on AD onset and progression, including the identification of genes relevant to AD that affect vascular function.

• Support studies that explore the role of the immune system by studying the communication between the peripheral and central immune systems and how this communication relates to AD susceptibility.

• Support genotyping of individuals who are at high risk for the development of AD but who have maintained normal cognition into old age. These studies can potentially identify mutational variants that can protect against AD.

• Support longitudinal studies focused on deepening understanding of the physiology of healthy brain aging with the purpose of comparing results to the physiological changes of AD brains and potentially identifying physiological processes and/or genes that protect against AD.

AD RESEARCH IS CONDUCTED IN SILOS

THE PROBLEM

Alzheimer’s research is currently conducted in silos, meaning that research conducted on different aspects of the disease is not always linked together in an efficient way. For example, a researcher studying tau pathology may not regularly communicate with a researcher studying vascular system changes in AD patients.

These silos also unintentionally facilitate duplication of efforts. For example, drug leads that are either highly similar or the same are often developed at multiple institutions because there is no efficient way of knowing

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exactly which molecules have been created and tested if the results are not published. This is an enormous waste of resources and time, particularly if the drug lead has failed testing and the data have not been shared. Often, researchers are only able to build on the work of others once that work has been published or shared pre-‐publication through an agreed collaboration between researchers.

POTENTIAL SOLUTIONS

The silos that are currently impacting acceleration of AD research can be broken down by:

• Providing more in-‐person opportunities to communicate and share ideas among experts working in areas of the field that are currently not well connected.

• Providing additional centralized infrastructures to support sharing of ideas and data among researchers.

• Developing and using a systems-‐based infrastructure that can be populated with all published information on AD research with the aim of creating a knowledge network that will enable the assembly of a more complete picture of the etiology, pathology, and progression patterns of AD.


• Support interactive workshops for AD experts working in diverse fields, as well as outside experts working in related fields (e.g., immunologists, data scientists, etc.), to come together to present their work, discuss research roadblocks, identify ways to address these roadblocks, and potentially build collaborations.

• Support initiatives that incentivize sharing of medicinal chemistry data, which can serve as key starting points for motivated stakeholders in the AD community to develop new chemical entities and ultimately diverse drug classes. Consider funding projects that will:

§ Provide an infrastructure for academic centers to catalogue agents being developed in their labs and incentivize the use of this type of resource.

§ Incentivize drug development companies to share structural safety databases.

• Support the development of a “Bloomberg-‐like” data infrastructure that can be populated with all published information on AD research and used to create a knowledge network that will enable rational testing of drug candidates based on human AD pathology and molecular pharmacology. This will attenuate (but not completely alleviate) the AD community’s current dependence on seemingly encouraging results from animal models, which often do not translate to humans, leading to failed clinical trials.

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KEY STAKEHOLDERS IN THE ALZHEIMER’S COMMUNITY

RESEARCH GRANTMAKING ORGANIZATIONS

This section provides a brief overview of the nonprofit organizations involved in AD research. Their involvement can be through directly funding research or supporting research (for example, by charting the research roadmap for the disease or collecting tissue samples). This analysis includes only organizations with a research focus. Organizations that are involved solely in patient support, advocacy, awareness, or whose mission is to fund one specific research center are also excluded here. Figure 10 shows the top three funders of AD research exclusively. The sections below describe these organizations as well as others that do not exclusively fund AD research, but are considered to be major grantmakers in the field.

ALZHEIMER’S ASSOCIATION

Incorporated in 1980 as the Alzheimer’s Disease and Related Disorders Association, the Alzheimer’s Association is a voluntary health organization dedicated to Alzheimer’s research, support, care, and education. Its mission is “to eliminate Alzheimer’s through the advancement of research, to provide and enhance care and support for all affected, and to reduce the risk of dementia through the promotion of brain health.” It has a national office in Chicago, along with a nationwide presence through a network of 77 chapters. Providing research funding is one of the key activities of the Alzheimer’s Association. Research grants accounted for $15.6 million (12.7 percent of total expenses) in 2013. In addition to directly funding research, the organization also emphasizes its role as a nonprofit entity, focusing on building collaboration and leveraging resources for research advancement. The Alzheimer’s Association is currently sponsoring the Global Alzheimer’s Association Interactive Network (GAAIN). GAAIN is a big data community that enables data sharing and collaboration among AD researchers around the world.

The organization also has multiple activities focused on strengthening the AD research community, including organizing scientific meetings, publishing a journal, and building a professional society. In addition, the association is also active in providing patient support, increasing public awareness on AD, providing information for healthcare professionals, and conducting advocacy efforts.

$4,576

$7,137

$15,601

$0 $3,000 $6,000 $9,000 $12,000 $15,000 $18,000

Cure Alzheimer's Fund

Alzheimer's Drug Discovery Foundaron

Alzheimer's Associaron

THOUSANDS

2013 RESEARCH EXPENDITURES (THOUSANDS)

Figure 10: Expenditures on AD research grants by AD research funding organizations, FY2013.

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ALZHEIMER’S DRUG DISCOVERY FOUNDATION

The Alzheimer’s Drug Discovery Foundation (ADDF) was founded in 2004 as an affiliate to the Institute for the Study of Aging, a private foundation of the Estee Lauder family founded in 1998. The ADDF focuses its funding on pre-‐clinical and early-‐stage clinical trials involving new drug targets that may not be far enough along in the pipeline to receive financial support from the pharmaceutical industry or other partners. By bridging the gap between basic research and drug development, ADDF enables scientists to pursue innovative and novel therapies that might otherwise go unexplored. Over the years, ADDF has successfully used the venture philanthropy model to invest more than $14 million in drug discovery research and clinical trials, and nearly $3 million of that investment has been returned and immediately invested in other drug research programs. In 2013, its grants amounted to $7.1 million, or 92 percent of total expenses.

BRIGHTFOCUS FOUNDATION

Founded in 1973 (and known as the American Health Assistance Foundation until 2013), the BrightFocus Foundation is based in Clarksburg, Md. Supporting research and public education to eradicate brain and eye disease, including AD, macular degeneration, and glaucoma, this nonprofit is “working to save mind and sight.” The AD research program was initiated in 1985 and currently supports 64 research projects out of 133 total foundation grants. In 2013, its total research grant budget amounted to $7.5 million, or 32 percent of total expenses. The research program focuses on providing initial funding for highly innovative or experimental ideas. Most awardees use the funding to demonstrate key findings that lead to later interest and additional funding.

CURE ALZHEIMER’S FUND

Cure Alzheimer’s Fund was founded in 2004 and has raised $48.3 million since its inception. The mission of the organization is “to fund research with the highest probability of slowing, stopping, or reversing Alzheimer’s disease.” Instead of funding investigator-‐initiated project proposals, the fund’s Research Consortium selects the researchers who are aligned with its research agenda and solicits proposals directly. In 2013, research grants amounted to $4.5 million, or 71 percent of total expenses. The fund’s research approach is to identify all genes associated with late-‐onset AD, clarify their roles, and facilitate treatment development based on the knowledge derived. The fund does not support indirect costs of the grant recipient’s institution, and all of the fund’s administrative costs are funded by the founders and board members.

NEW YORK STEM CELL FOUNDATION

The New York Stem Cell Foundation (NYSCF) was founded in 2005 with the mission of accelerating cures for the major diseases of our time through stem cell research. Its programs focus on research, fellowships and investigator awards, their conference and symposia, and the Robertson prize (awarded to a stem cell researcher under the age of 40). NYSCF works in a variety of disease areas including ALS, Alzheimer’s, diabetes, multiple sclerosis, and Parkinson’s disease. Its work in AD includes collecting patient samples to develop stem cells that can aid in studying Alzheimer’s and screening chemical compounds to find new drugs. In 2013, its total research grant budget amounted to $6.1 million, about 31 percent of total expenses.

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KEY INITIATIVES AND STRATEGIC PARTNERSHIPS

ALZHEIMER’S DISEASE INTERNATIONAL

Alzheimer’s Disease International (ADI) is the international federation of more than 80 Alzheimer associations around the world. The organization works to focus attention on the AD epidemic and campaign for policy change from national governments and the World Health Organization. The group runs a series of workshops – Alzheimer’s University – that focuses on helping local Alzheimer’s associations strengthen their organizations. The group also hosts the longest-‐running annual conference on dementia, the Annual International Conference of ADI.

DEMENTIA DISCOVERY FUND

The Dementia Discovery Fund is a $100 million global venture fund that aims to accelerate efforts to find treatments and a cure for Alzheimer’s. Announced in March 2015, this venture fund is the first of its kind solely focused on dementia. Initial financing for the fund has been committed by the British government, Alzheimer’s Research UK, Johnson & Johnson, Eli Lilly, Pfizer, Biogen Idec, and GlaxoSmithKline. Resources from the fund will be used to support innovative research in academia and small biotech firms. Research projects that secure funding will also gain mentored guidance from industry partners throughout the funding cycle. Once a project matures, individual pharmaceutical companies will have an opportunity to bid on the rights to commercially develop the technology. The money raised from the bidding process will be reinvested in the fund.

GLOBAL ALZHEIMER’S AND DEMENTIA ACTION ALLIANCE

In May 2014, Alzheimer’s Disease International, the Alzheimer’s Society (England, Wales, and Northern Ireland), and the Department of Health in England announced the formation of the Global Alzheimer’s and Dementia Action Alliance (GADAA). This alliance was formed in response to a call for action during the 2013 G8 Summit on Dementia, which called for research funding increases, improved infrastructure to support dementia care, and community programs to change societal attitude towards dementia. GADAA is designed to foster global collaboration among international non-‐governmental organizations, professional associations, governments, and international statutory bodies to deliver on these actions while continuously raising Alzheimer’s and dementia awareness.

GLOBAL CEO INITIATIVE ON ALZHEIMER’S

The Global CEO Initiative on Alzheimer’s represents an acceptance of the invitation from public authorities, domestically and internationally, to the private sector to forge robust public-‐ private partnerships to stop Alzheimer’s and dementia. According to its Web site, its “vision is that the CEO Initiative becomes the leading business voice on this seminal public health issue of our time, which will have profound impact in fiscal, social, and political matters as we ‘change the game’ on Alzheimer’s.” Among other efforts, the group is currently working to develop a Global Alzheimer’s Platform, which will be a global network of clinical trial sites, functioning under a globally convergent and synchronized regulatory body with alignment on key issues related to clinical trial design. The vision of this effort is to create a global infrastructure in which sites can quickly and efficiently recruit participants, with the aim of reducing redundancy, expense, and time. This platform will also support data sharing to advance basic discovery and translational research.

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US AGAINST ALZHEIMER’S

US Against Alzheimer’s (USA2) is fiercely devoted to advocacy by pressuring political, business, and civic leaders to devote the necessary resources to outcomes-‐oriented research and to reform the drug development systems that currently impede the development and availability of promising treatments. The organization is committed to increasing public-‐ and private-‐sector resources to stopping Alzheimer’s disease, accelerating the drug development process to deliver therapies to patients in need, and dramatically improving the care infrastructure for Alzheimer’s patients and caregivers. Key milestones highlighted by the organization include helping to secure more than $200 million in additional public funding for AD research over the past few years, driving global efforts that have resulted in the collaboration of G7 world leaders to embrace the goal of curing Alzheimer’s by 2025, forging collaborations to improve efficiencies for expedited drug discovery and approval for AD, and inspiring clearer research milestones to measure progress of the National Alzheimer’s Project Act.

WORLD DEMENTIA COUNCIL

The World Dementia Council was formed in 2014 as a result of a commitment declared during the G8 Dementia Summit in December 2013. The primary goals of the council are to stimulate innovative development and commercialization of life-‐enhancing treatments and care for people with dementia, or at risk of dementia, within a generation. The council has committed to executing on these goals by providing independent, non-‐governmental advocacy and global leadership.

ACADEMIC CONSORTIA

ALZHEIMER’S DISEASE NEUROIMAGING INITIATIVE

The Alzheimer’s Disease Neuroimaging Initiative (ADNI) is a public-‐private research partnership tasked to identify diagnostic biomarkers for AD. Through the analysis of brain scans, genetic profiles, and biomarkers in blood and CSF, the group hopes to identify reliable biomarkers that can consistently detect AD and indicate progression. The study includes scientists at 55 research centers in the United States and Canada, and involves more than 800 study participants at various stages of AD, including no memory problems, MCI, and dementia due to AD. To date the ADNI study has helped to develop a diagnostic test that can help diagnose the beginning stages of AD sooner and more accurately by measuring tau and amyloid beta in CSF.

In 2010, the ADNI study moved into the second phase of development, termed ADNI GO. This research effort focuses on participants that exhibit the earliest signs of memory loss in mild cognitive impairment. This work is ongoing.

ADNI stakeholders are currently planning for the next phase of ADNI (ADNI 2), which will focus on identifying the earliest signs of AD by building on the successes of ADNI and ADNI GO. This study is based on the hypothesis that measurable changes in the brain likely occur well before AD symptoms appear. This study will enroll a large number of new volunteers in the earliest stages of cognitive impairment.

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COHORTS FOR ALZHEIMER’S PREVENTION ACTION

Cohorts for Alzheimer’s Prevention Action (CAPA) is a consortium focused on optimizing how existing observational data are used to answer questions about actionable strategies for prevention of Alzheimer’s. The study evaluates large datasets gathered from different groups of people to determine lifestyle and risk patterns that may correlate to the development of AD. By the end of 2014, CAPA successfully received consent from more than 180,000 people included in 40 data cohorts.

GLOBAL ALZHEIMER’S ASSOCIATION INTERACTIVE NETWORK

GAAIN is a big data community sponsored and managed by the Alzheimer’s Association. GAINN enables data sharing among a federated, global network of data partners who are studying Alzheimer’s and other dementias. The platform is meant to assist scientists working to advance research in AD and other neurodegenerative disorders by enabling integration and search of aggregated datasets.

GLOBAL BIOMARKER STANDARDIZATION CONSORTIUM

The Global Biomarker Standardization Consortium (GBSC) was established by the Alzheimer's Association to convene key stakeholders in Alzheimer’s research to achieve consensus on the best ways to both standardize and validate biomarkers for use in the clinical settings worldwide. The regularly convened stakeholders include leading researchers and clinicians, as well as industry, regulatory, and government leaders. Some of the key issues that the group works to address and develop standards for are the following:

• Variability in the extraction, handling, and storage of cerebrospinal fluid for biomarker measurement.

• Variability in brain imaging protocols used to diagnose AD by measuring the volume of the hippocampal region of the brain.

ALZHEIMER'S DISEASE COOPERATIVE STUDY

The Alzheimer’s Disease Cooperative Study (ADCS) is a cooperative agreement between the National Institute on Aging and the University of California, San Diego that was established in 1991. The overall mission of ADCS is to facilitate the discovery, development, and testing of new drugs for the treatment of AD. The organization specifically focuses on developing drugs for AD that might not be developed by industry, including agents that lack patent protection, are under patent protection but are already marked for other indications, and novel compounds developed by individuals, academic institutions, and drug discovery units. The mandate of ADCS is to:

• improve cognition, slow the rate of decline, or delay the appearance of AD;

• develop studies for promising agents designed to ameliorate behavioral symptoms;

• design new instruments for use in clinical studies;

• conceive of novel and innovative approaches to clinical study design and AD clinical study analysis;

• expand the range of patients in AD studies; and

• enhance the recruitment of minority groups into AD studies.

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Key ADCS activities include:

• the development of AD centers capable of carrying out AD studies in the United States and Canada; • widespread sharing of assessment tools, trial methods, and data with academic investigators and

commercial entities around the world; • development of the concept of mild cognitive impairment as a treatable entity and a clinical study to

delay conversion from mild cognitive impairment to AD; and • standardization and development of worksheets for the use of the Clinical Dementia Rating Scale.

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GLOSSARY

Acetylcholine: a neurotransmitter released at autonomic synapses and neuromuscular junctions, active in the transmission of nerve impulses.

Active immunotherapy: administration of a vaccine into the body to induce an immune response leading to the natural production of antibodies against a target.

Amyloid plaques: aggregates of beta-‐amyloid protein molecules that accumulate in the spaces between the brain’s neurons. They are one of the two anatomical hallmarks that define Alzheimer’s disease; the other hallmark is neurofibrillary tangles.

Amyloid precursor protein (APP): a transmembrane protein found in neuronal synapses from which beta-‐amyloid protein is derived.

Axon: the appendage of a neuron that transmits impulses away from the cell body.

Beta-‐amyloid protein: a protein that is derived from amyloid precursor protein and is the primary component of plaques characteristic of Alzheimer’s disease.

Biomarker: a distinct biochemical, genetic, or molecular characteristic that is objectively measured and evaluated as an indicator of a particular biological condition or process.

Blood-‐brain barrier: a layer of cells lining the inner surface of brain capillaries. It protects the brain from infectious agents and toxic compounds by letting nutrients and oxygen in and waste products out. Because the barrier strictly regulates the passage of larger molecules and often prevents drug molecules from entering the brain, it has long posed one of the most difficult challenges in developing treatments for brain disorders.

Cholinesterase: an enzyme that catalyzes the hydrolysis of acetylcholine.

Clinical trials: prospective biomedical or behavioral research studies on human subjects that are designed to answer specific questions about potential interventions (vaccines, drugs, medical devices, etc.), generating safety and efficacy data.

Dementia: a usually progressive condition marked by the development of multiple cognitive deficits, such as memory impairment, aphasia, and inability to plan and initiate complex behavior. Types of dementia include Alzheimer’s disease, vascular dementia, Lewy body dementia, and Parkinson’s disease.

Enzyme: a protein originating from living cells that catalyzes specific biochemical reactions.

Etiology: the cause(s) of a disease or abnormal condition.

Excitotoxicity: pathological process by which neurons are damaged and killed by the overactivation of receptors for the excitatory neurotransmitter glutamate.

Glutamate: an excitatory neurotransmitter that controls communication among neurons by regulating intracellular calcium ion levels.

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Kinase: an enzyme that catalyzes the addition of phosphorous and oxygen groups to a protein.

Microtubule: a hollow cylindrical protein structure in neurons that holds the cell in its proper shape and also helps transport nutrients within the cell.

Neurofibrillary tangles: collections of twisted protein threads found inside diseased neurons, composed primarily of abnormally modified tau protein. They are one of the two anatomical hallmarks that define Alzheimer’s disease; the other hallmark is amyloid plaques.

Neuron: a cell that processes and transmits information through electrical and chemical signals.

Neurotransmitter: an endogenous chemical that transmits signals across a synapse from one neuron to another.

Parasympathetic nervous system: the part of the nervous system that regulates activities such as salivation, urination, digestion, defecation, and tear generation.

Passive immunotherapy: administration of antibodies or other immune system components that are made outside of the body (i.e., in the laboratory) to patients in order to activate their immune systems.

Phosphorylation: the addition of phosphorus and oxygen groups onto a protein.

Serotonin: a neurotransmitter that is involved in sleep, depression, memory, and other neurological processes.

Synapse: specialized connections between neurons where information is transmitted.

Tau protein: a protein that binds to and regulates the assembly and stability of neuronal microtubules; found in an abnormal form in Alzheimer’s disease.

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