ARRA IMPACT REPORT:
Alzheimer’s Disease


Public Health Burden
Alzheimer's disease (AD) is a progressive, at present irreversible brain disease that slowly destroys memory and thinking skills and eventually the ability to carry out even the simplest tasks of daily living. Based on current trends, the number of Americans affected by AD is expected to increase substantially as the population ages.

Basic Research
Basic research to better understand the development and progression of AD are laying the foundation for new prevention and treatment interventions. ARRA-supported researchers have discovered that amyloid beta (Aß) a pathologic hallmark of AD, interacts with fibrinogen, a protein important for blood clotting, to form blood clots that are difficult to break apart. Aß and fibrinogen are deposited on the walls of blood vessels, contributing to memory impairment in a mouse model of AD. These findings suggest that therapies that prevent Aß from binding with fibrinogen may improve cerebral blood flow and promote neuronal survival in people with AD.1

Genetic Risk Factors
The ability to identify individuals at risk for AD is increasingly important as preventive interventions are developed for testing and as we learn more about how those at risk may be able to reduce their odds of developing the disease. ARRA-supported investigators have identified new genetic risk factors for late-onset AD (the more common form of the disease), including variants of several genes, such as CR1, CLU, PICALM,2,3 MS4A4/MS4A6E, CD2AP, CD33 and EPHA1.4

Biomarkers for Detection and Diagnosis
Research suggests that the earliest AD pathology begins to develop in the brain long before clinical symptoms yield a diagnosis. Therefore, it is critical to find ways to detect signs of the disease as early as possible to facilitate testing of interventions and, ultimately, treatment of the disease as early as possible. ARRA-supported investigators have determined that the two most commonly used cerebrospinal fluid (CSF) biomarker assays perform equally well in detecting and measuring amyloid plaque pathology in people with and without the disease, providing further support for the eventual use of CSF biomarker analysis as a diagnostic tool for AD.5

Possible Prevention and Treatment Strategies
ARRA-supported investigators have made the following advancements:

  • Extended the results of the Alzheimer’s Disease Anti-inflammatory Prevention Trial (ADAPT), finding that the effects of treatment with the NSAIDS naproxen and celecoxib differed at various stages of disease; both had an adverse effect during the first 2.5 years of the trial, especially when given to individuals with cognitive impairment. However, asymptomatic individuals treated with naproxen but not celecoxib experienced reduced AD incidence, but only after 2 to 3 years.6
  • Established a clinical trial of the drug methylphenidate to treat apathy, which is one of the most common behavioral symptoms of AD and one for which there is currently no effective treatment.7
  • Determined that modestly reducing levels of two enzymes in the brain, BACE-1 and γ-secretase, reduced Aß accumulation and improved cognition in a mouse model of AD. BACE-1 and γ-secretase are involved in generating Aß from amyloid precursor protein and are therapeutic targets for AD. However, large reductions and/or strong inhibition of these enzymes have been associated with unfortunate side effects in animal models. Previous animal studies have demonstrated that more modest reductions in either of these proteins alone reduces side effects but provides only mild protection against accumulation of Aß. These results suggest that a combination therapy that moderately inhibits both proteins could potentially be both safe and more effective than therapies that target only one of these proteins.8
  • Determined that low-dose treatment with the anti-epileptic drug levetiracetam improves cognitive performance in individuals with amnestic Mild Cognitive Impairment, a precursor condition to AD, possibly by reducing overactivity in the hippocampus.9

Contributing NIH Institutes & Centers

  • National Institute on Aging (NIA)
  • National Institute of Neurological Disorders and Stroke (NINDS)

  1. 2R01NS050537-06, http://www.ncbi.nlm.nih.gov/pubmed/20547128 - STRICKLAND, SIDNEY - ROCKEFELLER UNIVERSITY - NEW YORK - NY
  2. 5R01AG016208-11 - GOATE, ALISON M - WASHINGTON UNIVERSITY - SAINT LOUIS - MO
  3. 5RC2AG036528-02, http://www.ncbi.nlm.nih.gov/pubmed/20697030 - SCHELLENBERG, GERARD DAVID - UNIVERSITY OF PENNSYLVANIA - PHILADELPHIA - PA
  4. 1RC2AG036535-01, http://www.ncbi.nlm.nih.gov/pubmed/21460841 - WEINER, MICHAEL W - NORTHERN CALIFORNIA INSTITUTE RES & EDUC - SAN FRANCISCO - CA
  5. 1RC2AG036535-01, http://www.ncbi.nlm.nih.gov/pubmed/21555603 - WEINER, MICHAEL W - NORTHERN CALIFORNIA INSTITUTE RES & EDUC - SAN FRANCISCO - CA
  6. 2U01AG015477-06A2, http://www.ncbi.nlm.nih.gov/pubmed/21784351 - BREITNER, JOHN C S - SEATTLE INST FOR BIOMEDICAL/CLINICAL RES - SEATTLE - WA
  7. 1R01AG033032-01 - MINTZER, JACOBO E. - MEDICAL UNIVERSITY OF SOUTH CAROLINA - CHARLESTON - SC
  8. 2R01NS041438-06A2, http://www.ncbi.nlm.nih.gov/pubmed/20371462 - WONG, PHILIP C - JOHNS HOPKINS UNIVERSITY - BALTIMORE - MD
  9. http://www.ncbi.nlm.nih.gov/pubmed/22578498