Research Projects

Project 1

Principal Investigator: Michael Rugg, Ph.D.
Title: Neural Correlates of Episodic Memory in Older Adults

The long-term objectives of this research are to characterize age-related changes in the neural correlates of episodic memory, determining which of these changes underlie the decline in episodic memory that accompanies aging, and which may reflect compensatory mechanisms that ameliorate such decline. The findings will provide information relevant to the understanding and remediation of memory decline in healthy aging, and facilitate future investigations of the more severe memory impairments that are associated with age-associated pathology such as Alzheimer’s disease.

Project 2

Principal Investigator: Doug Wallace, Ph.D.
Title: Assessing mtDNA Variation in AD in Man and a Canine Model

The mitochondria provide most of the energy of our cells by the process of oxidative phosphorylation (OXPHOS). Late-onset AD patients are more likely to have an affected mother than father, several mildly deleterious mtDNA mutations have been reported in AD patients and certain inherited mtDNA lineages have been found to be protected against AD, and associated with increased longevity. We discovered that mtDNA control region mutations are markedly elevated in AD brains relative to age-matched controls. To determine if the deleterious mtDNA control region mutations detected in AD brains are also found systemically in AD patients, we propose to test the blood cells of AD patients for these mutations. To determine if AD is associated with mtDNA CR mutations in other long-lived animals, we propose to look for deleterious mtDNA CR mutations in demented beagle dogs. We will examine beagles for improved mitochondrial function that are on anti-oxidant therapy for the level of deleterious the mtDNA CR mutations.

Project 3

Principal Investigator: Frank LaFerla, Ph.D.
Title: Effect of Aß Immunotherapy on Tau Aggregates

One of the most fundamental and unresolved questions in the Alzheimer’s disease (AD) field is whether therapies aimed at clearing Aß will suffice to stop the progression of this insidious disease. In other words, will removing Aß plaques impact the subsequent development of AD neuropathology, including the progression of the neurofibrillary pathology? This question, to date, has been intractable in humans. The approach we utilized involved the administration of anti-Aß antibodies into the hippocampus of the 3xTg-AD mice. Our preliminary findings show that Aß immunotherapy effectively clears early tau pathology in the brains of the 3xTg-AD mice, although hyperphosphorylated tau aggregates are resistant to clearance. Our results have direct application for the clinical treatment of AD and provide an opportunity to investigate the mechanisms by which Aß and tau interact. In summary, the implications for AD and other tauopathies is highly significant as it suggests that interventions such as vaccinations will work provided that it is administered early in the disease course, prior to tau hyperphosphorylation. Moreover, these data provide strong evidence for a link between Aß and tau in an in vivo, physiologically relevant system.