Alzheimer’s disease (AD) is the most common form of dementia, currently affecting more than 5 million Americans and more than 25 million people worldwide. The prevalence of AD increases progressively with aging, and increased age itself is the single most important risk factor for AD.  With the aging of the population, the number of older adults with AD will increase dramatically in the coming decades unless effective preventive strategies are developed. Although breakthroughs in the treatment of AD have been made, these therapies work mainly to delay further loss of function rather than restore cognitive abilities. With the projected dramatic increase in AD prevalence over the coming decades, there is increased urgency to find effective ways to prevent or delay the onset and progression of the disease.

The Wisconsin Alzheimer's Disease Research Center is a collaborative team of investigators with research interests spanning from basic science to clinical research. The focus of our program is to investigate ways to distinguish normal aging from abnormal cognitive decline, to identify persons at risk for AD before any symptoms of memory loss occur, and to find effective treatments to prevent or delay the onset and progression of AD.  Our current studies cover the basic science of how hormones and growth factors affect aging and cognition, neuroimaging studies that assess early brain changes leading to AD, clinical trials investigating the potential role of statins and estrogen in the prevention of AD, treatment studies of soy and other novel medications for AD patients, and outreach projects to improve screening for dementia throughout the State of Wisconsin. Through collaboration with researchers locally and nationwide as well as partnerships with participants and organizations from the community, W-ADRC investigators seek to answer questions as to what causes AD and how this devastating disease can be prevented.

Detailed descriptions of ongoing research in the W-ADRC are listed below. If you are interested in finding out more information about these studies, please contact one of our study coordinators.

Treatment Studies

Sanjay Asthana, MD

Kronos Early Estrogen Prevention Cognitive Affective Study (KEEPS-CA)

The KEEPS-CA Study is a 4 year, multisite, randomized, placebo-controlled, double-blind, parallel-group design trial addressing major hormone-related issues raised by recent findings of Women’s Health Initiative Memory Study (WHIMS). The objective of the KEEPS- CA Study is to evaluate differential efficacy of oral conjugated equine estrogen (CEE or Premarin®) and transdermal 17 β-estradiol (tE2) with 12 days/month progesterone (Prometrium®) on mood and cognition in healthy women who have not had a hysterectomy who are within 6 months - 3 years of menopause. This hormone therapy study will address questions on which type of estrogen is the preferred method for hormone therapy as well as whether earlier intervention with hormone therapy in perimenopausal women provides greater benefit.

Study Coordinator:       Whitney Wharton, PhD, 608-256-1901 ext 11516
wlwharto@medicine.wisc.edu

Midwest INitiative for Dementia Screening (MINDS) Project

The objective of the MINDS project is to evaluate the efficacy of regional community-based dementia screening and educational outreach in Wisconsin. The MINDS Project provides interested participants with a free-of-charge, thorough dementia screening service, the results of which are used by primary care and subspecialty clinicians to aid in the diagnostic process.  The target population for the MINDS Project includes older adults residing in Wisconsin within a 140-mile radius of Madison, the headquarters of the Wisconsin Alzheimer's Disease Research Center.

Study Coordinator:       Whitney Wharton, PhD, 608-256-1901 ext 11516
wlwharto@medicine.wisc.edu

Carey Gleason, PhD  

Soy’s Potential Effect on Cognition in the Treatment of Alzheimer’s (SPECTRA) Study

The SPECTRA study examines the cognitive effects of soy isoflavones, a class of phytoestrogens, in older adults with AD. Soy isoflavones may serve as an alternative therapy to traditional hormone replacement therapy (HRT) and can be used in both men and women. The effects of soy isoflavones offer intriguing but preliminary support for isoflavones' beneficial actions on cognition. Sixty older adults with AD will be enrolled in this randomized, placebo-controlled, double-blind, parallel-group design clinical study. Subjects will receive either 100mg/day of soy isoflavones or a placebo for 6 months and cognitive data will be collected.

Study Coordinator:       Kirsten Walth, 608-256-1901 ext 11514
klwalth@medicine.wisc.edu

Prevention Studies

Cynthia Carlsson, MD, MS

Evaluating Simvastatin’s Potential Role in Therapy (ESPRIT)

The ESPRIT trial is a 9-month randomized, placebo-controlled, clinical trial which will provide pivotal information concerning possible mechanisms underlying the potential efficacy of statins to reduce the risk for Alzheimer’s disease (AD). This study involves a unique population of middle-aged (35-69 years) men and women who are adult children of persons with clinically confirmed probable AD. The study investigates the effect of simvastatin 80mg vs. placebo on cerebrospinal fluid (CSF) biomarkers for AD, namely CSF b-amyloid and tau. In addition, measures of inflammation, cholesterol turnover, brain perfusion and cognitive measures are assessed in participants.

Study Coordinator:       Hanna Blazel, MS, 608-256-1901 ext. 11692
hmb@medicine.wisc.edu

Brain Imaging Studies

Sterling Johnson, PhD

Functional MRI (fMRI) of Vulnerable Brain Regions in Persons at Risk for AD (ALZ Study)

In the ALZ study, fMRI, structural MRI, and additional clinical information is collected in persons at risk for AD. The primary areas of the brain that are studied in this trial are the posterior cingulated gyrus and the mesial temporal lobe- limbic structures that may change before clinical symptoms appear.  By investigating these structures in this longitudinal study, Dr. Johnson hopes to clarify the neurobiological changes occurring in preclinical AD with the hopes of identifying who may benefit from future preventive strategies.

Awareness of Deficit after Combat-related Brain Injury (Veterans)

In this study, Dr. Johnson is evaluating veterans with traumatic brain injury using fMRI. The brain is pictured while “at work,” meaning that imaging is collected while the study participant is completing word recall and other memory screenings while in the MRI.

For more information on MRI imaging and aging research, pleasevisit:

http://www.brainmap.wisc.edu/

Study Coordinators:      Sandy Harding, 608-256-1901 ext 11075
sjharding@medicine.wisc.edu
Amy Hawley, 608-256-1901 ext. 11418
ahawley@medicine.wisc.edu

Michele Ries, PhD

fMRI of Anosognosia in Amnestic Mild Cognitive Impairment (MCI) and AD

A subset of patients with amnestic MCI and those patients with AD will undergo fMRI and be screened for anosognosia- a condition relating to one’s insight into their deficits. A person’s awareness of their cognitive decline can be notably changed as their disease progresses. Understanding this process can be part of the physiologic changes occurring in the cortical midline structure.  Awareness of one’s own changes in cognition may play an important role in the management and safety of persons with AD.

Principal Investigator:    Michele Ries, PhD, 608-256-1901 ext. 11452
mlr@medicine.wisc.edu

Basic Science Research

Craig Atwood, PhD

Cell Cycle Life and Reproductive Hormone’s Contribution to Alzheimer’s Disease

Dr. Atwood’s research interests include understanding the role of reproductive hormones in modulating healthy aging and lifespan. His work links reproduction to aging, using gene expression and pituitary hormone lowering drugs to dissect hormonal pathways that promote longevity and their mechanism of action. A number of different in vivo (from C. elegans to humans) and in vitro (cell lines and primary cells) models are used to address how the dysregulation of the hypothalamic-pituitary-gonadal axis during menopause/andropause drives both aging and age-related diseases, particularly AD.

Recent work has been instrumental in showing that leuprolide acetate may be effective in reversing AD pathology and the study of the hypothalamic-pituitary gonadal axis in neurodegeneration associated with Alzheimer's disease (i.e. in synaptic and neuronal loss, amyloid deposition and neurofibrillary tangle formation).

For more information on the research of Dr. Atwood please visit:

http://www.wisc.edu/agingresearch/

Luigi Puglielli, MD, PhD

Aging and Alzheimer’s disease

Dr. Puglielli’s laboratory has identified a novel molecular pathway that connects the aging program mediated by the insulin-like growth factor 1 receptor (IGF-1R) to neurotrophin signaling and b-amyloid generation, a key event in the pathogenesis of AD. IGF-1R is the common regulator of lifespan in all organisms. In fact, hyper-activation of IGF-1R leads to accelerated aging and short lifespan, whereas a partial block of IGF-1R leads to delayed aging and increased lifespan. Finally, genetic variations that cause reduced IGF-1R signaling appear to be beneficial for old age survival in humans suggesting an evolutionary conserved regulation of lifespan and age-associated events in all animals. Dr. Puglielli’s laboratory employs a combination of biochemical, genetic, and molecular approaches on in vitro, ex vivo, and in vivo settings.

For more information on the research of Dr. Puglielli, please visit: http://www.wcmp.wisc.edu/faculty_puglielli_luigi.shtml