The National Alzheimer's Coordinating Center:
The Eye of the Storm

By W.A. Kukull, Ph.D.
Professor, Department of Epidemiology, and director, National Alzheimer's Coordinating Center

Bud Kukull

From the Alzheimer’s Association, we have the newest statistics: 5.3 million Americans have been diagnosed with Alzheimer’s disease (AD), and there’s a new case diagnosed every 70 seconds. It’s a tremendous burden on families, the health care system, and society, and as Americans age, the burden will only get heavier. To try to find ways to cure and perhaps even prevent the disease, the NIH’s National Institute on Aging funds 29 Alzheimer’s Disease Centers (ADCs) at major medical institutions across the US and also funds the National Alzheimer’s Coordinating Center to facilitate collaboration among the ADCs and to serve as a central data repository for all the ADCs.

As you might imagine, 29 Centers produce a lot of data. Enter the National Alzheimer’s Coordinating Center (NACC), here at the UW School of Public Health. Closely woven into the Alzheimer’s research community, NACC not only maintains the database but also produces two Center-wide Directors’ meetings each year and facilitates communication and interaction between the Centers. Yes, we are the eye of the storm—though sometimes it feels like Katrina is at our door. (Please visit our Web site for more information.)

NACC was first funded in 1999 as a five-year Cooperative Agreement; it was renewed in 2004 and again in March of this year. Each cycle includes about $15 million in funding.

Looking at the Data
The NACC database includes the “Minimum Data Set (MDS)” of retrospective data reflecting the clinical enrollment experience of the ADC program between 1984 and 2004 (approximately 74,000 individuals). In 2005, NACC implemented a much more detailed standardized clinical evaluation and data collection protocol with annual follow-up—the Uniform Data Set (UDS). The UDS includes approximately 16,500 individuals, some of whom are also represented in the MDS. In addition, detailed neuropathology data are available for all subjects who have died and undergone autopsy (approximately 10,600 persons who were originally represented in either the MDS or the UDS).

Each of these data sets includes cognitively normal persons, people who have been diagnosed with dementia, and people who are just beginning to experience cognitive problems, termed Mild Cognitive Impairment. Most dementia subtypes are represented, though AD is the most common. NACC not only maintains the database but also provides funding (from the NACC grant award) to member Centers for collaborative research. NACC is currently collaborating with the Alzheimer’s Disease Genetics Consortium, the National Cell Repository for Alzheimer’s Disease, and the ADCs on a series of genome-wide association studies based on the NACC database. With these studies we hope to identify new genetic associations with disease as well as potential targets for intervention treatment or risk reduction.

Dementia Defined
We often describe cognitive impairment as a decline in our usual and customary abilities to reason and remember and, basically, to think. When this impairment affects more than one cognitive domain (like memory and judgment) and affects our ability to function, socially or occupationally, the cognitive decline meets clinical criteria for “dementia.” As the dementia progresses, it doesn’t take a rocket scientist to notice that something is wrong; sometimes, though, the person with dementia can’t see it.

There are many types of dementia. The most common type is believed to be AD, accounting for approximately 70% of dementia cases. But AD can coexist with other subtypes, such as vascular dementia (related to strokes, insufficiency, or white matter insults within the brain), Lewy body disease (a similar pathology to Parkinson’s disease but occurring in other brain regions), and frontotemporal lobar degeneration, which can cause frontotemporal dementia, primary progressive aphasia, semantic dementia, progressive supranuclear palsy and several other conditions.

Neurodegenerative dementias (i.e., those other than vascular dementia) appear to be caused when specific proteins in the brain misfold, aggregate, and act to destroy synapses (the connections between nerve cells) and kill the nerve cells themselves. The locations in the brain that are affected, along with the specific type of protein, seem to account for the observable clinical dementia symptoms that we characterize as AD, Dementia with Lewy Bodies (DLB), or frontotemporal dementia (FTD). While one set of symptoms may predominate clinically, such as memory loss in AD, sleep disturbance and visual hallucinations in DLB, or disinhibition in FTD, various combinations of the underlying misfolded proteins can be present in all brains. In fact, these protein aggregations may start forming a decade or more before any clinical dementia symptoms are observed—long before we, our spouses, or our children notice any subtle decline in our usual and customary abilities to reason, remember, plan, or think.

Looking to the Future
The principal proteins involved in AD pathology are called Aβ (amyloid beta protein) and tau. They form the characteristic pathology of AD noted by Alois Alzheimer in his 1906 lecture, “An Unusual Disease of the Cerebral Cortex,” which described the clinical course and pathological findings of August D., a woman whom he began following clinically when she was 51 (in 1901). The pathologic characteristics of AD remain essentially the same as Alzheimer first described them. However, between 1906 and about 1980, AD was thought to be very rare, limited to a dementia that affected relatively young persons between 35 and 55. The dementia older people got was thought to be just normal “senility” and was sometimes said to be due to “hardening of the arteries” or “chronic brain syndrome.” Around 1980, Dr. Robert Katzman and others noticed that the disease pathology was largely the same in older and younger dementia patients. Because of Dr. Katzman’s observations, we now recognize that AD, the same disease Dr. Alzheimer described, occurs much more commonly among persons age 70 and older.

AD risk increases rapidly among those age 70 or greater. If we started with a group of people age 70 or greater who had no clinical symptoms, we would expect new AD cases to occur at an average rate of 1–2 per 100 per year. Alzheimer’s patients may live 5 to 15 years after being diagnosed, so it is pretty easy to guesstimate that the number of people with the disease—the public health burden—will rise dramatically as the population ages. The impact will be great in the US, as more people live into their 80s and 90s, but the phenomenon will be felt to an even greater degree in China and the western Pacific because of the sheer numbers of persons in those countries who will be living to advanced ages.

Currently, we have no approved treatments that will modify the underlying disease process or interventions that will prevent the disease pathologically or its clinical manifestations. Indeed, we are only at the threshold of being able to presumptively detect asymptomatic, pathologic disease through neuroimaging modalities such as MRI, FDG-PET, and amyloid imaging. There are not yet any blood tests or other simple biological specimen tests that can be used to detect AD pathology. Such tests must be discovered and developed if we hope to avoid the catastrophic public health burden and personal tragedy of AD.

Science must move forward rapidly.

NACC owes its accomplishments and continued existence not just to the cooperation and good will of the NIA and everyone at the Alzheimer’s Disease Centers nationwide but also to its dedicated faculty and professional staff.

• Bud Kukull, a professor in the Department of Epidemiology, is director and principal investigator.
• Professor and former chair of Epidemiology Tom Koepsell is NACC’s associate director, and Professor Andrew Zhou of Biostatistics is senior biostatistician.
• Duane Beekly is our computing systems chief and architect of the database systems (without his expertise we would still be using file cabinets to store data); he is assisted by Mary Jacka, Janene Hubbard, Joylee Wu, and Woodrow Dietrich.
• Maggie Dean is our administrative manager; she is assisted by Miki Meahan.
• Leslie Phillips is a research scientist active in analysis and quality assurance issues (also an Epidemiology doctoral candidate)
•  Mike Sachs is an RA in Biostatistics
• Dawn Gill is an Epidemiology postdoctoral fellow; Baojiang Chen is a postdoctoral fellow in Biostatistics.