Scientists and physicians have been studying AD for over a century. The first described case was a patient, August D., who was treated by Dr. Alois Alzheimer in 1901. Five years later that patient died, and Alzheimer undertook a detailed study of her brain tissue, describing the presence of neurofibrillary tangles and amyloid plaques, the histological hallmarks of AD—and the keys to understanding it. However, even after resolving the structure of plaques and tangles in the 1960s, twenty years would pass before researchers identified the molecules that compose them (3), and even today researchers are still trying to determine what happens first in the onset of AD: The appearance of plaques, the appearance of tangles? Or is there some other, more subtle, event that triggers the pathology?
The genetic and molecular studies of AD are numerous and deep and continue to yield information that may help design an effective treatment or cure for the disease. Equally important, though, are the epidemiology studies that focus on environment and behaviors as risk factors for the disease. One of the most fascinating epidemiological studies is the “Nun Study,” begun in 1986 with volunteers from the School Sisters of Notre Dame convent in Mankato, MN, USA. The pilot study looked at aging in 100 nuns to see if there were any environmental factors that correlated with “successful” aging. In that pilot study, researcher David Snowden, found a clear correlation between educational level and successful aging—in the population studied, higher educational levels correlated with successful aging (physical and mental) and longevity (4).
In 1988 Snowdon presented work from the pilot study, and he was approached by Jim Mortimer from the Minneapolis Veterans Administration Medical Center(4) about designing an Alzheimer disease study using the volunteer nuns. Snowdon received funding for a larger-scale study, and he moved to the University of Kentucky to work with the other members of the Sanders-Brown center there. The “Nun Study” involved 678 volunteer nuns belonging to the order of the School Sisters of Notre Dame. The nuns agreed a take a battery of tests over the course of the study, to open their biographical records and life stories to the researchers, and finally to donate their brains for scientific study after their death (4).
Perhaps the single most important conclusion from the study is that Alzheimer disease is not straight forward. In several cases, pathology studies of brain tissue from the deceased nuns did not correlate with their performance on cognitive function tests. Sometimes the pathologist would score a brain as having signs of extremely advanced AD, only to learn later that the nun herself scored extremely well on all cognitive tests. Other times a brain would show only slight damage associated with AD, and the nun was characterized as exhibiting the signs of advanced cognitive decline and dementia.
The study did provide a hint that people suffering from chronic depression early in life tended to be more likely to show outward signs of AD, even though the actual damage to the brain was minimal (4), and clinicians recognize today that treating depression in AD patients can improve their function. So, there does appear to be a correlation between depression and developing outward symptoms of AD; however, the mechanism behind this relationship is not understood.
Another finding from the Nun Study is that participants who had well developed language skills, as demonstrated by analysis of the autobiographies that they wrote as postulates, tended not to develop Alzheimer disease. Autobiographies that could be identified as original and unedited were analyzed for two characteristics: idea density and grammatical complexity. High idea density and to some extent, grammatical complexity, were associated with a decreased likelihood of developing AD (4). Idea density was measured by calculating the number of individual ideas expressed in ten words, and grammatical complexity was measured by rating sentences on a scale of 0 (simple clause) to 7 (complex sentences with embedded grammatical structures and subordination). By the time the researchers finished the analysis, they were able to predict with 80% accuracy from essays written in a woman’s early twenties whether or not she would develop Alzheimer disease at age 80.
With the retirement of Snowdon, the records and tissue samples are back at the University of Minnesota. The data and tissues will be available to researchers around the world, so that researchers and clinicians can continue to learn from these nuns. Additionally, the University of Minnesota has announced that it will begin a second study, with a new group of volunteer nuns, to delve further into the mysteries of Alzheimer disease: Why do some people develop symptoms and not others? Why do some people with advanced brain damage: plaques, tangles and tissue loss, not show any symptoms, while others with minimal brain damage show symptoms of advanced AD?
- Thomas, P. and Fenech, M. (2007) A review of genome mutation and Alzheimer disease. Mutagenesis 22, 15–33.
- Lovell, M.A. and Markesbery, W.R. (2007). Oxidative DNA damage in mild cognitive impairment and late-stage Alzheimer disease. Nucl. Acid Res. 35, 7497–504.
- Goedert, M. and Spillantini, M.G. (2006) A Century of Alzheimer’s Disease. Science 314, 777–780.
- Snowdon, D.A. (2001) Aging with Grace. Bantam Books. New York, NY.
Isobel Maciver also contributed to this article.