Two Unique Alzheimer’s Studies

by Guy McKhann, M.D.

May 3, 2016

This is a column from Dana’s print publication, Brain in the News.

I would like to highlight two longitudinal studies involving religious order participants that have and still are providing valuable information about Alzheimer’s disease. These studies are outlined in an Atlas Obscura article by Natalie Zarrelli.

The “Nun Study” was started in 1986 by David Snowden, who was at the University of Minnesota at that time. Dr. Snowden was interested in cognitive changes with aging, and approached the School Sisters of Notre Dame in nearby Mankata, Minnesota. The sisters, 85 percent of whom had been teachers, were delighted to be involved.

The preliminary results of the original study were excellent, and when Dr. Snowden moved to the University of Kentucky in 1990, he took the study with him. He moved to Kentucky in part because investigators there, particularly Dave Clark and Bill Markesbery, were already involved in a study of more than 1000 Kentuckians, so the mechanisms of follow-up and data collection were already in place. Dr. Snowden quickly expanded his study to include other participants from other School Sisters of Notre Dame convents, eventually recruiting 678 participants. The participants ranged from 75 to 103 years old, with an average of 85. They agreed to annual assessments of cognitive and physical function, medical exams, blood drawing for multiple studies including genetic studies, and most importantly, brain donation at death. That study is ongoing—there are eight subjects left; the youngest is 100. In total, 600 brains have been collected. Dr. Snowden, in his mid-80s, recently retired, and the Nun Study has been reestablished at Minnesota. One of the conditions placed on the university is that the clinical and pathological data be made available to other investigators.

The other study, The Religious Orders Study of Rush University, started a few years after the Nun Study, in 1992, under the direction of David Bennett. This study is considerably larger, currently at 1,350 subjects. As of 2013 there has been a 94 percent autopsy rate (539 of 574 deaths). This study includes more than 40 religious orders including both males (priests and brothers) and females (nuns). Dr Bennett’s study is much more far-reaching than the Nun Study: It’s being used to answer questions about normal aging, the relation of risk factors to clinical outcomes, risk factors to neuropathology, and the relation between cognitive activity and time and rate of onset of Alzheimer’s.

The advantage of these studies is that they involve homogenous populations. Elder congregants tend to live in a given place and not move. Certain environmental variables present in the general population, such as alcohol, drugs, and dietary variations, are virtually eliminated. Further, there are archives of information on participants that go back to their first entry into the order. The medical histories of the participants are well documented, as are the use of medications. For example, one of the findings from the Nun Study is that low verbal skills early in one’s career correlated with the later appearance of Alzheimer’s symptoms and pathology.

The negative aspect to these studies is that they involve non-representative populations. The participants are primarily white, educated, Catholic women and men. Can findings from these studies be applied to other populations? It depends on what questions are being asked. If the questions relate to the basic biology of dementia such as the effects of age, the relation with cognitive activity, or genetic factors, these populations are ideal. Dr. Bennett and his colleagues are involved with two studies that involve other communities, one primarily black and the other mostly Hispanic. Dr. Bennett will be in a position to compare findings between groups.

Dr. Bennett’s group has been pouring out so much data in recent years—publishing more than 200 papers—that it is difficult to get a handle on all that they’ve done. There are recentpapers summarizing their findings.

Perhaps the most important finding from this group, and also from others, is that pure Alzheimer’s pathology is relatively rare. The majority of subjects were found on post mortem to have a mixed picture combining Alzheimer’s with vascular disease, particularly in older subjects. This opens the door to therapies that alter vascular disease as an approach to modifying Alzheimer’s.

These studies indicate the value of carefully developed longitudinal studies.