Neurobiolo~,y qlAv, inje, Vol. 7, p. 423, 1986. " Ankho International Inc. Printed in the U.S.A. 0197-4580/86 $3.00 + .00

On the Continuing Mystery of Alois Alzheimer's 'Strange Changes in Neurofibrils and Strange Substances in the

Cerebral Cortex'

AN important component of A. Alzheimer's classic case in- volving a 55 year old demented woman included the descrip- tion of certain pathologic markers found in her brain at au- topsy. He described these as "strange changes in the neurofibrils . . . . the invasion of a strange substance in the cerebral cortex . . . . and large pockets of fatty substance." With this description, Alzheimer accurately characterized the primary pathological features of the disease. Those markers, now commonly referred to as senile plaques and neurofibrillary tangles, distinguish the disease and provide the primary diagnostic criteria. It is not surprising, therefore, that when scientific interest in AD began to accelerate rapidly during the past ten to fifteen years, one primary focus of research involved studying the origin and composition of the plaques and tangles. Indeed, investigators interested primarily in other facets of AD (e.g., neurochemical disturb- ances, clinical progression, genetic role), at some point, must incorporate current knowledge about plaques, tangles and amyloid into their thinking (see numerous examples in following sections of this Issue).

Despite the fact that the study of plaques and tangles has been a popular area of research for some time, and more recently has benefited from the application of powerful molecular biology tools, a number of questions involving some very fundamental issues persist. The very fact that the plaques and tangles in AD primarily represent quantitative differences (in that their presence is not limited to individuals with AD), creates serious problems for investigators trying

to study and understand the disease (see especially the sec- tion on Genetics in this Issue).

In the following review, Dr. Selkoe provides a com- prehensive overview of what is known about the origin and composition of the plaques and tangles of AIzheimer's brains, many of the controversies that exist, and a discussion of some of the problems and limitations of current methodol- ogy. From a more provocative standpoint, Dr. Selkoe and the commentators discuss the question of how the lack of clear, qualitatively unique pathological features in AD fit into the concept that AD represents a distinct disease entity. Similarly, the possibility of heterogeneity within Alzheimer's disease is debated. Other interesting questions include: Are the classic pathological markers cause or effect? Is the origin of the different markers closely related or independent'? What role is played by a genetic predisposition, breakdown in the blood brain barrier, tropic factors, or aluminum'? Is Alzheimer's necessarily a brain-specific disease'?

In some sense the issues raised and discussions offered by the participants of this section serve as a looking glass into the future--an interesting view of things certain to come. Some of these issues are so fundamental that the reader will find them recurring throughout the other sections. However. the real significance of this dialogue should ultimately be measured by the insight that is likely to be gained from the research that is directed toward resolving these issues.

The Editor

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