MCKHANN 283disorders of glycolipids: Tay Sachs disease, Gaucher disease, and other
diseases of lipid metabolism. First, the accumulation was identified, then
the enzymes involved, and later they were used for diagnosis. That was
a pattern that really started at the NIH with Brady and he carried the re
search forward: in the mid 1970s, by bringing other techniques in en
zyme therapy, and now in the 2000s, by looking at risk-factor genetics,
transgenics. That is not so much looking at enzymes anymore but at
what proteins are abnormal in these disorders.
If we take another disorder, like Alzheimer’s disease, we go through
exactly the same steps that Brady began at the NIH. When I first began
in neurology, it was considered a very rare disease; it was considered a pre-
senile dementia. It had about the same frequency as Creutzfeldt-Jacob
disease, and if a neurologist saw one or two cases in his practice, that
would be a lot. In the 1960s, we did not think the disease existed. In the
1980s, we had anti-cholinesterases and antioxidants as therapies. Now
we have a whole pattern of approaches–none of them magic bullets–
but at least we have a logical approach to what we are trying to do. What
changed all this was the work of the group at the Albert Einstein
College of Medicine who recognized that the pathology of what was
called pre-senile dementia and what we were calling senility or harden
ing of the arteries was essentially the same. Raymond Adams, with whom
I trained, made essentially the same observations. So, in the 1970s, we
were looking at disease incidence and the dominant forms, but we went
back to exactly the same steps that Brady had gone through with his
diseases: the accumulation of a particular compound, the mechanism
by which that compound was being metabolized, the enzymes involved,
how they might be used for diagnosis, and how they might be used for
therapy. I would argue that the genetic approach that Brady pioneered
in the NINDS intramural research program is now, some 25 to 30 years
later, currently being applied very effectively to another disease process.
Another field was cognitive neuroscience, because at that time we
were not doing much better than Paul Broca had done in the nineteenth
century. We talked about lesions in disease and postmortem, and that
was our approach to the association of behavior and neurological
lesions. Patients were examined, some years later they died, and then the
brains were looked at.