By Penny Stern, MD
NEW YORK, Mar 02 (Reuters Health) -- Alzheimer's disease has been the focus
of intense research for decades. A new study published in the Proceedings of the
National Academy of Sciences may help unravel the mystery of why the presence of
a particular protein in the brain leads to the dementia and degeneration
associated with this dreaded disease.
Dr. David M. Holtzman of the Washington University School of Medicine in St.
Louis, Missouri, together with colleagues there and at the Lilly Research
Laboratories in Indianapolis, Indiana, studied mice to explore how
apolipoprotein E (apoE) influences amyloid-beta plaque-forming deposits in the
brain.
The accumulation of this amyloid protein in the brains of Alzheimer's
patients is believed responsible for the damage done to brain nerve cells,
Holtzman told Reuters Health.
"In this study, we show that an interaction between apoE and amyloid-beta is
critical not only for the buildup of amyloid-beta, but also for an important
part of its toxicity in the brains of living animals," he said.
There are several variants of apoE and earlier work seemed to indicate a
greater risk for Alzheimer's disease attached to the presence of the apoE4 form
of the protein, although the specific mechanism was unclear.
Study co-author, Dr. Steven M. Paul of Lilly Research Laboratories,
explained to Reuters Health that the apoE gene is actually "a risk factor gene.
If you have two copies of the E4-variant, you have about a 10-fold greater risk
of getting Alzheimer's disease." He added that "about half the people with two
copies will get the disease by age 65 and about 80% will get it by age 85." In
contrast, the presence of the apoE2 variant is protective and reduces the risk
of Alzheimer's.
Interestingly, about 10% of people with two copies of the apoE4 gene will
never get the disease and Paul speculates that another factor may need to be
superimposed on this genetic background to allow the disease to occur.
According to Holtzman, "the apoE4 variant is much worse (than other human
variants) in causing the toxicity" because it seems to encourage more amyloid
deposition and the formation of nerve tangles and plaques in areas of the brain
that function in learning and memory.
Thus, Holtzman said, "apoE4 appears to be a critical element" in producing
the kinds of tissue changes that ultimately contribute to the impairments
characteristic of Alzheimer's.
Studies such as these "indicate that modification of human apoE levels or
interactions with amyloid-beta, will modify Alzheimer's disease," he said, which
may open the way for innovative strategies to treat or perhaps prevent the
disease.
Paul concurs. "If we could find a way to reduce apoE expression, since we
know what cells make it in the brain, we think we could come up with a drug that
might prevent plaque deposition," he said.
Holtzman and Paul both subscribe to the prevailing amyloid deposition
cascade theory of Alzheimer's disease development and believe that drugs could
conceivably "prevent and certainly reverse Alzheimer's disease," Paul added.
He cautions, however, that such a medication is likely some years away from
the market but that the current study is an important step "in solving the
genetic riddle" of Alzheimer's.
