A recent paper by a huge international collaborative group of researchers has re-fired the controversy over what really causes Alzheimer's disease. An article written by Dr. Michael Mullan, an Alzheimer's researcher. Read more...

1. Controversy - The Cause of
Alzheimer's
By Michael Mullan

2. Controversy - The Cause of Alzheimer's
By Dr. Michael Mullan
A recent paper by a huge international collaborative group of
researchers has re-fired the controversy over what really
causes Alzheimer's disease. For many years, researchers have
argued that the amyloid protein is the central cause of the
disease. However, in commenting on the recent finding,
Professor Julie Williams said, "There is something in the
immune response which is causing Alzheimer's disease…."
according to a BBC report. Dr. Williams' use of the term
"causing" is strong language and contrasts sharply with the
beliefs of other scientists who promote the "amyloid cascade
theory." According to that theory, amyloid is the cause of
Alzheimer's disease and brings about the demise of neurons
by toxic and inflammatory processes as it accumulates in the
brain.
In the new findings of 11 more genes associated with
Alzheimer's disease (bringing the total to 21), the immune
system seems to be implicated. Several other studies have
previously implicated the immune system. For instance, a
1999 paper from our own group, published in Science,
implicated the molecule CD40 which plays a central role in
the immune system. Knocking out CD40 dramatically reduced
the amount of amyloid accumulation in transgenic mouse
models of Alzheimer's expressing human mutations which
trigger early onset disease.

3. The new gene findings also point to a process called
endocytosis which is the internalization of the cell membrane
typically after a receptor has been triggered. Interestingly, we
have also shown that CD40 triggers endocytosis and, in so
doing, it increases the amount of amyloid produced by brain
cells. Although the new genetic findings do not give any clear
indication of why the immune system may be important, the
implication of immune proteins will generate many new
theories. Previously, many researchers have noted the role of
inflammation and innate immunity in Alzheimer's disease
and it may be that these new genetic findings will assist in
our understanding of the role of the immune system.
However, the sheer size of the study, which according to the
BBC website required over 17,000 patients and 37,000
healthy controls, suggests that the effect of some of these
genes may be very small. This then naturally gives rise to the
question of whether the findings are generalizable to all
Alzheimer patients. In addition, the key question of whether
any treatments will emerge from these genetic findings is
another area hotly debated.
Although the genetic role of genes like APP has been known
for over 20 years, no therapies have yet been approved which
are directed towards the amyloid protein. Similarly, although
the APOE gene was implicated in Alzheimer's disease 20
years ago, no treatments have emerged as a consequence.

4. Scientists argue that if a gene such as APOE which has such a
large influence on the population's risk for Alzheimer's has not
resulted in a new treatment, why would the discovery of genes
of much smaller effect be likely to result in new treatments?
However, Professor Williams' comment may suggest that one
of the values of such studies is to move the field away from
focusing so intently on amyloid towards other potential
therapeutic targets.
Although the hunt for amyloid therapies has been incessant
over the last 20 years, major vaccine studies have failed or
shown minimal effect and consequently, researchers are trying
to advance anti-amyloid treatments at an early age. Others
vehemently oppose this approach, suggesting that amyloid is
just the wrong target and that other molecular targets should
be sought. Perhaps this new study will switch the focus away
from amyloid to the immune and other systems?
The origins of Alzheimer's disease have always been hotly
debated with researchers taking very strong opinions on the
cause of the disease. This intellectual battle seems set to
continue with new findings such as those revealed by the
present study.