SCIENCE AND MEDICINE
New mechanism proposed for NSAID reduction of Alzheimers disease incidence
S ome non-steroidal anti-inflam-
matory drugs (NSAIDs) may
reduce the prevalence of Alzh-
eimers disease by decreasing brain
concentrations of the 42-residue
isoform of the peptide amyloid-
(A42), claim Edward Koo
(University of California, San
Diego, CA, USA) and colleagues.
This effect is independent of
ability to inhibit cyclo-oxygenase
[COX] activity, says Koo, and if
our data are correct, it may be
possible to develop a compound
that looks like a NSAID, has no
COX-related side-effects, yet still
reduces the risk of developing
Alzheimers disease.
Considerable epidemiological
evidence shows an inverse relation
between sustained NSAID use and
the risk of developing Alzheimers
disease. However, although a
small clinical trial of indo-
methacin for the treatment of
Alzheimers disease provided
Restenosis often occurs without symptoms
ore than half of patients whose
M heart arteries re-narrow after
angioplasty may have no symptoms
of possible renewed disease, accord-
ing to US researchers this week.
These patients may therefore have a
risk of future coronary events, such
as myocardial infarctions, but would
have no symptoms.
55% of restenosis
[the re-narrowing Rights were not granted
of arteries after to include this image in
they are un- electronic media. Please
clogged] in the refer to the printed
populations we
studied was symp- journal.
tomless, therefore
these patients
remain well, but Silent but deadly
with a potentially
significant coronary problem, says
investigator Peter Ruygrok, (Green
Lane Hospital, Auckland, New
Zealand). Yet, they believe they
have had a successful treatment for
their obstructive artery narrowing.
In a study of 2690 patients
treated for obstructed heart arteries,
the investigators identified factors,
including sex, age, and smoking his-
tory that influenced whether patients
were more or less likely to develop
symptomless heart disease
within 6 months after initial angio-
plasty. Of importance, men were
more likely to have silent restenosis
1616
For personal use. Only reproduce with permission from The Lancet Publishing Group.
supporting data for these epidemi-
ological studies, a larger trial on
the COX-2 inhibitor celecoxib
failed, and a small trial on
diclofenac was inconclusive.
NSAIDs are generally thought to
work in Alzheimers disease by
reducing brain inflammatory
responses, but Koo and colleagues
now suggest a different mecha-
nism. They have found that in
tissue culture cells engineered
to produce large amounts of amy-
loid precursor protein (APP), high
doses of some, but not all,
NSAIDs preferentially reduce
the concentration of the highly
amyloidogenic A42 peptide.
Additionally, short-term ibupro-
fen treatment of transgenic mice
expressing mutant APP reduces
concentrations of A42 in the
brain (Nature 2001; 414: 21216).
We think that the NSAIDs may
be inducing a subtle change in the
activity of -secretase, the enzyme
than women, noted Ruygrok, which
he suggested was perhaps because
women have arteries with smaller
diameters (Circulation 2001; 104:
228994).
Previous studies have indicated
that there are clearly sex differences
in treatment of patients with coro-
nary heart disease.
Patients with less-
severe blockage
and those whose
arteries had a
Science Photo Library
wider reference
diameter were also
more likely to have
silent restenosis.
Although our
research will prob-
ably not cause any
changes in clinical practice, it may
lead to raised clinical suspicion in
patients in whom the clinical
diagnosis in not clearcut, says
Ruygrok.
According to Neal Kleiman
(Baylor College of Medicine,
Houston, TX, USA) these data
seem to imply that in patients with
compelling anatomy and risk factors,
increased vigilance with either
aggressive non-invasive testing or
surveillance angiograms may be
needed.
Sally Hargreaves
responsible for A42 production,
says Koo.
This is interesting work, says
Patrick McGeer (University of
British Columbia, Vancouver,
Canada), but how well do in-vitro
datain which individual cells are
put under enormous pressure by
high levels of APP and very high
doses of NSAIDsreflect what goes
on in the living brain? There is
plenty of epidemiological data
available that should now be
reanalysed to tease out what
different NSAIDs do to reduce the
risk of Alzheimers disease. In
addition, the US National Institutes
of Health (NIH) are sponsoring a
large trial of naproxen, a NSAID
that had no effect in Koos assays.
The NIH trial ends in January, so
clinical data might soon be avail-
able to support or refute Koos
results.
Jane Bradbury
News in brief
UK guidelines on chemotherapy
The UK government has published
guidelines on safe administration of
intrathecal chemotherapy drugs.
Since 1985, 13 patients have died or
been paralysed due to accidental
intrathecal administration of
vincristine, rather than intravenous
delivery. The guidelines state that
intrathecal chemotherapy should
only be prescribed by a consultant or
specialist registrar, and hospitals will
be required to set up a register of
staff who are trained and authorised
to prescribe intrathecal chemother-
apy. Doctors must also follow a set
procedure laid out on a specially
designed chart (www.doh.gov.uk).
New phase for landmark study
The Framingham Heart Study is
entering a new phase by recruiting a
third generation of participants.
The investigators plan to recruit
about 3500 grandchildren of the
studys original participants. Key
goals of the third-generation study
are to identify genes that contribute
to good health and to development
of cardiovascular, lung, and blood
diseases, and the development of
new imaging tests to detect very
early stages of atherosclerosis in
otherwise healthy individuals.
THE LANCET Vol 358 November 10, 2001