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Article abstract-In a 6-month, double-blind, placebo-controlled study,

1100 to 150 mg/d indomethacin appeared to protect mild to moderately
Clinical trial of impaired Alzheimer’s disease patients from the degree of cognitive decline
exhibited by a well-matched, placebo-treated group. Over a battery of cogni-
indomethacin in tive tests, indomethacin patients improved 1.3% (+1.8%), whereas placebo
Alzheimer’s disease patients declined 8.4% (+2.3%)-a significant difference ( p < 0.003). Caveats
include adverse reactions to indomethacin and the limited scale of the trial.
NEUROLOGY 1993:43:1609-161 7

J. Rogers, PhD; L.C. Kirby, MD; S.R. Hempelman, MD; D.L. Berry, EdD; P.L. McGeer, MD, PhD;
A.W. Kaszniak, PhD; J. Zalinski, PhD; M. Cofield, PhD; L. Mansukhani, MHSA;
P. Willson, PhD; and F. Kogan, MD, PhD

Alzheimer’s disease (AD) is a progressive, age-
related dementing disorder characterized patholog-
ically by neuritic plaques, neurofibrillary tangles,
neuronal and neuritic damage, and excessive depo-
sition of p-amyloid peptide (p-AF’). Although classi-
cally defined inflammation, which typically
includes edema and neutrophil invasion, is not a
characteristic of the AD brain, numerous acute
phase reactants and immune-related markers are
present, particularly in association with compacted
P-AP deposits. These recently reviewed findings1
include increased or unique AD expression of MHC
class I a n d I1 cell surface glycoproteins on
microglia, IL-1, IL-2 receptors, serum amyloid P,
complement receptors, complement regulatory fac-
tors, and virtually the full range of activated classi-
cal pathway complement proteins from C l q
through C5b-9, the membrane attack comp1ex.l In
vitro experiments also demonstrate that P-AP may
bind Clq and fully activate the classical pathway
in an antibody-independent fashion.2 These data,
together with retrospective studies suggesting that
rheumatoid a r t h r i t i s patients, many of whom
would be expected to be taking anti-inflammatory
medication, may have a lower frequency of
provide basic science and clinical underpinnings for
the hypothesis t h a t anti-inflammatory agents
might be therapeutic in AD.I
Indomethacin is a nonsteroidal anti-inflammatory
drug (NSAID) with a nearly three-decade history of
relative safety in the treatment of arthritis and other
inflammatory disorder^.^ It also appears to cross the
blood-brain barrier.6 We report here the results of a
6-month, double-blind, placebo-controlled trial of
indomethacin in patients with probable AD.
M e t h o d s . Following I n s t i t u t i o n a l Review B o a r d
approval, 66 volunteer patients with a preliminary diag-
nosis of AD were recruited from the northwest Phoenix
m e t r o p o l i t a n a r e a . Of t h e s e , 44 p a t i e n t s m e t t h e
entrance criteria for inclusion in the study. Entrance cri-
teria were confirmation by the participating neurologists
of the diagnosis of probable AD7 and a Mini-Mental State
Examination (MMSE) score of 16 or more. Patients were
then randomly assigned to one of two treatment condi-
tions, indomethacin administered three times a day with
meals or placebo administered under the same regimen,
in a double-blind protocol. Drug dosage was adjusted to
weight such t h a t p a t i e n t s weighing 100 lbs or less
received a total of 100 mg/d, patients weighing 101 to
150 lbs received a total of 125 mg/d, and patients weigh-
ing more than 150 Ibs received a total of 150 mg/d. A 3-
month supply of 25-mg capsules was provided to each
caregiver, and the bottles were checked for compliance a t
t h e e n d of each 3-month period. P a t i e n t s received
indomethacin or placebo for 6 consecutive months.
Immediately before and after the 6-month trial, patients
received a b a t t e r y of t h e following cognitive t e s t s :
MMSE, Alzheimer’s Disease Assessment Scale (ADAS),
Boston Naming Test (BNT), and Token Test (TK).
Efficacy of treatment was assessed by expressing
changes in cognitive s t a t u s scores from baseline to 6
months as percent change from baseline (ie, for each test
the difference between a patient’s score at baseline and
score after 6 months of treatment was expressed as a per-
centage of the patient’s baseline score). This measure
helps normalize scales for the MMSE, ADAS, BNT, and
TK, permitting the application of more powerful statistical
methods that encompass all the data (eg, multivariate
analysis of variance, t tests on the mean percent change
across the four cognitive status tests). Variance estimates
for the two groups on the various cognitive tests were sim-
ilar and did not show significant deviations from homo-
geneity, underscoring the appropriateness of the paramet-
ric statistical methods employed. Transformation of the
raw scores to z scores, as well as an arc sine transforma-
tion, did not alter the pattern of significance of the results.
Results. Twenty-eight of the original 44 patients
August 1993 NEUROLOGY 43 1609
Table. Patient demographics and response to treatment
I
Group Sex
Indomethacin 14 78 f 2 9M15F
Placebo 14 77f 1 6M18F
*p < 0.003 compared with placebo.
completed the trial. Gastrointestinal side effects of
indomethacin were the most common cause of drop-
out in the drug treatment group (5124 patients).
Other bases for t h e removal of indomethacin
patients were stroke (1/24 patients), headache (1/24
patients), loss of caregiver (2/24 patients), and
death of the patient (no autopsy) (1/24 patients).
Gastrointestinal problems (1/20 patients) and
death of t h e patient (1/20 patients) were also
encountered i n the placebo group, but stroke,
headache, a n d loss of caregiver were not.
Interestingly, 4/20 placebo patients developed
increasingly severe behavioral problems during the
trial, rendering them noncompliant with respect to
drug administration, cognitive testing, or both. No
indomethacin patients were lost because of such
changes. It is therefore possible that, if anything,
the trial may have been biased toward a null result
because of patient drop-out.
Entrance characteristics and summary statistics
for patients completing the trial are presented in
the table. Indomethacin and placebo groups were
well matched for age, sex, and entry-level MMSE,
ADAS, BNT, and TK scores, and did not differ sig-
nificantly on any of these entrance measurements.
Across t h e b a t t e r y of mental s t a t u s t e s t s ,
indomethacin p a t i e n t s exhibited a n average
improvement of 1.3% (k1.8%) after 6 months of
treatment, whereas placebo patients declined by an
average of 8.4% (+2.3%).This difference was signifi-
cant by analysis of variance (Fl,z6= 10.88, p <
0.0031, as well as by a simple t test wherein an over-
all measure of change was computed for each
patient by averaging the percent change on the
MMSE, ADAS, BNT, and TK ( t 1 , Z G = 3.30, p <
0.003). On a n individual basis, 12/14 placebo
patients exhibited an overall decline of 4% or more
over t h e b a t t e r y of t e s t s , whereas only 2/14
indomethacin patients declined by this amount. We
note that the deterioration observed in our placebo
group matches well the deterioration reported for
untreated and placebo-treated AD patients in other
studies that have used the same cognitive status
tests. For example, Mortimer et a18 reported that
MMSE scores in untreated AD patients declined
approximately 13.0% over 6 months (2.23 points per
6 months, with a 17.2-point baseline). Similarly, our
placebo group’s MMSE scores declined by an aver-
age 13.4%over this same time period.
With respect to the individual mental status
tests, the most consistent differences between
indomethacin and placebo patients were recorded
1610 NEUROLOGY 43 August 1993
Percent change from baseline (+SEM)-
ADAS MMSE BNT TK X all tests
+1.4 i 4.9 -0.9 i 4.8 +4.4 5 3.7 +0.5 5 1.0 +1.3 f 1.8*
-13.3 If- 5.6 -13.4 k 4.4 -6.6 +_ 5.5 -0.4 If- 2.9 -8.4 f 2.3
on the MMSE (t,,ZG = 1.90, p = 0.069) and ADAS
(tl,z6 = 1.96, p = 0.061). These differences were sig-
nificant by a one-tailed test, the appropriate mea-
sure given our a priori hypothesis of a beneficial
effect of indomethacin, and they approached signif-
icance by a two-tailed test. Although the results on
the less sensitive BNT (tl,,6= 161, p = 0.120) and
TK ( t 1 , Z G = 0.29, p = 0.773) were not significant, the
group means were in t h e predicted direction
(table).
Discussion. Over a battery of cognitive tests,
indomethacin in doses of 100 to 150 mg/d appeared
to protect mild to moderately impaired AD patients
from the degree of cognitive decline exhibited by
placebo patients in a 6-month-long7double-blind,
placebo-controlled study. There are several caveats
to be considered, however.
Over 20% of indomethacin-treated patients
developed sufficient drug-related adverse effects,
primarily g a s t r o i n t e s t i n a l , t o w a r r a n t t h e i r
removal from the study. Gastroprotective measures
should be considered i n f u r t h e r t r i a l s of
indomethacin o r other NSAIDs f o r A D , a n d
patients should be carefully monitored for gastro-
intestinal and other adverse effects.
Second, the choice of anti-inflammatory drug for
testing should be carefully weighed. In an earlier
pilot study, for example, we administered 10 mg/d
prednisone t o four AD patients for a period of 6
months. Over the course of study, these patients
developed increasingly severe behavior problems,
including sleep impairments and increased wan-
dering. These adverse effects may reflect interac-
tions of the psychogenic effects of steroidsg with
dementia, the possibility that steroids are neuro-
toxic to hippocampal neurons,1° or both.
Finally, the scale of the clinical trial that we
have been able to mount is small. Multicenter tri-
als will be necessary t o establish in a definitive
manner the efficacy of indomethacin or other
NSAIDs as a treatment for AD. However, given
that indomethacin is a decades-old drug with rela-
tively mild and well established toxicologic proper-
ties,5 and given that there are significant basic
research ~nderpinningsl-~ for its application in AD,
we are hopeful that our data will give impetus to
more extensive testing in the near future.
Acknowledgments
We thank Ms. Hiromi Povio and Ms. Betty Stump for invaluable
clerical help, Dr. Richard Mohs for advice on the cognitive test-
ing protocols, Dr. Leslie Rosenstein for help with pilot studies,
and Dr. Michael Schulzer for advice on statistical methods.
From the L.J. Roberts Center for Alzheimer’s Research (Drs. Rogers,
Kirby, Hempelman, Berry, Zalinski, Cofield, Willson, and Kogan, and L.
Mansukhani), Sun Health Research Institute, Sun City, AZ;the Kinsmen
Laboratory for Neurological Research (Dr. McGeer), University of British
Columbia, Vancouver, BC, Canada; and the Department of Psychology
(Dr. Kaszniak), University of Arizona, Tucson, AZ.
Received September 29, 1992. Accepted for publication in final form
December 7, 1992.
Address correspondence and reprint requests to Dr. Joseph Rogers, Sun
Health Research Institute, P.O. Box 1278, Sun City, AZ 85372.
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August 1993 NEUROLOGY 43 1611
 Clinical trial of indomethacin in Alzheimer's disease
J. Rogers, L. C. Kirby, S. R. Hempelman, et al.
Neurology 1993;43;1609
DOI 10.1212/WNL.43.8.1609

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