M. Woodward
INTRODUCTION
While Alzheimer’s disease (AD) is pathologically best recognized for the presence of amyloid plaques and neurofibrillary tangles, there is also considerable evidence for active inflammation. Alzheimer himself recognized the presence of activated microglial cells around the plaques and tangles and subsequently other markers of inflammation have been identified. This has led to the neuroinflammatory hypothesis for the neurodegeneration of AD. This hypothesis has gained additional support from large epidemiological studies, which have demonstrated that use of anti-inflammatory agents, particularly the non- steroidal anti-inflammatory drugs (NSAIDs), is associated with a reduced risk of develop- ing AD. There have now been several trials of NSAIDs and other anti-inflammatory agents for the treatment of AD and one trial commenced to assess whether NSAIDs may play a role in preventing AD.
To date no trial has demonstrated a role for anti-inflammatory therapy in AD, but the strong evidence for inflammation in the pathogenesis of AD and the results from population studies will lead to further research in this area.
INFLAMMATION IN AD
AD is characterized by the presence of activated microglial cells – enlarged, rod-like cells with long tortuous processes that are quite different from the thin, straight processes of resting microglia [1]. These cells belong to the mononuclear phagocyte system and are the main cell line that initiates and controls inflammatory reactions in the central nervous system. It is unclear what leads to activation of microglial cells in AD. Upon activation, these cells gen- erate a number of neurotrophic substances, which are important in the development, homeo- stasis and repair of the central nervous system [2]. Activated microglia are also the source and target for various cytokines that are used for communication between themselves and other cells. Foremost among these is interleukin-1 (IL-1) that amplifies the inflammatory response and, it is hypothesized, may induce damage, including death, in surrounding nerve cells. Many markers of inflammation have been identified in AD brain tissue [3]. The complement cascade is also activated in AD [4]. Indeed, the whole neuropathological cas- cade of AD, including the development of plaques and tangles, may be generated by this inflammatory response [5]. IL-1 drives a number of cellular and molecular responses that are central to Alzheimer pathogenesis, as shown in Table 9.1.
Michael Woodward, MBBS, FRACP, Associate Professor, Consultant Geriatrician and Medical Director, Aged and Residential Care, Heidelberg Repatriation Hospital, Austin Health, Heidelberg, Victoria, Australia
©Atlas Medical Publishing Ltd 2007
It may be that inflammation converts diffuse amyloid plaques into mature senile plaques [3], although it is now recognized that these senile plaques may not be the pathogenic element in AD.
There are also peripheral markers of inflammation in AD. In a case cohort study within a large epidemiological study, the Rotterdam study, high plasma levels of the inflammatory markers ␣1-anti-chymotrypsin, IL-6 and, to a lesser extent, C-reactive protein were associ- ated with an increased risk of dementia [7]. Prospectively, increased levels of C-reactive pro- tein have been associated with an increased risk of dementia 25 years later [8]. Higher plasma levels of ␣1-anti-chymotrypsin have also been associated with an increased risk of cognitive decline [9].
ANTI-INFLAMMATORY DRUGS AND NEUROINFLAMMATION
Non-steroidal anti-inflammatory drugs may modify the neuroinflammation seen in AD. There is in vivoevidence that NSAIDs diminish microglial activation [10, 11]. There are also in vitro studies showing that NSAIDs inhibit not only production of prostaglandins, which are central to inflammation, but also a number of other inflammatory functions of microglia including production of inflammatory cytokines and directly neurotoxic agents [12–16].
The effects of NSAIDs may be more related to their cyclo-oxygenase -1 (COX-1) inhibitory effects than COX-2 inhibition. This is supported by findings that the anti-neurotoxic actions of various NSAIDs are independent of their selectivity towards the two COX isoforms [12]
and that COX-1 appears to be the predominant COX isoform expressed by human microglial cells [17–19]. Therapeutic trials of NSAIDs need to consider this, and results with COX-2 selective inhibitors may not automatically translate to similar results with COX-1 or non-selective inhibitors.
NSAIDs may interfere with the formation of senile plaques or suppress the microglial- mediated inflammation associated with these plaques. In post-mortem brain tissue there was no difference between NSAID-treated and untreated groups in the mean number of plaques or in the type of plaques, but NSAID use was associated with less microglial acti- vation. These results suggest that if NSAID use is effective in treating AD, the mechanism is more likely to be through suppression of microglial activity than through directly inhibiting the formation of senile plaques [3].
ANTI-INFLAMMATORY DRUGS AND THE RISK OF AD
In support of the possibly central role that inflammation plays in the pathogenesis of AD, many observational studies have demonstrated a link between longer-term anti-inflammatory drug use and a reduced risk of AD [20–42]. These individual studies have, however, not all shown such an association. This variability of results may be explained by varying designs, sample sizes and populations. In most of these studies information about NSAID use was obtained retrospectively from patients or relatives, or from medical records. These approaches may lead to inaccurate conclusions as they can misclassify drug exposure.
A more accurate approach is a prospective population-base cohort study design. Such a study was carried out using the Rotterdam study cohort and examined 6,989 subjects
Excessive synthesis, translation and processing of neuronal APP Activation of astrocytes
Excessive synthesis of acetylcholinesterase Phosphorylation of tau
Decreased expression of synaptic proteins
Table 9.1 IL-1 driven responses central to AD pathology (with permission from reference [6])
initially 55 years of age or older and who were free of dementia at baseline [43]. The risk of AD was estimated in relation to the use of NSAIDs as documented in pharmacy records.
Four mutually exclusive categories of use were defined: non-use, short-term use (1 month or less of cumulative use), intermediate-term use (more than 1 but less than 24 months of cumulative use) and long-term use (24 months or more of cumulative use). During an aver- age follow-up period of 6.8 years, dementia developed in 394 subjects, of which most (293) had AD; 56 developed vascular dementia and 45 other types of dementia. Cox regression analysis adjustments were made for age, sex, education, smoking status and the use or non- use of salicylates (aspirin was not classified as an NSAID), histamine H2-receptor antago- nists, antihypertensive agents and hypoglycaemic agents. The relative risk of AD was 0.95 (95% confidence interval [CI] 0.70–1.29) in subjects with short-term use compared to non- use of NSAIDs, 0.20 (95% CI 0.05–0.83) in those with long-term use (Figure 9.1).
The risk did not vary according to age. The use of NSAIDs was not associated with a reduction in the risk of vascular dementia. This study provides powerful evidence for an association between NSAID use and a reduced risk of developing AD, and supports a cen- tral role of neuroinflammation in AD pathogenesis. More recently a systematic review and meta-analysis of observational studies between 1966 and October 2002 has also supported this possible protective effect [44]. The analysis included nine studies of NSAID use in adults over age 55. Six were cohort studies, with a total population of 13,211 participants, and three were case–control studies with a total of 1,443 participants. The results are shown in Table 9.2.
0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0
No NSAID
Relative risk
<1 month
NSAID exposure
Between 1 and 23 months
2 years or more
Figure 9.1 Relative risk of Alzheimer’s disease (with permission from reference [43]).
Relative risk (95% CIs) Length of use of NSAID 0.95 (0.70–1.29) ⬍1 month
0.83 (0.65–1.06) ⬍24 months 0.27 (0.13–0.58) ⬎24 months 0.72 (0.56–0.94) Any use 0.97 (0.70–1.07) Aspirin use
Table 9.2 Risk of Alzheimer’s disease in NSAID users [44]
These results do need to be seen simply as hypothesis-generating rather than evidence of a protective effect of NSAIDs. Epidemiological evidence is subject to a range of potential biases including recall bias, prescription bias and publication bias. An analysis of 25 case–control and cohort studies used relative risks weighted by the inverse of their vari- ances to obtain pooled relative risks and 95% confidence intervals [45]. These pooled rela- tive risks were 50% in studies with prevalent dementia cases but declined to 20% in studies with incident dementia cases and there was no protective effect where cognitive decline was used as the endpoint. These differences suggested that biases were indeed influencing this proposed protective effect of NSAID use.
Individual studies have suggested a protective effect of NSAID use on cognitive decline, which can be seen as further supporting a potential protection against AD. In a prospective study of 16,128 Nurses’ Health Study participants, six tests of cognitive function were administered by telephone over 6 years [46]. Compared to never users, the relative risk of a low baseline cognitive score was 0.75 (95% CI 0.59–0.96) for current users of aspirin with at least 15 years’ use, and 0.79 (95% CI 0.62–1.02) for current NSAID users of at least 8 years’
use. The relative risk for substantial subsequent cognitive decline was 0.93 (95% CI, 0.68–1.26) for long-term aspirin users and 0.77 (95% CI 0.57–1.05) for long-term NSAID users. Those results suggest an association between aspirin use and a baseline better cogni- tive score, but the follow-up showed no definite association between NSAID use and a lack of cognitive decline.
In an analysis of 2,651 participants in the UK Medical Research Council (MRC) treatment trial of hypertension in older adults, there was a significant but modest association between NSAID use and less decline over 54 months in one measure of cognition, the Paired Associate Learning Test [47]. A population-based sample of 7,671 subjects in three commu- nities showed that those who had used NSAIDs for at least 3 years had better cognitive function than non-users, as assessed by the Short Portable Mental Status Questionnaire [48].
After controlling for potential confounders, the relative risk of cognitive decline in NSAID users was 0.82 (95% CI 0.69–0.98) compared to non-users.
THERAPEUTIC TRIALS OF NSAIDs IN DEMENTIA
The finding that NSAIDs may attenuate or reverse the neuropathological changes of AD has led to several trials of NSAIDs in the treatment of established AD. Initially (1993) there was a small promising pilot trial of indomethacin [49]. This was followed by a small trial of diclofenac with misoprostol conducted in Melbourne, Australia [50]. This 25-week trial with 41 participants fell well short of statistical significance on all primary endpoints (ADAS-Cog, Global Deterioration Scale [GDS] and Clinical Global Impression of Change [CGIC]), largely as the placebo group failed to decline as expected. Another small trial with 40 participants found nimesulide to be ineffective over 24 weeks [51]. Larger trials have assessed the thera- peutic effects of several other agents and are summarized in Table 9.3. To date, there has been no statistically significant evidence of a benefit of any anti-inflammatory agent on AD.
These negative results probably indicate that anti-inflammatory agents will not in the future have a role in the treatment of AD and other dementias. However, it is possible that these results could be explained by other factors [57]. The doses used may have been inad- equate, but higher doses would almost certainly have increased the risk of adverse effects.
The dose of prednisone used, for instance, at 10 mg in the maintenance phase, was quite low [55]. However, the 25 mg daily dose of rofecoxib used in both trials was at the upper limit of the usual dose used for inflammatory conditions [53, 54].
It may be that anti-inflammatory agents are more effective if initiated early in the disease process. In the therapeutic trials to date, baseline Mini-mental State Examination (MMSE) score has been around 20, and the disease duration at trial entry has averaged over a year but is often considerably longer. The ultimate test of the benefits of early use of NSAIDs
would be primary prevention trials, and at least one has commenced. It is also possible that the endpoints chosen in the trials to date are inappropriate. The ones chosen reflect a symp- tomatic response and are the standard endpoints in AD therapeutic trials. These endpoints, however, may miss an underlying disease–modifying effect of therapy. The separation of disease-modifying and symptomatic effects is however problematic [58] and any purported disease-modifying effect would be difficult to support if not accompanied by a symptomatic effect. Disease modification could generally be expected to take longer to demonstrate and all but one trial to date was only of a relatively short 12 months’ duration.
It is also possible that only specific anti-inflammatory agents are effective in AD. The majority of trials have selected cyclo-oxygenase-2 (COX-2) inhibitors, due to concerns about gastrointestinal toxicity with the non-selective inhibitors. However, this COX-2 selectivity may not be as useful in the reduction of brain inflammation. For instance, in the brain COX- 2 is preferentially expressed by neurones but not by the microglial cells that are key to inflammation [17, 59]. It is possible that some beneficial effects of NSAIDs in AD could be mediated in part by their action on neuronal COX. There is upregulation of neuronal COX-2 in early AD [17, 59, 60]. Alternatively, COX-2 may play a compensatory, beneficial effect in AD pathology, and inhibition of COX-2 would have adverse effects. It is known that COX-1 is the predominant COX isoform expressed by microglia in the human brain [17–19] and this suggests that it will be the non-selective COX inhibitors, that are relatively more active towards COX-1, that may be a better choice for AD treatment [61]. Thus, it may be that we need trials of other, non-selective NSAIDs in the treatment of AD before we completely close the door on their possible beneficial effects. At this stage, NSAIDs and other anti- inflammatory agents cannot be recommended for the treatment of AD.
Duration No of Primary
Agent Reference (months) Trial design participants endpoint Results
Hydroxy- [52] 18 Double-blind 168 ADL No significant
chloroquine placebo- (function) differences in
controlled Cognition any outcome,
Behaviour compared to placebo
Rofecoxib [53] 12 Double-blind 692 ADAS-Cog No significant
placebo- CIBIC⫹ differences
controlled compared to
placebo Rofecoxib or [54] 12 Double-blind 351 ADAS-Cog No significant
Naproxen placebo- differences
controlled with either
agent compared to placebo Prednisolone [55] 12 Double-blind 138 ADAS-Cog No significant
placebo- difference
controlled compared to
placebo
Celecoxib [56] 12 Double-blind 425 ADAS-Cog No significant
placebo- CIBIC⫹ difference
controlled compared to
placebo Table 9.3 Large trials of anti-inflammatory agents in AD
NSAIDs IN THE PREVENTION OF AD
While NSAIDs appear ineffective in the treatment of established AD, they may have a role in the prevention of AD. Both the epidemiological and neuropathological evidence could be interpreted as demonstrating that NSAIDs will be most effective if used early and long-term. The main trial to test this hypothesis has been the Alzheimer’s Disease Anti- inflammatory Prevention Trial (ADAPT). This trial, sponsored by the USA National Institute of Aging (NIA) randomized 2,400 cognitively normal people over age 70 and at increased risk of developing AD to either celecoxib, naproxen or placebo. The trial planned for treat- ment for 3 years but due to concerns about the possible safety of celecoxib was terminated prematurely, in December 2004. All patients continue to be followed up and it may be that treatment effects will become apparent despite the early termination. At the time of termi- nation, no significant safety concerns of celecoxib were apparent. There was, however, an apparent increase in cardiovascular and cerebrovascular events compared to placebo among patients taking 220 mg of naproxen twice-daily. No other primary prevention trials with anti-inflammatory agents are in progress or completed and at this time NSAIDs and other anti-inflammatories cannot be recommended for the primary prevention of AD.
A logical target group for primary prevention trails is those with mild cognitive impairment (MCI). This group of people have an increased risk of progression to AD – around 15% ‘convert’ to AD [62] each year. There have been trials of several agents for MCI, includ- ing cholinesterase inhibitors but no agent to date has demonstrated efficacy in preventing progression to AD or other dementias. No trial of NSAIDs in MCI has yet been reported.
An alternative approach to preventing or treating AD is to utilize an NSAID that has additional effects apart from attenuating inflammation. One such potential agent is flur- biprofen, an anti-inflammatory drug that also appears to reduce A1–42production [63].
Trials of this agent have commenced but results are not expected until around 2007. There are other COX-independent activities of NSAIDs that may lead to further trials. These include activation of peroxisome proliferators-activated receptor-␥(PPAR-␥), which may modify amyloid production [64]. The concentration of drug required for these COX-inde- pendent actions are higher than those currently used and risk considerable toxicity so such trials have as yet not proceeded [2].
SUMMARY
While there is strong evidence for inflammation as a pivotal event in the pathogenesis of AD, at this stage there is no proven role for anti-inflammatory agents in the treatment of AD.
These agents may have a role in AD prevention, but this has yet to be proven. Newer agents with additional actions, such as flurbiprofen, may have a role but evidence is awaited.
So what is the clinician to do? If an anti-inflammatory agent is required longer term for the treatment of an inflammatory condition such as rheumatoid or other arthritis, it may be reasonable to tell the patient that such treatment may also have beneficial effects on the risk of AD. However, such agents should not be primarily prescribed to prevent, or treat, AD. It would appear that selective COX-2 inhibition offers no advantage in AD prevention or treatment, and indeed non-selective NSAIDs may be more effective than COX-2 selective inhibitors.
More research is needed, especially with newer agents and in AD prevention. Anti- inflammatory agents may also have a role in the prevention or treatment of non-AD demen- tias, but this has yet to be proven.
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