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Is Alzheimer's Disease Autoimmune Inflammation of the Brain That Can be Treated With Nasal Nonsteroidal Anti-Inflammatory Drugs?

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American Journal of Alzheimer's Disease & Other Dementias
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Steven Lehrer
Steven Lehrer
Steven Lehrer
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Abstract

The Alzheimer's Association recently reported that a woman's estimated lifetime risk of developing Alzheimer's at age 65 is 1 in 6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer's disease could well be an autoimmune disorder. Like Alzheimer's, multiple sclerosis, an autoimmune inflammation of the central nervous system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer's resembles the autoimmune inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce the risk of Alzheimer's disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogenesis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.
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Opinions and Controversies
Is Alzheimer’s Disease Autoimmune
Inflammation of the Brain That Can
be Treated With Nasal Nonsteroidal
Anti-Inflammatory Drugs?
Steven Lehrer, MD
1
, and Peter H. Rheinstein, MD, MS, JD
2
Abstract
The Alzheimer’s Association recently reported that a woman’s estimated lifetime risk of developing Alzheimer’s at age 65 is 1 in
6, compared to nearly 1 in 11 for a man (ie, female to male ratio 1.8). Based on female to male ratio, Alzheimer’s disease could
well be an autoimmune disorder. Like Alzheimer’s, multiple sclerosis, an autoimmune inflammation of the central nervous
system, has a female to male ratio of 2.3. Also based on female to male ratio, Alzheimer’s resembles the autoimmune
inflammatory disease rheumatoid arthritis, which has a female to male ratio of 2.7. The reasons for the female preponderance in
autoimmune disease are unclear, but nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and successfully employed to
treat autoimmune anti-inflammatory disease and dramatically relieve symptoms. Moreover, oral NSAIDs consistently reduce
the risk of Alzheimer’s disease, although they have been totally ineffective as a treatment in multiple failed clinical trials. A basis
for this failure might well be that the brain dose after oral administration is too small and not sufficiently early in the pathogen-
esis of the disorder. But NSAID brain dose could be significantly increased by delivering the NSAIDs intranasally.
Keywords
autoimmunity, NSAIDs, brain, nasal
The Alzheimer’s Association recently reported that a woman’s
estimated lifetime risk of developing Alzheimer’s at age 65 is 1
in 6, compared to nearly 1 in 11 for a man (ie, female to male
ratio 1.8). The magnitude of this difference cannot be attributed
solely to the fact that women live longer than men.
1
Multiple
effects are involved.
Increased Longevity of Women Effect
Using the Social Security Administration’s life expectancy cal-
culator (http://www.socialsecurity.gov/cgi-bin/longevity.cgi)
yields 21.6 years and 19.5 years for a 65-year-old female and
a 65-year-old male, respectively, 21.6/19.5 ¼1.1. Assuming
the age-specific incidence of Alzheimer’s is the same for both
sexes, this would also be the expected effect of longevity on the
incidence of Alzheimer’s. In other words (1.1 - 1.0)/(1.8 - 1.0) ¼
1/8 or 12.5%of the observed increased Alzheimer’s in women
is due to the increased longevity of females.
Cardiovascular Disease Effect
The Framingham Study found that the death of men from car-
diovascular disease between ages 45 and 65 was reducing the
pool of men at high risk of Alzheimer’s disease at later ages.
The Framingham Study estimated that this effect explained
20%to 50%of the difference in incidence of Alzheimer’s dis-
ease among men and women older than 65.
2
Autoimmune Inflammation Effect
Biochemical and neuropathological studies of brains from indi-
viduals with Alzheimer’s disease provide clear evidence for an
activation of inflammatory pathways and glial inflammation.
3
Long-term use of anti-inflammatory drugs is linked with
reduced risk of developing Alzheimer’s disease.
4
Amyloid-b
plaques and t protein tangles, hallmarks of the pathology, are
most likely a nonspecific result of the disease process, rather
than a cause.
5
Based on female to male ratio, Alzheimer’s disease could
well be an autoimmune disorder. Like Alzheimer’s, multiple
sclerosis, an autoimmune inflammation of the central nervous
system,
6
has a female to male ratio of 2.3.
7
Also based on
1
Fermata Pharma, Inc, New York, NY, USA
2
Severn Health Solutions, Severna Park, MD, USA
Corresponding Author:
Steven Lehrer, MD, Fermata Pharma, Inc, 30 West 60th Street, New York, NY
10023, USA.
Email: steven@fermatapharma.com
American Journal of Alzheimer’s
Disease & Other Dementias
®
2015, Vol. 30(3) 225-227
ªThe Author(s) 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1533317514545478
aja.sagepub.com
female to male ratio, Alzheimer’s resembles the autoimmune
inflammatory disease rheumatoid arthritis, which has a
female to male ratio of 2.7.
8
In addition, incidence of Alzhei-
mer’s disease
1
and autoimmune disease
9
is increasing.
There is other evidence that Alzheimer’s disease has an
autoimmune component. D’Andrea has suggested that the
presence of antineuronal autoantibodies in the serum, whose
importance had been previously dismissed, may be without
pathological consequence until there is a blood–brain barrier
dysfunction, which allows these autoantibodies to access their
targets with deleterious effect.
10,11
And there is a relationship
between autoimmune thyroid disease and Alzheimer’s dis-
ease.GenovesietalreportthatpatientswithAlzheimer’sdis-
ease showed a significant increase in the mean values of
antithyroglobulin and antimicrosomial autoantibodies com-
pared to nondemented controls.
12
Autoimmunity is a factor in cancer regression,
13
and Alzhei-
mer’s disease is associated with decreased risk of cancer-specific
mortality.
14
Therefore, a predisposition to autoimmunity
could predispose to Alzheimer’s disease while lowering the
risk of cancer.
Features of autoimmunity have been associated with both
Alzheimer’s disease and diabetes. In both diseases, high levels
of advanced glycation end products and their receptor have
been detected in tissues and in the circulation.
15
With 20%to 50%of increased Alzheimer’s disease in women
due to the effect of death from heart disease in men before age
65
2
and another 12.5%due to the effect of increased longevity
of women, the potential role of autoimmunity is reduced. Never-
theless, a significant part of the observed female male incidence
difference remains unexplained and may indeed suggest autoim-
munity as a factor in the etiology of Alzheimer’s.
Autoimmune Disease Preponderance
in Women
Most autoimmune diseases are female sex related. Nearly 75%
of the more than 23.5 million Americans who suffer from
autoimmune disease are women. The reasons for the female
preponderance in autoimmune disease are unclear. Men and
women respond similarly to infection and to vaccination, argu-
ing against intrinsic sex differences in immune response. Endo-
genous hormones could cause sex discrepancy if their effect is
a threshold off–on switch rather than quantitatively variable.
16
Moreover, women with autoimmune diseases manifest a higher
rate of circulating cells with a single X chromosome. There
have been several reports on the role of X chromosome gene
dosage through inactivation or duplication in autoimmunity.
17
Pregnancy appears to increase the risk of autoimmune dis-
ease, and the small exchange of cells between mothers and their
children during pregnancy may induce autoimmunity.
16
Beeri
et al have reported that number of children is associated with
neuropathology of Alzheimer’s disease in women but not in
men. Beeri et al suggest that since the associations between
number of children and neuropathology of Alzheimer’s disease
were found for women only, they might reflect sex-specific
mechanisms (such as variations in estrogen or luteinizing
hormone levels) rather than social, economic, biological, or
other mechanisms common to both men and women.
18
Also,
the association between number of children and neuropathol-
ogy may be due to increased autoimmunity or the influence
of estrogen and different progestins on the development of
cognitive decline.
19
Autoimmune disease, while common in women, is rarely
found for the first time in people older than 65 years. In con-
trast, clinical Alzheimer’s disease is much more prevalent in
persons older than 65years. But in Alzheimer’s disease, the pre-
clinical phase of detectable lowering of cognitive functioning
precedes the appearance of clinical disease by many years.
20,21
Nonsteroidal Anti-Inflammatory Drugs
and Alzheimer’s Disease
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely and
successfully employed to treat autoimmune anti-inflammatory
disease and dramatically relieve symptoms.
22
Moreover, oral
NSAIDs consistently reduce the risk of Alzheimer’s disease
in retrospective
23
and prospective studies,
24
although they
have been totally ineffective as a treatment in multiple failed
clinical trials.
25
A basis for this failure might well be that the
brain dose after oral administration is too small.
26
Ibuprofen, flurbiprofen, and indomethacin, which are highly
lipophilic, readily cross the blood–brain barrier after an oral
dose but are poorly distributed.
27
The amount of ibuprofen,
flurbiprofen, and indomethacin that reach the brain after an oral
dose is small. Most NSAIDs that exhibit good activity against
Alzheimer’s disease models, such as ibuprofen, flurbiprofen,
and indomethacin, distribute poorly to the brain.
28
Plasma pro-
tein binding limits brain NSAID uptake by reducing the free
fraction of NSAID in the circulation,
27
although the blood–
brain barrier is dysfunctional in Alzheimer’s disease.
29
The NSAID brain dose could be significantly increased by
delivering the NSAID intranasally. Nasal drug delivery that
exploits the olfactory and trigeminal neuronal pathways to
convey drugs to the brain is being widely explored by pharma-
ceutical companies.
30
Low-molecular-weight lipophilic drugs,
such as ibuprofen, are readily absorbed into the brain by the
intranasal route.
30
Intranasal insulin is already being tested as
a treatment for Alzheimer’s disease.
31
In addition, Alzheimer’s
disease starts in the entorhinal cortex, which is connected to the
olfactory nerves and spreads outward in an anatomically
defined pattern.
32
Therefore, nasal NSAIDs would readily
reach the region of the brain where they are most likely to be
therapeutic. Indeed, NSAIDs can restore neurogenesis through
attenuation of microgliosis.
33
If animal studies can validate the
nasal route as a means of delivering a specific NSAID to the
entorhinal cortex, then a trial of an intranasal formulation of
that NSAID may be justified.
Authors’ Note
Dr Lehrer has filed a patent application for nasal NSAID treatment of
Alzheimer’s disease.
226 American Journal of Alzheimer’s Disease & Other Dementias
®
30(3)
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to
the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship,
and/or publication of this article.
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Lehrer and Rheinstein 227
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Chapter
  • Apr 2021
Cognition can be defined as neurocognitive processes of how humans learn and remember. As humans age, threats of neurocognitive disturbances are probably the most feared psychiatric problems, but these processes also can be disrupted by biological abnormalities closely connected to other psychiatric problems. The theme of this article is that basic research in areas of cognition and advances in the discovery of novel pharmacotherapy for neurocognitive and psychiatric disorders that affect the elderly are inextricably intertwined. Drug evaluations in animal models should be conducted in, three basic types of learning/memory paradigms (habituation, classical conditioning, and operant conditioning) and should assess the effects of agent on learning, retention, and retrieval. The importance of this strategy involves issues of single or multiple learning processes in the paradigms, whether different types of paradigms give rise to different kinds of memories or whether the same paradigm may produce several fundamentally different types of memories that may or may not be interdependent. Medications currently in use for ameliorating neurocognitive disorders are mostly ineffective. New pharmacotherapy is urgently needed, and a seemingly innumerable collection of drugs has been proposed as the latest “key” to unlock mechanisms of dysfunction in neurocognition. In some cases, new agents have functioned (biochemically) exactly as advertised, but virtually all have proved unacceptable for clinically use. Future therapies for neurocognitive disorders will likely benefit from the recognition that multiple cellular mechanisms and neurotransmitter processes are involved and that administration of combinations of agents that provide “wide‐spectrum” actions may be most useful.
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Curcumin inhibits LPS-induced neuroinflammation by promoting microglial M2 polarization via TREM2/ TLR4/ NF-κB pathways in BV2 cells
Article
  • Oct 2019
Microglia mediate multiple facets of neuroinflammation, which plays a double-edged role in various brain diseases via distinct microglial phenotypes (deleterious M1 and neuroprotective M2). Therefore, the inhibition of overactivated inflammatory M1 microglia by switching to the protective M2 phenotype appears to be a potential therapeutic strategy in neuroinflammatory disorders. Curcumin has been shown to exhibit anti-inflammatory and neuroprotective activities. The present study investigated the potential effects of curcumin on microglial M1/M2 polarization and elucidated the possible molecular mechanisms of action in vitro. In this study, the BV2 microglial cell line was pretreated with different curcumin concentrations in the presence or absence of lipopolysaccharide (LPS) to assess the anti-inflammatory efficacy of curcumin based on the morphological and inflammatory changes. The cytotoxicity of curcumin for BV2 cells was evaluated using the CCK-8 assay. Further, the effect of curcumin concentrations on LPS-induced BV2 cells was studied. The morphological changes were observed using an optical microscope and immunofluorescent staining. Nitric oxide (NO) expression was determined using the Griess reagent. The expression of cytokines and inflammatory mediators was also measured by ELISA, qRT-PCR, flow cytometry, and immunofluorescence. Western blot analysis was used to determine the levels of triggering receptor expressed on myeloid cells 2 (TREM2), toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB) p65, p-NF-κB p65, IκB, and p-IκB expression. Results showed that curcumin concentrations less than 10 μM did not induce any detectable cytotoxicity but decreased BV2 cell viability up to 20 μM. Curcumin inhibited LPS-induced microglial activation. Curcumin treatment switched the M1 pro-inflammatory phenotype to the M2 anti-inflammatory phenotype by decreasing the expression of M1 markers (i.e., iNOS, IL-1β, IL-6, and CD16/32) and elevating the expression of M2 markers (i.e., arginase 1, IL-4, IL-10, and CD206). Interestingly, curcumin attenuated the activation of TLR4/NF-κB pathways and the downregulation of TREM2 expression in LPS-activated BV2 cells. Collectively, these results suggest that curcumin significantly alleviates LPS-induced inflammation by regulating microglial (M1/M2) polarization by reducing the imbalance of TREM2 and TLR4 and balancing the downstream NF-κB activation.
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Nasal NSAIDs for alzheimer's disease
Article
Full-text available
  • Aug 2014
Alzheimer's disease may result from low-grade inflammation of the brain, and the characteristic amyloid β may be a protective response. Epidemiological observation indicates that long-term oral administration of nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen to patients having rheumatoid arthritis results in reduced risk and delayed onset of Alzheimer's disease. However, oral ibuprofen, flurbiprofen, and other NSAIDs are not an effective treatment. The NSAIDs may work as an Alzheimer's preventive but not a treatment because the oral dose to the brain is too small, 1% to 2% of the total plasma concentration. The NSAID brain dose could be significantly increased by delivering the drug intranasally. Flurbiprofen would be preferable to ibuprofen because flurbiprofen has 12&frac12; times the potency of ibuprofen. The smaller nasal dose of flurbiprofen than ibuprofen could significantly increase patient compliance. Alzheimer's disease starts in the entorhinal cortex, which is closely connected to the olfactory nerves, and spreads anatomically in a defined pattern. Therefore, a nasal NSAID would readily reach the region of the brain where it is most likely to be therapeutic.
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Alzheimer’s Association report
Article
This report discusses the public health impact of Alzheimer’s disease (AD), including incidence and prevalence, mortality rates, costs of care, and overall effect on caregivers and society. It also examines the impact of AD on women compared with men. An estimated 5.2 million Americans have AD. Approximately 200,000 people younger than 65 years with AD comprise the younger onset AD population; 5 million are age 65 years or older. By mid-century, fueled in large part by the baby boom generation, the number of people living with AD in the United States is projected to grow by about 9 million. Today, someone in the country develops AD every 67 seconds. By 2050, one new case of AD is expected to develop every 33 seconds, or nearly a million new cases per year, and the total estimated prevalence is expected to be 13.8 million. In 2010, official death certificates recorded 83,494 deaths from AD, making AD the sixth leading cause of death in the United States and the fifth leading cause of death in Americans aged 65 years or older. Between 2000 and 2010, the proportion of deaths resulting from heart disease, stroke, and prostate cancer decreased 16%, 23%, and 8%, respectively, whereas the proportion resulting from AD increased 68%. The actual number of deaths to which AD contributes (or deaths with AD) is likely much larger than the number of deaths from AD recorded on death certificates. In 2014, an estimated 700,000 older Americans will die with AD, and many of them will die from complications caused by AD. In 2013, more than 15 million family members and other unpaid caregivers provided an estimated 17.7 billion hours of care to people with AD and other dementias, a contribution valued at more than 220billion.Averageper−personMedicarepaymentsforservicestobeneficiariesaged65yearsandolderwithADandotherdementiasaremorethantwoandahalftimesasgreataspaymentsforallbeneficiarieswithouttheseconditions,andMedicaidpaymentsare19timesasgreat.Totalpaymentsin2014forhealthcare,long−termcare,andhospiceservicesforpeopleaged65yearsandolderwithdementiaareexpectedtobe220 billion. Average per-person Medicare payments for services to beneficiaries aged 65 years and older with AD and other dementias are more than two and a half times as great as payments for all beneficiaries without these conditions, and Medicaid payments are 19 times as great. Total payments in 2014 for health care, long-term care, and hospice services for people aged 65 years and older with dementia are expected to be 214 billion. AD takes a stronger toll on women than men. More women than men develop the disease, and women are more likely than men to be informal caregivers for someone with AD or another dementia. As caregiving responsibilities become more time consuming and burdensome or extend for prolonged durations, women assume an even greater share of the caregiving burden. For every man who spends 21 to more than 60 hours per week as a caregiver, there are 2.1 women. For every man who lives with the care recipient and provides around-the-clock care, there are 2.5 women. In addition, for every man who has provided caregiving assistance for more than 5 years, there are 2.3 women.
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Researchers Test Strategies to Prevent Alzheimer Disease
Article
  • Apr 2014
  • J Am Med Assoc
A decade of disappointing clinical trial results for Alzheimer disease (AD)-modifying therapies in people suggests that treatment should be targeted at earlier stages in the disease—even before overt symptoms arise. Profound brain alterations—such as accumulation of the protein fragment called beta-amyloid—are found 10 to 20 years before dementia or even mild cognitive impairment is diagnosed. Alzheimer disease investigators estimate that by the time memory begins to erode and other cognitive problems emerge, too much damage has occurred in the brain to be reversed by the experimental treatments.
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Alzheimer's Disease is Associated with Decreased Risk of Cancer-Specific Mortality: A Prospective Study (NEDICES)
Article
  • Jan 2014
  • J ALZHEIMERS DIS
Previous studies have shown that Alzheimer's disease (AD) is associated with a reduced risk of cancer. However, most studies exclude those with undiagnosed dementia. The only way to overcome this methodological issue is to examine all the participants or to screen the population for symptoms of dementia with a validated instrument and confirm any suspected dementia patients with a clinical examination (i.e., a two-phase investigation method). We used this methodology to estimate whether cancer-specific mortality is associated with AD and other types of dementia in a prospective population-based study (NEDICES) involving 5,278 elderly people. Community-dwelling subjects with and without dementia were identified and followed for a median of 12.5 years, after which the death certificates of those who deceased were examined. A total of 1,976 (47.1%) died, including 277 who had possible or probable AD and 126 with non-AD dementia. Cancer was reported significantly less often in those with possible or probable AD (5.8%) or non-AD dementia (6.3%) than in those without dementia (26.5%). In an unadjusted Cox model, relative risk (RR) of cancer-specific mortality in participants with AD = 0.45 (p = 0.002) and RR in participants with non-AD dementia = 0.62 (p = 0.179) when compared to the non-demented group. In a Cox model that adjusted for a variety of demographic factors and co-morbidities, RRs of cancer-specific mortality in participants with AD = 0.50 (p = 0.028) and 0.97 (p = 0.942) in non-AD dementia. This study provides further evidence of an inverse association between cancer and AD.
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Gender and incidence of dementia in the Framingham Heart Study from mid-adult life
Article
Gender-specific risks for dementia and Alzheimer's disease (AD) starting in midlife remain largely unknown. Prospectively ascertained dementia/AD and cause-specific mortality in Framingham Heart Study (FHS) participants was used to generate 10- to 50-year risk estimates of dementia/AD on the basis of the Kaplan-Meier method (cumulative incidence) or accounting for competing risk of death (lifetime risk [LTR]). Overall, 777 cases of incident dementia (601 AD) occurred in 7901 participants (4333 women) over 136,266 person-years. Whereas cumulative incidences were similar in women and men, LTRs were higher in women older than 85 years of age. LTR of dementia/AD at age 45 was 1 in 5 in women and 1 in 10 in men. Cardiovascular mortality was higher in men with rate ratios decreasing from approximately 6 at 45 to 54 years of age to less than 2 after age 65. Selective survival of men with a healthier cardiovascular risk profile and hence lower propensity to dementia might partly explain the higher LTR of dementia/AD in women.
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Anti-Inflammatory Therapy in Chronic Disease: Challenges and Opportunities
Article
  • Jan 2013
  • SCIENCE
A number of widespread and devastating chronic diseases, including atherosclerosis, type 2 diabetes, and Alzheimer’s disease, have a pathophysiologically important inflammatory component. In these diseases, the precise identity of the inflammatory stimulus is often unknown and, if known, is difficult to remove. Thus, there is interest in therapeutically targeting the inflammatory response. Although there has been success with anti-inflammatory therapy in chronic diseases triggered by primary inflammation dysregulation or autoimmunity, there are considerable limitations. In particular, the inflammatory response is critical for survival. As a result, redundancy, compensatory pathways, and necessity narrow the risk:benefit ratio of anti-inflammatory drugs. However, new advances in understanding inflammatory signaling and its links to resolution pathways, together with new drug development, offer promise in this area of translational biomedical research.
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Female predominance and X chromosome defects in autoimmune diseases
Article
  • Aug 2009
  • J AUTOIMMUN
It is known that autoimmune diseases cumulatively affect 5–10% of the general population.Although knowledge of pathogenesis has become more refined, laboratory diagnosis more accurate, and therapy more effective, the reasons for the female preponderance of these conditions remain unclear. The most intriguing theory to explain the female preponderance is currently related to sex chromosomes, as women with autoimmune diseases manifest a higher rate of circulating cells with a single X chromosome (i.e. X monosomy). In addition, there have been several reports on the role of X chromosome gene dosage through inactivation or duplication in autoimmunity. Taken together, sex chromosome changes might constitute the common trait of the susceptibility to autoimmune diseases.
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Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease
Article
  • Feb 2012
Background: Alzheimer's disease (AD) is the most common form of dementia. The incidence of AD rises exponentially with age and its prevalence will increase significantly worldwide in the next few decades. Inflammatory processes have been suspected in the pathogenesis of the disease. Objectives: To review the efficacy and side effects of aspirin, steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) in the treatment of AD, compared to placebo. Search methods: We searched ALOIS: the Cochrane Dementia and Cognitive Improvement Group's Specialized Register on 12 April 2011 using the terms: aspirin OR "cyclooxygenase 2 inhibitor" OR aceclofenac OR acemetacin OR betamethasone OR celecoxib OR cortisone OR deflazacort OR dexamethasone OR dexibruprofen OR dexketoprofen OR diclofenac sodium OR diflunisal OR diflusinal OR etodolac OR etoricoxib OR fenbufen OR fenoprofen OR flurbiprofen OR hydrocortisone OR ibuprofen OR indometacin OR indomethacin OR ketoprofen OR lumiracoxib OR mefenamic OR meloxicam OR methylprednisolone OR nabumetone OR naproxen OR nimesulide OR "anti-inflammatory" OR prednisone OR piroxicam OR sulindac OR tenoxicam OR tiaprofenic acid OR triamcinolone OR NSAIDS OR NSAID. ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases (including MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS), numerous trial registries (including national, international and pharmacuetical registries) and grey literature sources. Selection criteria: All randomised controlled trials assessing the efficacy of aspirin, steroidal and non-steroidal anti-inflammatory drugs in AD. Data collection and analysis: One author assessed risk of bias of each study and extracted data. A second author verified data selection. Main results: Our search identified 604 potentially relevant studies. Of these, 14 studies (15 interventions) were RCTs and met our inclusion criteria. The numbers of participants were 352, 138 and 1745 for aspirin, steroid and NSAIDs groups, respectively. One selected study comprised two separate interventions. Interventions assessed in these studies were grouped into four categories: aspirin (three interventions), steroids (one intervention), traditional NSAIDs (six interventions), and selective cyclooxygenase-2 (COX-2) inhibitors (five interventions). All studies were evaluated for internal validity using a risk of bias assessment tool. The risk of bias was low for five studies, high for seven studies, and unclear for two studies.There was no significant improvement in cognitive decline for aspirin, steroid, traditional NSAIDs and selective COX-2 inhibitors. Compared to controls, patients receiving aspirin experienced more bleeding while patients receiving steroid experienced more hyperglycaemia, abnormal lab results and face edema. Patients receiving NSAIDs experienced nausea, vomiting, elevated creatinine, elevated LFT and hypertension. A trend towards higher death rates was observed among patients treated with NSAIDS compared with placebo and this was somewhat higher for selective COX-2 inhibitors than for traditional NSAIDs. Authors' conclusions: Based on the studies carried out so far, the efficacy of aspirin, steroid and NSAIDs (traditional NSAIDs and COX-2 inhibitors) is not proven. Therefore, these drugs cannot be recommended for the treatment of AD.
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Inflammation in Alzheimer Disease--A Brief Review of the Basic Science and Clinical Literature
Article
  • Jan 2012
Biochemical and neuropathological studies of brains from individuals with Alzheimer disease (AD) provide clear evidence for an activation of inflammatory pathways, and long-term use of anti-inflammatory drugs is linked with reduced risk to develop the disease. As cause and effect relationships between inflammation and AD are being worked out, there is a realization that some components of this complex molecular and cellular machinery are most likely promoting pathological processes leading to AD, whereas other components serve to do the opposite. The challenge will be to find ways of fine tuning inflammation to delay, prevent, or treat AD.
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