Mood stabilizers in Alzheimer's disease: symptomatic and neuroprotective rationales

OBJECTIVE: This paper provides a case study of 'reverse translational research', in which empirical clinical trials focused on relieving psychopathological symptoms of Alzheimer's disease (AD) ultimately led to mechanism-based trials addressing aspects of the underlying pathophysiology of Alzheimer's disease. AD is multi-dimensional in nature, characterized not only by cognitive and functional decline but by neuropsychiatric symptoms that develop commonly and are associated with considerable morbidity. There have been a large number of empirical trials of various pharmacological agents to reduce these symptoms, such as agitation. Although antipsychotics are used most frequently for agitation, the usual effect size is modest, and there is a range of tolerability and/or safety issues, leading to the hope that alternatives can be found. Furthermore, most clinical trials addressing psychopathology have not been mechanism-based and none have attempted an alternative approach, namely, to delay or prevent the emergence of psychopathology. FINDINGS: The evidence of clinical trials is reviewed regarding the safety, tolerability, and apparent efficacy of the mood stabilizers carbamazepine and valproate for agitation associated with AD. Possible mechanisms of action of valproate are reviewed, leading to the surprising conclusion that neuroprotective properties may account for some of its clinical effects. These mechanisms (including activation of wnt-dependent signaling and upregulation of bcl-2, among others) may be particularly relevant for long-term treatment of AD. CONCLUSIONS: These clinical and mechanistic findings were combined in the development of a novel clinical trial examining whether chronic valproate therapy can attenuate the clinical progression of AD, which will be implemented by the Alzheimer's Disease Cooperative Study. The design addresses valproate's potential to delay or prevent the onset of agitation in patients lacking agitation to begin with, as well as to slow progressive decline in cognition and daily functioning.     

Role of Cognitive Enhancer Therapy in Alzheimer’s Disease with Concomitant Cerebral White Matter Disease: Findings from a Long-Term Naturalistic Study

Background

Evidence is lacking for cognitive enhancer therapy in patients with Alzheimer’s disease (AD) and concomitant cerebrovascular disease (mixed AD) as such patients would have been excluded from clinical trials. Earlier studies of mixed AD have focused on large vessel cerebrovascular disease. The influence of small vessel cerebrovascular disease (svCVD) in the form of white matter hyperintensity (WMH) on treatment outcomes in mixed AD has not been addressed.

Objective

In this long-term naturalistic study, we evaluated the effectiveness of cognitive enhancers in patients with mixed AD with svCVD.

Methods

We conducted a retrospective analysis of a prospective clinical database from a memory clinic of a tertiary hospital. Magnetic resonance imaging WMH was used as a marker of svCVD. Demographic, cognitive, and treatment data were analysed. Linear mixed models with patient-specific random effects were used to evaluate cognitive outcomes over time while adjusting for confounders.

Results

Patients with mixed AD (n = 137) or AD without svCVD (pure AD) (n = 28) were studied over a median duration of 28.7 months. Patients with mixed AD had a higher prevalence of hypertension (62.8 vs. 35.7 %, p = 0.011). The majority (75.2 %) of the study sample were managed with monotherapy. Mini Mental State Examination (MMSE) scores decreased over time (−0.04, p = 0.007), and the decrease was similar for both diagnosis groups (−0.03, p = 0.246). Annual estimated mean MMSE decline was 0.84 for pure AD and 0.48 for mixed AD. Similar trends were observed with Montreal Cognitive Assessment (MoCA) scores, with annual estimated mean reduction of 0.72 and 0.48 for pure AD and mixed AD, respectively.

Conclusion

Cognitive enhancers are effective in slowing the rate of cognitive decline in patients with AD with svCVD. These findings would need to be confirmed in randomized clinical trials.     

Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: Pathogenic mechanisms and therapeutic potential

Alzheimer''s disease (AD), the most common neurodegenerative disorder, is characterized by memory loss and cognitive dysfunction. The accumulation of misfolded protein aggregates including amyloid beta (Aβ) peptides and microtubule associated protein tau (MAPT/tau) in neuronal cells are hallmarks of AD. So far, the exact underlying mechanisms for the aetiologies of AD have not been fully understood and the effective treatment for AD is limited. Autophagy is an evolutionarily conserved cellular catabolic process by which damaged cellular organelles and protein aggregates are degraded via lysosomes. Recently, there is accumulating evidence linking the impairment of the autophagy–lysosomal pathway with AD pathogenesis. Interestingly, the enhancement of autophagy to remove protein aggregates has been proposed as a promising therapeutic strategy for AD. Here, we first summarize the recent genetic, pathological and experimental studies regarding the impairment of the autophagy–lysosomal pathway in AD. We then describe the interplay between the autophagy–lysosomal pathway and two pathological proteins, Aβ and MAPT/tau, in AD. Finally, we discuss potential therapeutic strategies and small molecules that target the autophagy–lysosomal pathway for AD treatment both in animal models and in clinical trials. Overall, this article highlights the pivotal functions of the autophagy–lysosomal pathway in AD pathogenesis and potential druggable targets in the autophagy–lysosomal pathway for AD treatment.KEY WORDS: Alzheimer''s disease (AD), Amyloid beta (Aβ) peptides, MAPT/tau, Autophagy–lysosomal pathway, Autophagy enhancers, Autophagy, Mitophagy, Neurodegenerative diseases     

New therapeutics beyond amyloid-β and tau for the treatment of Alzheimer’s disease

As the population ages, Alzheimer’s disease (AD), the most common neurodegenerative disease in elderly people, will impose social and economic burdens to the world. Currently approved drugs for the treatment of AD including cholinesterase inhibitors (donepezil, rivastigmine, and galantamine) and an N-methyl-D-aspartic acid receptor antagonist (memantine) are symptomatic but poorly affect the progression of the disease. In recent decades, the concept of amyloid-β (Aβ) cascade and tau hyperphosphorylation leading to AD has dominated AD drug development. However, pharmacotherapies targeting Aβ and tau have limited success. It is generally believed that AD is caused by multiple pathological processes resulting from Aβ abnormality, tau phosphorylation, neuroinflammation, neurotransmitter dysregulation, and oxidative stress. In this review we updated the recent development of new therapeutics that regulate neurotransmitters, inflammation, lipid metabolism, autophagy, microbiota, circadian rhythm, and disease-modified genes for AD in preclinical research and clinical trials. It is to emphasize the importance of early diagnosis and multiple-target intervention, which may provide a promising outcome for AD treatment.     

Mitochondrial dysfunction: A potential target for Alzheimer’s disease intervention and treatment

Alzheimer's disease (AD) is an irreversible neurodegenerative brain disorder which manifests as a progressive decline in cognitive function. Mitochondrial dysfunction plays a critical role in the early stages of AD, and advances the progression of this age-related neurodegenerative disorder. Therefore, it can be a potential target for interventions to treat AD. Several therapeutic strategies to target mitochondrial dysfunction have gained significant attention in the preclinical stage, but the clinical trials performed to date have shown little progress. Thus, we discuss the mechanisms and strategies of different therapeutic agents for targeting mitochondrial dysfunction in AD. We hope that this review will inspire and guide the development of efficient AD drugs in the future.     

Combination therapy in Alzheimer's disease: a review of current evidence

Treating dementia has become a major challenge in clinical practice. Presently, acetylcholinesterase inhibitors are the first-line drugs in the treatment of Alzheimer's disease (AD). These options are now complemented by memantine, which is approved for the treatment of moderate-to-severe AD. Altogether, a minimum of six agent classes already exist, all of which are approved for clinical use and are either already being tested or ready for phase III clinical trials for the treatment of AD. These include cholinesterase inhibitors, blockers of the NMDA receptor, antioxidants or blockers of oxidative deamination (including Gingko biloba), anti-inflammatory agents, neurotrophic factors (including hormone replacement therapy and drugs acting on insulin signal transduction) and antiamyloid agents (including cholesterol-lowering therapy). These approaches hold promise for disease modification and have a potential to be used as combination therapy for cognitive enhancement. Presently, only nine clinical studies have been published that have investigated the effects of a combination regimen on cognitive performance or AD. Among those, one study was conducted in elderly cognitively intact persons; the others involved patients with AD. Only five of the treatment studies followed a randomised, controlled design. Not all studies favoured the superior efficacy of combination therapy over monotherapy. Some studies, however, showed some evidence for synergistic combination effects of symptomatic therapy, including delay or prevention of disease progression in AD patients. In addition, six studies investigated the effects of AChE inhibitor in combination with antipsychotic or antidepressant therapy on behavioural aspects of AD symptomatology. In four of those studies there were indications that combination therapy had greater efficacy over monotherapy. The treatment of AD patients requires optimised options for all stages of illness based on the available drugs. There is a great need for further well designed studies on combination therapy in AD.     

Recruitment and Retention Strategies for Clinical Trials in Alzheimer’s Disease

Recruitment for clinical trials is challenging for any disease but is particularly so for Alzheimer’s disease (AD). In the past three years, our site has recruited almost 600 subjects into our AD primary prevention and treatment trials, and diagnostic studies. In this article, we describe which strategies have had the best yield and which have had a modest or low yield. High yield is loosely defined as any recruitment activity that yields a high number of interested or eligible participants per the expense or time/staff invested in the recruitment effort. For example, a high-yield recruitment strategy is direct mailings for primary prevention trials. Low yield is defined as any recruitment activity that yields a low number of interested or eligible participants per the expense or time/staff invested in the recruitment effort. For example, direct mailing to physicians generally does not yield many subjects. Recruitment for primary prevention trials and treatment trials differ in approach. Recruitment of subjects is much more expensive than previously reported in the literature. It is important to build this expense into budgets. Subjects that do not qualify for their desired study may be candidates for other studies. Minority recruitment presents unique challenges above and beyond the overall challenges of successful recruitment in to AD clinical trials.     

Effects of cholinesterase inhibitors on behavioural disturbances in Alzheimer's disease: a systematic review

Behavioural disturbances, also termed neuropsychiatric symptoms, are a frequent clinical feature of dementia in Alzheimer's disease (AD). Many AD patients receive treatment with cholinesterase inhibitors (ChEIs). This review examines the evidence for behavioural effects of the four ChEIs that have been approved for the treatment of mild to moderate AD. A systematic search of the MEDLINE and EMBASE databases and the Cochrane Library was conducted to identify clinical trials that had a randomised, placebo-controlled design. Studies were included in this review if they enrolled patients who had received a diagnosis of probable AD, involved at least one ChEI, and used an appropriate instrument for the assessment of behavioural disturbances. Fourteen studies that matched the selection criteria were identified in the literature. A statistically significant difference between active treatment and placebo with regard to behavioural symptoms was observed in three of the 14 studies. Treatment effects varied between 2.0 and 6.2 points on the Neuropsychiatric Inventory. ChEIs have moderate effects when used as a blanket treatment for the cluster of behavioural disturbances in AD. With regard to the limitations of the available trials, and in view of the risks that are associated with the use of atypical antipsychotics, the potential of ChEIs for the management of specific neuropsychiatric symptoms in patients with AD should be explored in further studies.     

Role of Cerebrospinal Fluid Biomarkers in Clinical Trials for Alzheimer's Disease Modifying Therapies

Until now, a disease-modifying therapy (DMT) that has an ability to slow or arrest Alzheimer''s disease (AD) progression has not been developed, and all clinical trials involving AD patients enrolled by clinical assessment alone also have not been successful. Given the growing consensus that the DMT is likely to require treatment initiation well before full-blown dementia emerges, the early detection of AD will provide opportunities to successfully identify new drugs that slow the course of AD pathology. Recent advances in early detection of AD and prediction of progression of the disease using various biomarkers, including cerebrospinal fluid (CSF) Aβ_1-42, total tau and p-tau₁₈₁ levels, and imagining biomarkers, are now being actively integrated into the designs of AD clinical trials. In terms of therapeutic mechanisms, monitoring these markers may be helpful for go/no-go decision making as well as surrogate markers for disease severity or progression. Furthermore, CSF biomarkers can be used as a tool to enrich patients for clinical trials with prospect of increasing statistical power and reducing costs in drug development. However, the standardization of technical aspects of analysis of these biomarkers is an essential prerequisite to the clinical uses. To accomplish this, global efforts are underway to standardize CSF biomarker measurements and a quality control program supported by the Alzheimer''s Association. The current review summarizes therapeutic targets of developing drugs in AD pathophysiology, and provides the most recent advances in the     

Biomarkers in Amyloid-β Immunotherapy Trials in Alzheimer's Disease

Drug candidates directed against amyloid-β (Aβ) are mainstream in Alzheimer''s disease (AD) drug development. Active and passive Aβ immunotherapy is the principle that has come furthest, both in number and in stage of clinical trials. However, an increasing number of reports on major difficulties in identifying any clinical benefit in phase II–III clinical trials on this type of anti-Aβ drug candidates have caused concern among researchers, pharmaceutical companies, and other stakeholders. This has provided critics of the amyloid cascade hypothesis with fire for their arguments that Aβ deposition may merely be a bystander, and not the cause, of the disease or that the amyloid hypothesis may only be valid for the familial form of AD. On the other hand, most researchers argue that it is the trial design that will need refinement to allow for identifying a positive clinical effect of anti-Aβ drugs. A consensus in the field is that future trials need to be performed in an earlier stage of the disease and that biomarkers are essential to guide and facilitate drug development. In this context, it is reassuring that, in contrast to most brain disorders, research advances in the AD field have led to both imaging (magnetic resonance imaging (MRI) and PET) and cerebrospinal fluid (CSF) biomarkers for the central pathogenic processes of the disease. AD biomarkers will have a central role in future clinical trials to enable early diagnosis, and Aβ biomarkers (CSF Aβ42 and amyloid PET) may be essential to allow for testing a drug on patients with evidence of brain Aβ pathology. Pharmacodynamic Aβ and amyloid precursor protein biomarkers will be of use to verify target engagement of a drug candidate in humans, thereby bridging the gap between mechanistic data from transgenic AD models (that may not be relevant to the neuropathology of human AD) and large and expensive phase III trials. Last, downstream biomarker evidence (CSF tau proteins and MRI volumetry) that the drug ameliorates neurodegeneration will, together with beneficial clinical effects on cognition and functioning, be essential for labeling an anti-Aβ drug as disease modifying.     

Is It the Twilight of BACE1 Inhibitors?

β-secretase (BACE1) has been regarded as a prime target for the development of amyloid beta (Aβ) lowering drugs in the therapy of Alzheimer´s disease (AD). Although the enzyme was discovered in 1991 and helped to formulate the Aβ hypothesis as one of the very important features of AD etiopathogenesis, progress in AD treatment utilizing BACE1 inhibitors has remained limited. Moreover, in the last years, major pharmaceutical companies have discontinued clinical trials of five BACE1 inhibitors that had been strongly perceived as prospective. In our review, the Aβ hypothesis, the enzyme, its functions, and selected substrates are described. BACE1 inhibitors are classified into four generations. Those that underwent clinical trials displayed adverse effects, including weight loss, skin rashes, worsening of neuropsychiatric symptoms, etc. Some inhibitors could not establish a statistically significant risk-benefit ratio, or even scored worse than placebo. We still believe that drugs targeting BACE1 may still hide some potential, but a different approach to BACE1 inhibition or a shift of focus to modulation of its trafficking and/or post-translational modification should now be followed.     

Therapeutic intervention for Alzheimer's disease with γ-secretase inhibitors: still a viable option?

INTRODUCTION: Compounds that inhibit or modulate γ-secretase, the pivotal enzyme which generates β-amyloid (Aβ), are potential therapeutics for Alzheimer's disease (AD). AREAS COVERED: This article briefly reviews the profile of γ-secretase inhibitors that have reached the clinic and discusses the clinical issues surrounding this new class of anti-AD compounds. EXPERT OPINION: γ-Secretase inhibitors may cause significant toxicity in humans. Two large Phase III clinical trials of semagacestat in mild-to-moderate AD patients were prematurely interrupted because of detrimental cognitive and functional effects of the drug. These detrimental effects were mainly ascribed to the inhibition of Notch processing and the accumulation of the neurotoxic precursor of Aβ resulting from the block of the γ-secretase cleavage activity on amyloid precursor protein. New Notch-sparing γ-secretase inhibitors are being developed with the hope of overcoming the previous setbacks. It has also been argued that γ-secretase inhibitors should be used in the very early stages of the disease progression when neuronal loss is still limited. Thus, the inclusion of patients with mild-to-moderate AD in the semagacestat Phase III trials could also explain the negative outcome of these studies. Understanding the reasons for this failure may be important for future research on effective treatments for this devastating disease.     

Beyond immunotherapy: new approaches for disease modifying treatments for early Alzheimer’s disease

Introduction: Current pharmacological recommendations for the treatment of Alzheimer’s disease (AD) include the cholinesterase inhibitors and the N-methyl-D-aspartate antagonist, memantine. However, these medications only manage symptoms of AD, and do not target Aβ plaques and neurofibrillary tangles. As such, there is a need to develop effective and safe disease modifying treatments that directly target AD pathology and alter the course of AD progression.

Areas covered: This review evaluates ongoing phase 2 and 3 clinical trials, as well as those completed or published over the past five years. Studies for this review were obtained from clinicaltrials.gov, alzforum.org/therapeutics, and PubMed. Keywords and search criteria included: phase 2, or 3 trials related to Alzheimer’s disease, mild cognitive impairment, amyloid-beta and tau. Immunotherapies for AD have not been included as this is beyond the scope of this review.

Expert opinion: A substantial number of trials investigating disease modifying drugs in AD target amyloid-beta and tau pathology. However, many of these trials have relatively short treatment duration and do not include combined assessment of biomarkers and clinical outcomes. Future investigations are recommended to include biomarker assessments and clinical outcomes over a minimum treatment duration of 18 months in order to establish disease-modifying effects.     

An update on the efficacy of non-steroidal anti-inflammatory drugs in Alzheimer's disease

Several epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD), especially for patients carrying one or more ?4 allele of the apolipoprotein E. The biological mechanism of this protection is not completely understood and may involve inhibition of COX activity, inhibition of β-amyloid_1-42 (Aβ42) production and aggregation, inhibition of β-secretase activity, activation of PPAR-γ or stimulation of neurotrophin synthesis. Unfortunately, long-term, placebo-controlled clinical trials with both non-selective and COX-2 selective NSAIDs in AD patients produced negative results. A secondary prevention study with rofecoxib in patients with mild cognitive impairment and a primary prevention study with naproxen and celecoxib in elderly subjects with a family history of AD were also negative. All these failures have diminished the hope that NSAIDs could be beneficial in the treatment of AD. It is hypothesized that the chronic use of NSAIDs may be beneficial only in the normal brain by inhibiting the production of Aβ42. Once the Aβ deposition process has started, NSAIDs are no longer effective and may even be detrimental because of their inhibiting activity on activated microglia of the AD brain, which mediates Aβ clearance and activates compensatory hippocampal neurogenesis.     

Is long-term treatment of Alzheimer's disease with cholinesterase inhibitor therapy justified?

The cholinesterase inhibitors (ChEIs) donepezil, rivastigmine and galantamine are the current mainstays in the drug treatment of Alzheimer's disease (AD). There is convincing evidence that these agents provide at least modest cognitive, behavioural and functional benefit for 6-12 months at all stages of the disease. Longer term benefits cannot be directly examined by placebo-controlled trials. Nevertheless, the results of virtually all open-label extensions of the pivotal trials, studies of patients with AD at different levels of severity and clinical trials using other designs favour treatment over no treatment for periods of up to 5 years. There are plausible biological reasons why ChEIs might be expected to work over a prolonged period of time although, to date, studies using various markers to chart the effects of medication on long-term disease progression have yielded mixed results. The most contentious issue regarding long-term treatment is economic, but the majority of available economic analyses suggest net savings over the long term if patients with AD receive persistent treatment with ChEIs.     

Atopic dermatitis: understanding the disease and its management

ABSTRACT

Objective: Atopic dermatitis (AD) is a common, chronic, inflammatory skin disease that can significantly reduce the quality of life of not only patients but also entire families. This review will focus on the currently available non-pharmacologic and pharmacologic treatments for the control and management of AD.

Research design and methods: A review of English-language articles from January 1953 to May 2006 was performed within the MEDLINE database. Search terms included, but were not limited to, atopic dermatitis, topical corticosteroids, and topical calcineurin inhibitors. Studies evaluating the diagnosis, physical and psychological burden, and underlying pathophysiology of AD were included. Particular focus was placed on literature presenting key safety and efficacy data from clinical trials involving AD treatment.

Results: Although good skin care and trigger avoidance are fundamental to AD management, most patients also require pharmacologic intervention. Topical therapies comprise the foundation of AD treatment. In particular, topical corticosteroids have been a mainstay in AD treatment for several decades and the newer topical calcineurin inhibitors have become a valuable addition to the therapeutic armamentarium. TCIs are a safe and effective AD treatment; they limit the number of disease flares, extend the time between flares, and provide a steroid-sparing option that may be of particular benefit in the pediatric population. The use of more potent therapies, such as systemic (oral/injected) agents or phototherapy, is typically limited to the treatment of severe, refractory disease. Additionally, owing to the increased risk for bacterial, viral, and fungal infections in patients with AD, topical or systemic antimicrobials are an important component of treatment.

Limitations: Case reports and small-scale studies were typically not included in this analysis and owing to the limited number of trials evaluating TCSs, consensus statements and comprehensive review articles were used to obtain information pertaining to the use of this treatment in AD.

Conclusions: AD is a common, chronic disease requiring a long-term management strategy that incorporates preventive measures and a multipronged treatment approach.     

Non-steroidal anti-inflammatory drugs and cyclooxygenase in Alzheimer's disease

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference in the chronic inflammatory reaction, that takes place in AD. The best-characterized action of NSAIDs is the inhibition of cyclooxygenase (COX). There is special interest for anti-inflammatory treatment of AD using selective COX-2 inhibitors. These inhibitors reduce the inflammatory reaction but lack the side effects observed with non-selective NSAIDs. So far, clinical trials designed to inhibit inflammation or COX-2 activity have failed in the treatment of AD patients. Several lines of evidence can explain the failures of the anti-inflammatory and anti-COX-2 trials on AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in AD brain. Understanding the role of COX in AD pathogenesis could contribute to the development of an anti-inflammatory therapy for the treatment or prevention of AD.     

Pharmacological Treatment of Mild Cognitive Impairment as a Prodromal Syndrome of Alzheimer′s Disease

Mild cognitive impairment (MCI) is a syndrome which, depending on various neurobiological, psychological and social factors, carries a high risk of developing into dementia. As far as diagnostic uncertainty and the heterogeneous underlying pathophysiological mechanisms are concerned, only limited therapeutic options are currently available. Clinical trials involving a wide range of substances have failed to show efficacy on primary and secondary outcome parameters. Most results reflect not only a lack of effectiveness of drug therapy but also methodological constraints in true prodromal Alzheimer´s disease (AD) based on clinical criteria. Biomarkers may help to identify MCI as a prodromal phase of dementia, so it is important to use them to improve specificity of case selection in future studies. For MCI as a prodromal syndrome of AD, clinical trials with disease modifying drugs that target underlying pathological mechanisms such as amyloid-beta accumulation and neurofibrillary tangle formation may help develop effective treatment options in the future. Alternative pharmacological approaches are currently being evaluated in ongoing phase 1 and phase 2 studies. Nevertheless, a lack of approved pharmacotherapeutic options has led to specific interventions that focus on patient education and life-style related factors receiving increasing attention.     

阿尔采末病的实验性治疗研究进展

随着人们对阿尔采末病(AD)发病机制的深入研究,未来AD的治疗也将从传统的抗乙酰胆碱酶疗法转变为针对淀粉样斑块形成,淀粉样多肽介导的毒性作用及神经原纤维缠结形成的多发病机制的研究。这篇综述将对包括以分泌酶为基础的治疗、免疫治疗、抗神经原纤维缠结的治疗以及传统中医治疗在内的各种新的实验性疗法做一个大体的论述。     

The role of COX-1 and COX-2 in Alzheimer's disease pathology and the therapeutic potentials of non-steroidal anti-inflammatory drugs

Epidemiological studies indicate that anti-inflammatory drugs, especially the non-steroidal anti-inflammatory drugs (NSAIDs), decrease the risk of developing Alzheimer's disease (AD). Their beneficial effects may be due to interference of the chronic inflammatory reaction in AD. The best-characterised action of NSAIDs is the inhibition of cyclooxygenase (COX). So far, clinical trials designed to inhibit inflammation or cyclooxygenase activity have failed in the treatment of AD patients. In this review we will focus on the role, expression and regulation of COX-1 and COX-2 in neurodegeneration and AD pathogenesis. Understanding the pathological, physiological and neuroprotective role of cyclooxygenase will contribute to the development of a therapy for the treatment or prevention of AD.