Cholinergic Therapy Research Articles

Current therapies in dementia

Currently, cholinergic therapies for Alzheimer's disease (AD) have been developed and widely accepted based upon an observation that presynaptic cholinergic neurons in the basal nucleus of Meynert that widely project to the cerebral cortices are consistently damaged in AD brains. Since it is likely that the loss of central cholinergic activity may be associated with cognitive worsening in patients with AD, it is hypothesized that cholinergic augmentation could improve the cognitive ability of patients with AD. Cholinesterase inhibitors represent one way of implementing this strategy by inhibiting the breakdown of acetylcholine and increasing its availability in synapses. Indeed, several recent clinical trials of donepezil, galanthamine and rivastigmine have come to the conclusion that these cholinesterase inhibitors have overall beneficial effects in cognitive as well as global functions. American Academy of Neurology recommended a use of cholinesterase inhibitors as a first choice medicine in the treatment of AD. All 3 major studies of Donepezil from USA, Europe and Japan have reached the same conclusion favoring Donepezil in the treatment of mild to moderate AD. Donepezil can also be used as a safe and efficacious drug in the elderly aged 85 or older. Clinical trial of galantamine is in progress in Japan. Moreover, herbal medicines named kami-untan-to and hachimi-jiou-gan have been shown to be beneficial in some priority studies with a small sample size. It is critically needed to widen therapeutic windows in the treatment of AD.

Significance of syncope in patients with Alzheimer's disease treated with cholinesterase inhibitors.

We describe three cases of patients with Alzheimer's disease who presented with cardiac syncope soon after initiation of a cholinesterase inhibitor therapy (donepezil). Bradyarrhythmia was documented in two patients, considered probable in one, and was presumed related to the cholinergic therapy. Pacemaker implantation seemed justified rather than donepezil cessation. More over, it permitted an increase in donepezil dosage.

Consequences of low levels of nicotinic acetylcholine receptors in schizophrenia for drug development

AbstractThe incidence of smoking in the mentally ill is much higher than in the general population and is inordinately high in schizophrenia. It has been suggested that this might be an attempt to self‐medicate an underlying biological deficit. The receptors that mediate nicotinic responses are decreased in many regions of postmortem brain in schizophrenic smokers, compared to control smokers. Patients exhibit differential responses to nicotine in a number of behavioral, cognitive, and metabolic measures. As nicotine regulates the release of a large number of neurotransmitters, it is likely that differences in down‐stream neuroadaptation of other transmitter/receptor systems would result from the reduced level of nicotinic receptors in these patients. The disparate responses to nicotine have consequences for the development of cholinergic drug therapies in schizophrenia. Drug Dev. Res. 60:127–136, 2003. © 2003 Wiley‐Liss, Inc.

The role of the N-methyl-D-aspartate receptor in Alzheimer's disease: therapeutic potential.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder with an unknown etiology. Pathologic processes implicated in AD include b-amyloid-induced synaptic failure; tau hyperphosphorylation; inflammation; oxidative stress; abnormal neurotransmission involving acetylcholine, glutamate, norepinephrine, serotonin, and dopamine; and abnormalities in second messengers, protein kinases, and apoptosis. Although each of these pathways offers potential therapeutic targets, pharmacologic manipulation of the glutamatergic N-methyl-D-aspartate receptor pathway, alone or in combination with cholinergic therapies, is emerging as the next promising strategy for the treatment of AD and vascular dementia.

Comparison between Alzheimer's disease and vascular dementia: Implications for treatment

Virtually 90% of the elderly with late-onset dementia exhibit neuropathological features consistent with Alzheimer's disease (AD), vascular dementia (VaD) or dementia with Lewy bodies (DLB), alone or in combination. Both AD and DLB reveal extensive senile plaques containing amyloid β whereas neurofibrillary tangles evident as tau pathology are fewer in DLB, which also bears diffuse cortical Lewy bodies. Interestingly, however, there is considerable overlap between AD and VaD in terms of both risk factors and pathology. Cholinergic deficits are also encountered in VaD, which like AD may respond to cholinergic therapy. Cerebrovascular pathology, ischemic brain damage and autonomic dysregulation resulting in cerebral hypoperfusion appears fundamental in the pathogenesis of late-onset dementias.

Why Cholinergic Agents Help Alzheimer's Patients

Alzheimer's disease is a neurodegenerative disease that impairs cognition and ultimately results in death. Cholinergic agents are used to improve symptoms associated with the disease, and one mechanism may be the replacement of lost cholinergic input. Gu et al . provide a possible molecular mechanism for the benefits of cholinergic therapies by showing that the β-amyloid peptide (Aβ), which is a major constituent of senile plaques, stimulates intracellular signaling pathways in cortical neurons and that this can be blocked by the presence of agonists of the M1 muscarinic acetylcholine receptors (mAChRs). Cortical slices exposed to either the aggregated form of Aβ 25-35 or the full-length Aβ 1-42 or nonaggregated Aβ peptides exhibited increased phosphorylation of protein kinase C (PKC) and calcium-calmodulin-dependent kinase II (CaMKII), which was taken as a measure of activation of these enzymes. Treatment of the slices with N -methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists and antagonists of the voltage-dependent calcium channels blocked stimulation of PKC and CaMKII by Aβ peptides, as did chelation of calcium with EGTA and inhibition of action potentials by application of the sodium channel blocker tetrodotoxin. Thus, synaptic transmission appeared to be required for Aβ to stimulate intracellular signaling. Indeed, Aβ stimulated the frequency of action potentials and decreased the interval between excitatory postsynaptic currents (EPSCs). Application of a mAChR agonist or a γ-aminobutyric acid A (GABA A ) receptor agonist inhibited phosphorylation of PKC and CaMKII in response to Aβ peptides, suggesting that mAChR may stimulate inhibitory neuronal signals mediated by GABA. As expected, application of the mAChR agonist increased the frequency of inhibitory synaptic transmission in the slices and decreased the interval between inhibitory postsynaptic currents (IPSCs). Thus, increased inhibitory synaptic transmission stimulated by mAChR agonists may compensate for the increased excitatory transmission triggered by excess Aβ peptide produced during Alzheimer's disease. Z. Gu, P. Zhong, Z. Yan, Activation of muscarinic receptors inhibits β-amyloid peptide-induced signaling in cortical slices. J. Biol. Chem. 278 , 17546-17556 (2003). [Abstract] [Full Text]

Age-related mild cognitive deficit: a ready-to-use concept?

For better management of mild cognitive impairment in elderly patients, clinicians should be provided with instruments to detect early changes and predict their progression. To define this cognitive status between optimal and pathological aging, many concepts have been proposed, which actually describe various conditions and provide more or less precise criteria, leaving room for variable implementation. As a consequence, application of these criteria gave highly variable prevalence rates, Neuropathological studies indicate that the different criteria have variable power in detecting incipient Alzheimer's disease (AD) and suggest that the transition between mild cognitive impairment and ÀD is not merely quantitative. Follow-up studies have produced, according to the criteria used, a 2.5% to 16,6% annual rate for progression toward dementia, and have also shown that the criteria differ in their stability and predictive power. Baseline cognitive performances have some predictive value, but are difficult to apply in first-line medicine. Investigational techniques (structural and functional imaging, magnetic resonance spectroscopy, magnetization transfer imaging, cerebrospinal fluid neuro-chemistry, and apolipoprotein E genotype) are promising tools in the early diagnosis of AD, which remains the most frequent type of dementia in elderly people and probably the most frequent type developed by patients with mild cognitive deficit. The final goal is to offer early treatment to those patients who will evolve towards dementia, once they can be identified, in the case of AD, recent findings question the adequacy of cholinergic replacement therapies. In its current state, the criteria for mild cognitive deficit are hardly transferable to first-line medicine. However, disseminating the concept could help increase the sensitivity of general practitioners to the importance of cognitive complaints and signs in their elderly patients.

Immunotoxin Lesion of the Cholinergic Nucleus Basalis Causes Aβ Deposition: Towards a Physiologic Animal Model of Alzheimers Disease

Transgenic βAPP mice are valid and useful models of Alzheimers disease (AD) as they effectively recreate Aβ deposition, which is widely regarded as the central pathogenic event in the disease. Transgenic mice do not, however, replicate the initial pathogenic event of the most common form of AD. The majority of AD is not caused by any of the gene mutations employed to create these mice. As cortical Aβ deposition is a common, if not universal, occurrence in many mammalian species, its cause is likely to lie within the physiologic process of aging. We have created an animal model of Aβ deposition by inducing cortical cholinergic deafferentation, a well-known aging change, in the brains of young rabbits. Lesioning the cholinergic nucleus basalis magnocellularis (nbm) results in cortical cholinergic deafferentation and cortical Aβ deposition. The Aβ deposits are primarily vascular, with occasional perivascular plaques. The specificity of this change for cholinergic processes has been demonstrated by the reduction of lesion-induced Aβ deposition by cholinergic therapy with AF267B, an m1-selective muscarinic agonist, and physostigmine, an acetylcholinesterase inhibitor, and by showing that lesioning of the noradrenergic locus ceruleus does not cause Aβ deposition. Significant decreases in cortical synaptic antigen density occur at 6 months post-lesion. Examination of longer survival periods has been complicated by regeneration of cortical cholinergic afferents but repetitive nbm lesions are expected to overcome this obstacle. Agerelated degeneration of the nbm in humans may be a major contributor to Aβ deposition in normal aging and AD. Keywords: immunotoxin lesion, cholinergic nucleus, deposition, cholinergic differentiation

Strategic involvement of cholinergic pathways and executive dysfunction: Does location of white matter signal hyperintensities matter?

Cholinergic therapies have proven efficacious in the treatment of Alzheimer's disease, and recently in vascular and mixed dementia. We set out to evaluate the impact of putative cerebrovascular lesions involving cholinergic pathways in patients with cognitive impairment. White matter signal hyperintensities on magnetic resonance imaging involving cholinergic projections were classified according to a three-point rating scale for 171 individuals with cognitive impairment and 34 normal elderly controls. Medial temporal lobe width was measured, and a neuropsychological test battery was administered. Moderate or severe involvement of cholinergic pathways by white matter signal hyperintensities were identified in 60% of subjects with probable vascular dementia, 30% of subjects with possible/probable Alzheimer's disease, and 40% of subjects with cognitive impairment but no dementia. All control subjects were found to have minimal cholinergic pathway involvement. Medial temporal lobe width and signal hyperintensities on magnetic resonance imaging affecting cholinergic pathways were inversely related. Individuals with moderate and severe involvement of cholinergic pathways by white matter signal hyperintensities had greater impairment of executive function and visuospatial attention, despite equivalent degrees of global impairment and memory dysfunction when compared to those with minimal cholinergic pathway involvement. This is the first study to suggest that cerebrovascular disease may directly affect cholinergic projections and may exacerbate pre-existing cholinergic deficits of a degenerative nature, especially in probable Alzheimer's disease. Cerebrovascular compromise of cholinergic white matter projections may therefore be relevant in understanding the effects of cholinergic therapies. Copyright © 2003 by National Stroke Association

Cholinergic function and Alzheimer's disease.

Deficits in cholinergic function contribute to the pathology of Alzheimer's disease (AD), affecting cognition, behaviour and activities of daily living. Pharmacological intervention directed towards these deficits is based on acetylcholinesterase (AChE) inhibition. Whether such drugs have reached their therapeutic 'ceiling' is an open question and it is possible that cholinergic intervention may be usefully combined with other therapeutic mechanisms. Data relating to such issues are still being collected. In severe AD, levels of AChE and choline acetyltransferase are decreased by as much as 90% compared with normal, whilst butyrylcholinesterase (BuChE) increases. In such instances, it is possible that BuChE may be a more appropriate therapeutic target. Both AChE and BuChE are aggregated in senile plaques along with beta-amyloid, and investigations are being undertaken to determine whether drugs can be developed that inhibit AChE whilst also acting on beta-amyloid. Deficits in nicotinic binding sites have led to hopes for new nicotinic drugs. Cholinergic therapies can potentially cause unwanted side effects and the search for the 'ideal' inhibitor continues. Combinations of drugs may ultimately prove to be the most productive means of treating patients with AD.

Have cholinergic therapies reached their clinical boundary in Alzheimer's disease?

The cholinergic hypothesis suggests that Alzheimer's disease (AD) results from a selective loss in cholinergic neurons with decreased acetylcholine levels. Treatments that increase the level of acetylcholine would be expected to provide clinical benefit. Clinical trials of dietary precursors of acetylcholine and muscarinic receptor agonists have been unsuccessful. Further research is needed to confirm whether nicotine or nicotinic agonists are of value. The most successful approach has been to increase acetylcholine levels by inhibiting cholinesterase function. A number of cholinesterase inhibitors (ChEI) show clinical efficacy including phyostigmine but it is poorly tolerated. Tacrine, the first ChEI to be licensed for AD, needs frequent administration and causes a specific reversible hepatotoxicity. Three ChEI, donepezil, rivastigmine and galantamine are widely available. They are effective in mild to moderate (and possibly severe) AD. Tolerability is improved by slow dose titration and there are a significant number of non-responders. Donepezil appears to be effective, the simplest to use and the best tolerated. Rivastigmine is effective but less well tolerated: galantamine is also very effective with intermediate tolerability. Although there are pharmacological differences between the three compounds, it remains uncertain whether these are clinically relevant. There are still unanswered questions. It is difficult to predict who will respond to the drugs and it is unclear how long treatment benefits last. At present there are little data to support the suggestion of activity beyond symptomatic benefit. Trials are also being conducted in Mild Cognitive Impairment, other dementias and other conditions where cognitive impairment is a problem.

Biomarker 研究から見た Mild cognitive impairment とアルツハイマー病の早期診断

Elderly people are concerned about changes in their cognitive functioning. Since cholinergic therapies for Alzheimer's disease have been developed and become widely accepted, elderly people have come to visit clinics to seek medical advice about whether such a subtle change in cognitive ability may represent an early manifestation of Alzheimer's disease (AD). If they are likely to develop dementia or AD, they want to receive immediate medical treatment as soon as possible to prevent further loss of cognitive functioning so that they can live independently as long as possible. The first priority in the clinical application of a biomarker is that biomarker should contribute to early diagnosis of dementia. Among such biomarkers, we believe that cerebrospinal fluid markers and functional brain imaging are clinically the most applicable procedures. Since 1993, we have collected 623 cerebrospinal fluid (CSF) samples at The Tohoku University Hospital for evaluation of dementia (age: 42-93). We found that CSF/phospho-tau measures produced the most adequate sensitivity (85.2%) and specificity (85.0%) in the diagnosis of AD as a sole bio-marker. The CSF levels of A beta 1-42 showed a strong positive correlation with the Mini-mental state examination score and brain glucose metabolism by positron emission tomography. The baseline levels of both total-tau and phospho-tau in CSF increased in approximately 70% of patients with mild cognitive impairment who later developed AD, suggesting that pathological change in the brain might start years before dementia becomes clinically manifested. A combined use of CSF-tau and IMP-SPECT improved the predictability of the transition from mild cognitive impairment into AD.

Pharmacologic therapy of dementia with Lewy bodies.

As a clinicopathologically defined entity, dementia with Lewy bodies (DLB) has overlapping features of Alzheimer's disease (AD) and Parkinson's disease (PD). Analogous characteristics of DLB offer a provisional rationale for pharmacologic therapy based on remediating cholinergic and dopaminergic deficits, respectively. However, the distinct clinical manifestations and pathophysiologic substrates of DLB pose unique therapeutic opportunities and challenges. More severe cholinergic deficits in DLB relative to AD support clinical evidence that cholinergic therapy may be particularly beneficial in DLB patients. In contrast, DLB patients are generally more sensitive to the adverse effects of antipsychotic agents, warranting caution in treating visual hallucinations and other psychotic symptoms. Similarly, parkinsonian motor signs in DLB, often manifest as rigidity and bradykinesia, may be less amenable to dopaminergic therapies than in PD. Increasing recognition of DLB as a common form of dementia in the elderly underscores the need for large-scale, placebo-controlled therapeutic trials.

Cholinesterase-inhibitor therapy for dementia: novel clinical substrates and mechanisms for treatment response.

Historically, drugs that increase central cholinergic transmission have primarily been investigated for relieving cognitive symptoms in mild-to-moderate Alzheimer's disease. These efforts have led to the somewhat unexpected findings that cholinergic therapy has a beneficial effect on selected neuropsychiatric symptoms in AD across disease stages. In Parkinson's disease with dementia and dementia with Lewy bodies, cholinergic deficits are more severe than in AD, and there is emerging evidence that cholinesterase inhibitors are efficacious in treating core symptoms of attentional disturbance and psychosis. Recent data also suggest a rational basis for cholinergic therapy in vascular dementia. The cognitive and neuropsychiatric effects of cholinergic therapy observed in AD and other dementias form the crux of an integrative model of cholinergic therapeutic efficacy that encompasses the diverse central nervous system actions of acetylcholine and its complementary interactions with central monoamine transmitters. This heuristic framework highlights the broader therapeutic potential of cholinergic therapy for symptom-based indications in other neuropsychiatric disorders.

Comparative distribution of binding of the muscarinic receptor ligands pirenzepine, AF-DX 384, (R,R)-I-QNB and (R,S)-I-QNB to human brain

Quinuclidinyl benzilate (QNB) and its derivatives are being developed to investigate muscarinic receptor changes in vivo in Alzheimer's disease and dementia with Lewy bodies. This is the first study of [ 125I]-(R,R)-I-QNB and [ 125I]-(R,S)-I-QNB binding in vitro in human brain. We have compared the in vitro binding of the muscarinic ligands [ 3H]pirenzepine and [ 3H]AF-DX 384, which have selectivity for the M1 and M2/M4 receptor subtypes, respectively, to the binding of [ 125I]-(R,R)-I-QNB and [ 125I]-(R,S)-I-QNB. This will provide a guide to the interpretation of in vivo SPET images generated with [ 123I]-(R,R)-I-QNB and [ 123I]-(R,S)-I-QNB. Binding was investigated in striatum, globus pallidus, thalamus and cerebellum, and cingulate, insula, temporal and occipital cortical areas, which show different proportions of muscarinic receptor subtypes, in post-mortem brain from normal individuals. M1 receptors are of high density in cortex and striatum and are relatively low in the thalamus and cerebellum, while M4 receptors are mainly expressed in the striatum, and M2 receptors are most evident in the cerebellum and thalamus. [ 125I]-(R,R)-I-QNB and [ 125I]-(R,S)-I-QNB density distribution patterns were consistent with binding to both M1 and M4 receptors, with [ 125I]-(R,R)-I-QNB additionally binding to a non-cholinergic site not displaceable by atropine. This distribution can be exploited by in vivo imaging, developing ligands for both SPET and PET, to reveal muscarinic receptor changes in Alzheimer's disease and dementia with Lewy bodies during the disease process and following cholinergic therapy.

The cholinergic pathology in Alzheimer's disease--discrepancies between clinical experience and pathophysiological findings.

The cholinergic hypothesis of Alzheimer's disease (AD) states 1. that cholinergic neurons in the basal forebrain are severely affected in the course of disease, detectable both histopathologically by a loss of neurons and neurochemically, by a loss of marker enzymes for acetylcholine synthesis and degradation, and 2. that the resulting cerebral cholinergic deficit leads to memory loss and other cognitive and non-cognitive symptoms, which are characteristic for the illness. This hypothesis was mainly based on studies, which had been conducted on brains of patients with advanced dementia. Nevertheless, it has served as the rationale for the development of drugs, i.e. acetylcholine-esterase inhibitors (AChE-I), which have shown consistent, but modest clinical efficacy against cognitive decline and behavioural symptoms of dementia for a limited period of time. These drugs are presently regarded the standard treatment of dementia in Alzheimer's disease. Now, due to a more sensitive and reliable clinical diagnosis, neurobiological investigations can be performed on early stages of disease, when the changes detected presumably are more relevant for the pathogenesis. New studies on the pathophysiology of the cholinergic system in AD suggest 1. that the cholinergic deficit occurs only late in the disease, 2. that at the earliest stages there even is an upregulation of cholinergic activity in the brain, and 3. that an increased activity of AChE may develop under therapy with AChE-I's. These data show that there is a plasticity of the central cholinergic system in AD and that the positive clinical effects of AChE-I are to be weighted against possible detrimental effects on a pathophysiological level. These data challenge the cholinergic hypothesis in its present form, e.g. should stimulate studies on the underlying process, which leads the cholinergic system to increase its activity in patients in the early stage of AD and may have clinical consequences regarding cholinergic drug therapy.

Evaluation of Selective COX-2 Inhibitors for the Treatment of Alzheimer's Disease

Alzheimer's disease (AD) is a worldwide problem that affects 5 million people in the United States alone. Until the approval of tacrine in the mid-1990s, there was no effective therapy for the cognitive symptoms of AD. Although cholinergic therapy provides modest but significant symptomatic relief, the development of effective disease-modifying therapy is essential. It has been demonstrated that a number of inflammatory processes are active in the brain of patients with AD, and therefore it is believed that an anti-inflammatory regimen may offer some degree of neuroprotection. Several studies have indicated that use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with delayed onset and/or slowed cognitive decline in AD. Although not currently approved for this condition, recent findings have demonstrated that cyclooxygenase (COX)-2 is of primary importance in the inflammatory response and may have a role in neurodegeneration. Therefore, selective COX-2 inhibitors (coxibs) may have an advantage over traditional NSAIDs as potential therapeutic agents in AD. The Alzheimer's Disease Cooperative Study (ADCS) is conducting an ongoing multicenter, double-blind, placebo-controlled trial to determine whether rofecoxib, a coxib, or naproxen, a nonselective NSAID, will slow the rate of cognitive and clinical decline in AD. This study, along with other clinical studies currently under way, will determine the utility of selective and nonselective COX inhibitors for the prevention and treatment of AD.

Dementia with Lewy bodies.

Dementia with Lewy bodies (DLB) is a common dementia subtype that has only been recognised in the past decade and that remains widely underdiagnosed. To review the pathological and clinical features of DLB, to consider methods of investigation and diagnosis, and to recommend safe and effective management strategies. A selective review was made of the key literature. Using operationalised criteria, DLB can be clinically diagnosed with an accuracy similar to that achieved for Alzheimer's disease or Parkinson's disease. Underdetection is largely due to poor definition of the criterion of cognitive fluctuation. Ancillary investigations, particularly neuroimaging, can aid in differential diagnosis. Extreme caution in the use of neuroleptic medication is advised. Cholinesterase inhibitors may be particularly effective in DLB. Clinicians should be aware of DLB as part of a spectrum of Lewy body disorders. Neuroleptic sensitivity reactions and good response to cholinergic therapies are important aspects of management.

Acetylcholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine

Acetylcholinesterase is one of the most prominent constituents of central cholinergic pathways. It terminates the synaptic action of acetylcholine through hydrolysis and yields the choline moiety that is necessary for transmitter recycling. Despite these pivotal relationships, mice nullizygous for acetylcholinesterase established all principal anatomical components of central cholinergic pathways. No compensatory increase in the distribution of butyrylcholinesterase was detected. However, both the wild-type and nullizygous mice showed that butyrylcholinesterase enzyme activity extended to all parts of the brain receiving cholinergic innervation and that it could hydrolyze the acetylcholine surrogate acetylthiocholine. As opposed to acetylcholinesterase which was mostly of neuronal origin, butyrylcholinesterase appeared to be mostly of glial origin. These experiments lead to the unexpected conclusion that acetylcholinesterase is not necessary for the establishment of cholinergic pathways. They also show that butyrylcholinesterase can potentially substitute for acetylcholinesterase and that this enzyme is likely to play a constitutive (rather than just back-up) role in the hydrolysis of acetylcholine in the normal brain. The inhibition of butyrylcholinesterase may therefore provide a desirable feature of cholinergic therapies, including those aimed at treating Alzheimer’s disease.

Pharmacological Treatment Strategies for Alzheimer's Disease

Alzheimer's disease(AD) is one of the most common causes of mental deterioration in elderly individuals, accounting for around 45~60% of the overall cases of dementia over 65 years of age. Although there is presently no "cure" for AD, a large number of potential therapeutic interventions have emerged to correct cholinergic dysfunctions. Currently, cholinergic therapy, particularly cholinesterase inhibition, represents the most realistic approach to the symptomatic treatment of AD. Modest efficacy for mild to moderate AD has been shown in well-designed clinical trials for tacrine, donepezil, rivastigmine, and galantimine. Among other treatment options, estrogen replacement therapy in postmenopausal women is under active investigation, but recent studies showed somewhat disappointing results. Epidemiological and clinical data suggest that nonsteroidal anti-inflammatory drugs are beneficial in the treatment and prevention of AD. But prednisone and COX-2 inhibitor, celecoxib showed no clinical benefit in recent studies. Alpha-tocopherol and gingko biloba showed some beneficial effect in delaying the progression of AD and enhancing cognitive functions. Immunization with beta amyloid peptide was considered to be the only method to prevent and halt disease progression in patients with AD. Recently, phase II clinical trial using synthetic beta amyloid peptide (AN-1792) was discontinued because some patients showed neuro-inflammation which may be caused by autoimmune responses.