Research Article On Alzheimer's Disease

Research suggests that a number of brain health supplements may provide rays of hope for patients with Alzheimer’s disease by supporting critical functions like memory formation.

• A Research Article On Alzheimer's Disease
• Alzheimer's Disease Research
• Research Articles On Alzheimer's Disease

In the history of medicine, one means to progress is when we make the decision that our assumptions and definitions of disease are no longer consistent with the scientific evidence, and no longer serve our health care needs. The arc of scientific progress is now requiring a change in how we diagnose Alzheimer's disease. Both the National Institute on Aging—Alzheimer's Association (NIA-AA) 2011 workgroup and the International Work Group (IWG) have proposed guidelines that use detectable measures of biological changes in the brain, commonly known as biological markers, or biomarkers, as part of the diagnosis. This Special Report examines how the development and validation of Alzheimer's disease biomarkers—including those detectable in the blood or cerebral spinal fluid, or through neuroimaging—is a top research priority.

This has the potential to markedly change how we diagnose Alzheimer's disease and, as a result, how we count the number of people with this disease. As research advances a biomarker-based method for diagnosis and treatment at the earliest stages of Alzheimer's disease, we envision a future in which Alzheimer's disease is placed in the same category as other chronic diseases, such as cardiovascular disease or diabetes, which can be readily identified with biomarkers and treated before irrevocable disability occurs. A biomarker, or biological marker, is a measurable indicator of some biological state or condition in the human body. Clinicians use biomarkers to diagnose the presence or absence of disease, assess the risk of developing a disease, or understand how a patient has responded to a treatment. For example, a high blood glucose level (blood sugar) may indicate the presence of diabetes, and lowering that level can indicate the success of a prescribed diet or medication.Researchers are investigating several promising biomarkers for Alzheimer's disease. These include, but are not limited to, the amount of accumulation of the proteins beta-amyloid and tau in the brain. These proteins can be measured using brain imaging or the levels in cerebrospinal fluid.

Another kind of biomarker is changes in brain size and activity.Identifying and then validating biomarkers for Alzheimer's is critical. They will facilitate early diagnosis and treatment. Many researchers believe that early intervention—either at the mild cognitive impairment (MCI) stage or even before symptoms appear—offers the best chance of slowing or stopping the progression of Alzheimer's disease and therefore the best chance of preserving brain function.Biomarkers also have an important role in the discovery of treatments. They enable researchers to identify which individuals to enroll in clinical trials to test new therapies.

Biomarkers allow researchers to enroll those individuals with the brain changes that treatments target. (It's important to note that the most effective biomarker test or combination of tests may differ depending on the stage of the disease and other factors.) Biomarkers also allow researchers to monitor the effects of these treatments. The more a change in a biomarker maps onto the health of the patient, the better that biomarker is in assessment of whether a treatment is effective.Research on new strategies for earlier diagnosis, including ongoing efforts to identify and validate biomarkers for Alzheimer's disease, is among the most active areas in Alzheimer's science. Has, since 2011, charted a national plan to address Alzheimer's disease.

The first of the plan's five goals is to effectively treat and prevent the disease by 2025 x 22 U.S. Department of Health and Human Services. National Plan to Address Alzheimer's Disease 2012. Available at:. Accessed January 18, 2017. 22.

Researchers and those who translate research into clinical practice have reached a consensus. A core strategy to achieve this goal relies on studies testing drugs in persons who have biomarker confirmation of the presence of Alzheimer's disease x 23 Kozauer, N. Regulatory innovation and drug development for early-stage Alzheimer's disease. N Engl J Med. 2013;368: 1169–1171 23.

Studies such as the A4 Study discussed above, as well as trials in persons with Alzheimer's disease dementia, are enrolling persons who have these biomarkers x 24 Honig LS, Aisen PS, Carrillo MC, Vellas B, Seimers ER. Expedition 3: A Phase 3 Trial of Solanezumab in Mild Dementia Due to Alzheimer's Disease. Available at:. Accessed December 22, 2016., x 25 Sevigny, J., Suhy, J., Chiao, P., Chen, T., Klein, G., Purcell, D. Amyloid PET screening for enrichment of early-stage Alzheimer disease clinical trials: experience in a phase 1b clinical trial. Alzheimer Dis Assoc Disord. 2016;30: 1–7.This strategy aligns with approaches taken with other common diseases of aging, such as cardiovascular disease.

Clinicians use measures of biological change, such as elevated levels of blood pressure or cholesterol, to diagnose and treat individuals. Their goal is to prevent the person from suffering another heart attack or worsening heart failure, or to prevent these problems from happening in the first place. Someday, clinicians may have a similar strategy to diagnose and treat Alzheimer's disease.

They may use biological measures (biomarker-based) to diagnose and then prescribe treatments to these persons, treatments that trials have shown to slow cognitive and functional decline or even prevent the onset of symptoms of dementia.Alzheimer's-related brain changes—amyloid plaques and tau tangles among others—contribute to the cognitive impairment observed in dementia due to Alzheimer's x 26 Schneider, J.A., Arvanitakis, Z., Bang, W., and Bennett, D.A. Mixed brain pathologies account for most dementia cases in community-dwelling older persons.

2007;69: 2197–2204, x 27 Schneider, J.A., Arvanitakis, Z., Leurgans, S.E., and Bennett, D.A. The neuropathology of probable Alzheimer disease and mild cognitive impairment. 2009;66: 200–208, x 28 Mormino, E.C., Betensky, R.A., Hedden, T., Schultz, A.P., Amariglio, R.E., Rentz, D.M. Synergistic effect of beta-amyloid and neurodegeneration on cognitive decline in clinically normal individuals. 2014;71: 1379–1385, x 29 Sperling, R.A., Johnson, K.A., Doraiswamy, P.M., Reiman, E.M., Fleisher, A.S., Sabbagh, M.N. Amyloid deposition detected with florbetapir F 18 ((18)F-AV-45) is related to lower episodic memory performance in clinically normal older individuals. Neurobiol Aging.

2013;34: 822–831. A clinically effective intervention that targets these brain changes will help to validate the disease as a continuum that begins before cognitive decline. This confirmation will change how we identify (and therefore estimate) individuals with Alzheimer's disease. It will alter the estimated prevalence and incidence of the disease, just as the treatment of vascular disease has altered the estimated prevalence of dementia among individuals with primarily vascular lesions x 30 Langa, K.M., Larson, E.B., Crimmins, E.M., Faul, J.D., Levine, D.A., Kabeto, M.U. A comparison of the prevalence of dementia in the United States in 2000 and 2012. JAMA Intern Med.

2017;177: 51–58, x 31 Sposato, L.A., Kapral, M.K., Fang, J., Gill, S.S., Hackam, D.G., Cipriano, L.E. Declining Incidence of Stroke and Dementia: Coincidence or Prevention Opportunity? 2015;72: 1529–1531.

As these events unfold, they compel us to plan for a future when Alzheimer's disease is defined using biomarkers alone, not symptoms. (See sidebar: “Determining the incidence and prevalence of Alzheimer's disease.”). Today, we understand that Alzheimer's disease exists as a continuum beginning with a phase that may only be detectable through biomarkers and ending with the dementia stage. In the future, a biomarker-based diagnosis of Alzheimer's disease will impact the estimates of incidence and prevalence of Alzheimer's.

It will add a population of individuals that currently is not included in estimates (people with Alzheimer's biomarkers but no dementia) and remove a population that currently is included (people with dementia but no Alzheimer's biomarkers).The Alzheimer's Association 2017 Alzheimer's Disease Facts and Figures (DOI: ) reports the prevalence and incidence of Alzheimer's in the U.S. Among individuals age 65 and older, the prevalence in 2017 is estimated to be 5.3 million (one in 10 people age 65 and older, or 10 percent, have Alzheimer's dementia), and 480,000 people age 65 or older will develop Alzheimer's dementia in the U.S. In 2017.Epidemiologists, demographers, and biostatisticians will use these prevalence and incidence estimates to calculate other statistics, such as the numbers of people providing care and support for someone with the disease, the costs of care, and mortality. Even with scientific progress, a common question from the public has been, “What's the difference between Alzheimer's disease and dementia?” The NINCDS-ADRDA diagnostic criteria of 1984 aimed to help answer that question x 3 McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D., and Stadlan, E.M. Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.

1984;34: 939–944 3. Alzheimer's disease is the most frequent cause of the dementia syndrome.As dementia science has progressed, biomarker-based data have advanced our understanding of who has Alzheimer's disease as well as contributed to a more accurate clinical diagnosis of who has dementia due to Alzheimer's. Biomarker-based clinical criteria and future clinical trial data will continue to change our understanding of who has Alzheimer's disease, as improved diagnostic techniques will provide earlier identification of cognitive impairment, and of the brain changes that lead to it.As with cardiovascular disease, we must care not just about those who have had a disease-manifesting event, such as a heart attack, but everyone who has cardiovascular disease-related biological changes that precede the heart attack. All of these individuals represent the societal burden of cardiovascular disease.

Similarly, although we have known for years about the occurrence of dementia due to Alzheimer's, as a result of the recent use of biomarkers in studies, we have learned that a proportion of people previously thought to have cognitive impairment caused by Alzheimer's disease lack those biomarkers. The diagnosis of Alzheimer's disease will come to include the full spectrum of persons with Alzheimer's biomarkers, those who are symptomatic—with either dementia or MCI—and those who are still asymptomatic but have preclinical Alzheimer's disease.

All individuals with biomarkers of Alzheimer's disease, including those with and without dementia symptoms, will represent the full disease burden.Additional research and development of guidelines for the future use of biomarkers is urgently needed to optimize therapeutic strategies for this potentially much larger population of people with Alzheimer's disease. Successful validation of biomarkers will bring our definition of Alzheimer's disease in line with the remarkable advances we have seen in Alzheimer's research over the past decade. This latest research is now allowing us to envision a future in which Alzheimer's is no longer a disease leading to irrevocable cognitive and functional decline and death, but rather a chronic condition like cardiovascular disease, AIDS, or some cancers that can often be managed with early intervention.

Alzheimer’s dementia (AD) is increasingly being recognized as one of the most important medical and social problems in older people in industrialized and non-industrialized nations. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. Three cholinesterase inhibitors (CIs) are currently available and have been approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine, an N-methyl-D-aspartate receptor noncompetitive antagonist.

Treatments capable of stopping or at least effectively modifying the course of AD, referred to as ‘disease-modifying’ drugs, are still under extensive research. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation, oxidative damage, iron deregulation and cholesterol metabolism. In this review we discuss current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials. IntroductionDementia is increasingly being recognized as one of the most important medical problems in older people with a prevalence rising from 1% at the age of 60 to at least 35% at the age of 90.

Within the spectrum of dementias, Alzheimer’s disease (AD) is the most prevalent subtype, accounting for about 60% of all dementias. It is characterized clinically by progressive memory and orientation loss and other cognitive deficits, including impaired judgment and decision making, apraxia and language disturbances.

These are typically accompanied by various neuropsychiatric symptoms (i.e. Depression, apathy, anxiety, agitation, delusions, hallucinations).

The continuing expansion of life expectancy, leading to a fast growing number of patients with dementia, particularly AD, has led to an enormous increase in research focused on the discovery of drugs for primary, secondary or tertiary prevention of the disease. Despite all scientific efforts, at the moment there are no effective pharmacotherapeutic options for prevention and treatment of AD.To date, established treatments are only symptomatic in nature, trying to counterbalance the neurotransmitter disturbance of the disease. Three cholinesterase inhibitors (CIs) are approved for the treatment of mild to moderate AD. A further therapeutic option available for moderate to severe AD is memantine. At the same time antipsychotic and antidepressant treatments are used for the behavioral symptoms of the disease.Treatments under research include compounds that act on the pathological substrate of the disease: extracellular amyloid β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs).In this review, current symptomatic treatments and new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials are discussed. Cholinesterase inhibitorsThe cholinergic hypothesis of AD concludes that cholinergic systems in the basal forebrain are affected early in the disease process, including loss of acetylcholine neurons, loss of enzymatic function for acetylcholine synthesis and degradation, resulting in memory loss and deterioration of other cognitive and noncognitive functions such as neuropsychiatric symptoms ;. A strategy to enhance the cholinergic transmission by using CIs to delay the degradation of acetylcholine between the synaptic cleft has been proposed.

To date, three CIs are approved for the treatment of mild to moderate AD: donepezil (Pfizer, New York, NY, USA), rivastigmine (Novartis, Basel, Switzerland) and galantamine (Janssen, Beerse, Belgium). These drugs have been regarded as the standard and first-line treatment for AD.

Systemic reviews including many double-blind, randomized, placebo-controlled trials (RCTs) of these three CIs all showed benefit on cognitive functions, activities of daily living (ADL), and global function for patients with mild to moderate AD; there was no significant difference of efficacy between individual CIs ;. In addition, donepezil is now also approved for the treatment of severe AD in the USA. Although tacrine (First Horizon Pharmaceuticals, Alpharetta, Georgia, USA) was the first CI drug approved for AD in 1993, it is no longer used due to hepatotoxicity. Related systemic reviews showed that the incidence of gastrointestinal adverse effects, such as nausea, vomiting, diarrhea and abdominal cramp, was lower with donepezil than with rivastigmine and galantamine.

The incidence of adverse effects was associated with higher therapeutic dose. However, it may be that galantamine and rivastigmine may be equal to donepezil in tolerability if a careful and gradual titration routine of more than 3 months is used. The dermal form of rivastigmine provides a lower dose with fewer adverse effects but comparable efficacy, and is was preferred by some caregivers. Use of CIs is also reported to be associated with increased rates of syncope, bradycardia and pacemaker insertion. The risk of these adverse events must be weighed carefully against the drugs’ benefits.Reviews and meta-analyses on CIs that have recently been published showed that they delay the decline in cognitive function as measured by the AD Assessment Scale – cognitive subscale (ADAS-cog), global clinical rating, behavior and ADL over 6–12-month periods. These benefits seem to be applicable to mild, moderate and severe AD ;;.

Compared with those on placebo treatment, patients on CIs generally show an initial mild improvement in cognitive functions over the first 3 months. Thereafter, the mean decline in cognitive functions was also less rapid over the subsequent 3–9 months.

A Research Article On Alzheimer's Disease

At 6 months, the cognitive improvement ( versus placebo) was 2.7 points over the Mid range of ADAS-cog ;. Symptoms that were improved included attention, thinking, memory, praxis, language comprehension and communication.Initiation of CI treatment in the early stages of AD is preferred. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe AD reported that patients with AD who started the CI 6 months later achieved lower cognitive performance than those who started the drug immediately after the diagnosis. Preserved cognitive function was also observed after 12 months of treatment with rivastigmine in patients with mild AD in comparison to untreated patients who markedly worsened in cognition during the same period.

Alzheimer's Disease Research

N-methyl-D-aspartate antagonistA further therapeutic option for moderate to severe AD is memantine (Lundbeck, Valby, Denmark). This drug is an uncompetitive, moderate-affinity N-methyl-D-aspartate (NMDA) antagonist believed to protect neurons from excitotoxicity. A systemic review of double-blind, parallel-group, RCT studies of memantine showed improvement in cognition, ADL and behaviors in people with moderate to severe AD after 6 months of use. Another systemic review which included six RCT studies indicated that memantine may reduce behavioral and psychological symptoms of dementia.

The most frequently reported adverse events in memantine trials were dizziness, headache and confusion. A small group of patients might develop agitation. Treatment of behavioral and psychological symptoms of dementia in Alzheimer’s diseaseNoncognitive neuropsychiatric symptoms or behavioral and psychological symptoms of dementia (BPSD) are common in all clinical stages of AD and even in amnestic mild cognitive impairment (MCI) (the predementia stage of AD) with increasing prevalence when dementia progresses. They are the main determining factors for increased caregiver burden and institutionalization of patients. According to a large observational study, BPSD may be grouped into four major symptom clusters with high prevalence: psychosis (38% of the patients, e.g.

Delusions), affective symptoms (59%, anxiety and depression), hyperactivity (64%, e.g. Aggression, disinhibition) and apathy (65%).CIs and memantine may have an effect on behavioral symptoms ;;.

However, when BPSD become more severe, these antidementia drugs may not be as effective and other drugs also need to be given.Serotonin reuptake inhibitors (SSRIs: fluoxetine, sertraline, paroxetine, citalopram, fluvoxamine) are largely considered to be among the most efficient antidepressants to treat comorbid depression in AD dementia.Mirtazapine, venlafaxine and duloxetine, which are combined selective noradrenalin and serotonin inhibitors (SNRIs), and bupropion are other widely used antidepressants in this population. A few RCTs with limited numbers of patients as well as meta-analyses support their efficacy to treat depression in AD dementia. SSRIs may also be taken into consideration for the treatment of agitation and psychosis in AD dementia.

However, a recent randomized, multicenter, double-blind, placebo-controlled trial of sertraline or mirtazapine for depression in dementia (HTA-SADD) showed absence of benefit compared with placebo and increased risk of adverse events. The trial concluded that the current practice of using these antidepressants, with usual care, for first-line treatment of depression in Alzheimer’s disease should be reconsidered.Psychotic symptoms and agitation/aggression are commonly treated with antipsychotics in patients with AD dementia. Atypical agents (olanzapine, risperidone, quetiapine, ziprasidone and aripiprazole) are preferred due to their milder parkinsonian effects. The use of antipsychotics has been discussed controversially, as cerebrovascular morbidity and higher mortality have been found in patients with dementia taking antipsychotics. Furthermore, the use of antipsychotics may be associated with a higher risk of hip fracture and pneumonia, as well as worsening cognitive impairment. The increased mortality may be reduced if antipsychotics are only given over a short period, as stopping the antipsychotic medication may not be associated with a subsequent increase in BPSD.Benzodiazepines are used to reduce agitation and anxiety.

However, they can also trigger further agitation in older people. An association of greater benzodiazepine use with more rapid cognitive and functional decline has been reported in AD and indeed in older people in general.Anticonvulsant drugs like carvamazepine can also reduce BPSD in AD to some degree.It is obvious that drugs currently used for the treatment of AD have weak beneficial effects on cognitive function or offer some relief of BPSD. The discovery of new drugs that act during the early stages of AD could be considered a ‘medical need’. Early intervention is critical because a delay in treatment is associated with nonreversible symptom progression.

The amyloid hypothesisThe primary histopathologic lesions of Alzheimer’s pathology are amyloid plaques, NFTs and neuronal loss. Mature plaques consist of a central amyloid core with surrounding degenerating neurons affected by the toxic effect of the Aβ. NFTs consist of hyperphosphorylated tau protein that has assumed a double helical filament conformation.The Aβ derives from the amyloid precursor protein (APP) through sequential proteolysis by β secretase (BACE1) in the extracellular domain and γ secretase in the transmembrane region.Full-length APP undergoes sequential proteolytic processing. It is first cleaved by α secretase (nonamyloidogenic pathway) or β secretase (amyloidogenic pathway) within the luminal domain, resulting in the shedding of nearly the entire ectodomain and the generation of α or β C-terminal fragments (CTFs). The major neuronal β secretase, named BACE1 (β-site APP cleaving enzyme), is a transmembrane aspartyl protease that cleaves APP within the ectodomain, generating the N-terminus of Aβ. The second proteolytic event in APP processing involves intramembranous cleavage of α and β CTFs by γ secretase. Major sites of γ-secretase cleavage correspond to positions 40 and 42 of Aβ.

Research Articles On Alzheimer's Disease

Amyloidogenic processing is the favored pathway of APP metabolism in neurons because of the greater abundance of BACE1, whereas the nonamyloidogenic pathway predominates in other cells.According to the ‘amyloid hypothesis’ Aβ production in the brain initiates a cascade of events leading to the clinical syndrome of Alzheimer’s dementia. Aβ is a protein consisting of two major forms, Aβ40 and Aβ42. Aβ42 is the most soluble form and has the tendency to aggregate into fibrils that form the major composite of amyloid plaques. It is the predominant form found in the brain parenchyma of patients with AD.

Aβ40 is mostly found in the cerebral vasculature as part of ‘cerebral amyloid angiopathy’. Aβ has a tendency to cluster into oligomers. Oligomers can form Aβ-fibrils and protofibrils that will eventually form amyloid plaques, which are believed to be nontoxic. It is the forming of amyloid oligomers to which neurotoxicity is attributed and initiates the amyloid cascade. The elements of the cascade include local inflammation, oxidation, excitoxicity (excessive glutamate) and tau hyperphosphorylation. As a result of this process, tau proteins fold into intraneuronic tangles, which results in cell death. Progressive neuronal destruction leads to shortage and imbalance between various neurotransmitters (e.g.

Acetylcholine, dopamine, serotonin) and to the cognitive deficiencies seen in AD ;.On the basis of findings on AD pathogenesis, novel treatments under development aim to interfere with the pathogenic steps previously mentioned in an attempt to block the course of the disease in its early stages ;. For this reason they have been termed ‘disease-modifying’ drugs. In this review, possible strategies for the development of novel disease-modifying therapies will be discussed. Disease-modifying approaches to Alzheimer’s diseaseThe production of Aβ, which is a crucial step in AD pathogenesis, is the result of cleavage of APP, which is overexpressed in AD. Aβ forms highly insoluble and proteolysis-resistant fibrils known as senile plaques (SPs). NFTs are composed of the tau protein.

In healthy subjects, tau is a component of microtubules, which are the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Microtubules also stabilize growing axons necessary for the development and growth of neurons.

In AD, tau protein is abnormally hyperphosphorylated and forms insoluble fibrils, causing deposits within the cell.Thus, both Aβ and tau are prime targets for disease-modifying therapies in AD. From this point of view, AD could be prevented or effectively treated by decreasing the production of Aβ and tau; preventing aggregation or misfolding of these proteins; neutralizing or removing the toxic aggregate or misfolded forms of these proteins; or a combination of these modalities.A number of additional pathogenic mechanisms have been described, possibly overlapping with Aβ plaques and NFT formation, including inflammation , oxidative damage , iron deregulation and cholesterol metabolism. Aβ, amyloid β; IVIg, intravenous immunoglobulin.The only Aβ aggregation inhibitor reaching phase III is the synthetic glycosaminoglycan 3-amino-1-propaneosulfonic acid (3APS, tramiprosate). It is designed to interfere with the binding of glycosaminoglycanes and Aβ. Disappointing results of the North American phase III trial in the year 2007 have led to discontinuation of the European phase III trial.

Nevertheless, 3APS will now be commercialized as a branded nutraceutical. However, recent data suggest that tramiprosate promotes an abnormal aggregation of the tau protein in neuronal cells. These results emphasize the importance of testing the potential drugs for the treatment of AD on both types of pathology (amyloid and tau).Another molecule undergoing testing is colostrinin, a proline-rich polypeptide complex derived from sheep colostrum (O-CLN; ReGen Therapeutics, London, UK). Colostrinin inhibits Aβ aggregation and neurotoxicity in cellular assays and improves cognitive performance in animal models. Although a phase II trial demonstrated modest improvements in Mini Mental State Evaluation scores for patients with mild AD over a treatment period of 15 months, this beneficial effect was not sustained during an additional 15 months of continued treatment.Another compound named scyllo-inositol is able to stabilize oligomeric aggregates of Aβ and inhibit Aβ toxicity in mouse hippocampus. An 18-month, randomized, double-blind, placebo-controlled, dose-ranging, safety and efficacy study of oral scyllo-inositol (ELND005) in participants with mild to moderate AD has been carried out by Transition Therapeutics (Toronto, ON, Canada)/Elan (Dublin, Ireland). A long-term follow-up class II study in subjects with AD provided insufficient evidence to support or refute a benefit of ELND005.Primary clinical efficacy outcomes were not significant.

The safety and cerebrospinal fluid (CSF) biomarker results will guide selection of the optimal dose for future studies, which will target earlier stages of AD.Drugs interfering with metals Zinc (Zn) and copper (Cu) are both involved in the aggregation of Aβ42. Several chelators of Zn/Cu have been shown to inhibit Aβ aggregation in vitro and in animal studies. PBT2 is a second-generation 8-OH quinoline metal-protein-attenuating compound that affects the Cu2+-mediated and Zn2+-mediated toxic oligomerization of Aβ. A recent phase IIa study concluded that the safety profile is favorable for the ongoing development of PBT2. The effect on putative biomarkers for AD in CSF but not in plasma suggests a central effect of the drug on Aβ metabolism.

Cognitive efficacy was restricted to two measures of executive function. In the post hoc analysis, the cognitive, blood marker and CSF neurochemistry outcomes from the trial were subjected to further analysis.

Ranking the responses to treatment after 12 weeks with placebo, PBT2 50 mg and PBT2 250 mg revealed that the proportions of patients showing improvement were significantly greater in the PBT2 250 mg group than in the placebo group. These findings further encourage larger-scale testing of PBT2 for AD. Selective Aβ42-lowering agentsAβ is generated through proteolytic processing of the transmembrane peptide APP. APP can be cleaved by two competing proteases, α secretase and β secretase. Only cleavage by β secretase, followed by γ-secretase cleavage, which in AD is the dominant pathway, will lead to production of Aβ40 and Aβ42. By inhibiting β secretase and γ secretase or by increasing α-secretase cleavage, Aβ production may be reduced.β-site AP- cleaving enzyme inhibition The β-secretase enzyme BACE1 is a promising therapeutic target, although the development of a BACE1 inhibitor therapy is problematic for two reasons.

First, BACE1 has been found to have important physiological roles. Therefore, inhibition of the enzyme could have toxic consequences. Second, the active site of BACE1 is relatively large, and many of the bulky compounds that are needed to inhibit BACE1 activity are unlikely to cross the blood–brain barrier. Many of compounds able to inhibit BACE are still in the preclinical phase.

Inhibitors based on the peptidomimetic strategy suffer from well known difficulties associated with polypeptides, such as blood–brain barrier crossing, poor oral bioavailability and susceptibility to P-glycoprotein transport. Efforts to overcome these problems led to the design of new nonpeptidomimetic β-secretase inhibitors that show high selectivity over BACE2 (BACE1/BACE2 selectivity 100) and other human proteases (cathD, pepsin and renin).

Their weak or nonpeptidic character favors CNS penetration and oral bioavailability. A ligand-based computational approach is currently used to identify the molecular chemical features required for the inhibition of BACE1 enzyme.Only a few β-secretase inhibitors have entered clinical trials to date.

The first publicly announced phase I clinical trial on a β-secretase inhibitor CTS-21166 was conducted by CoMentis (South San Francisco, USA) ;;. Phase I clinical trials on CTS-21166 have been carried out in healthy young men and evaluated for safety and preliminary Aβ responses. In these clinical trials, β-secretase inhibitor has been shown to reduce human plasma Aβ. Clearly, the hope for the next step would be to develop inhibitors with better pharmaceutical properties and to carry out well designed efficacy trials to determine if they can rescue cognitive decline in patients with AD.γ-Secretase inhibition γ Secretase is a nucleoprotein complex with at least four different proteins from which preseniline PS-1 and PS-2 seem to be responsible for the enzymatic action on APP. Unfortunately, besides APP, γ secretase has many other substrates and cleaves several other transmembrane proteins, including the Notch receptor 1, which is necessary for growth and development. Notch-related side effects of γ-secretase inhibition (severe gastrointestinal and hemopoetic side effects) have been hampering the development of clinically useful γ-secretase inhibitors so far.The most studied γ-secretase inhibitor, which is semagacestat (LY-450139), was shown to dose-dependently decrease the generation of Aβ in the CSF of healthy people.

Unfortunately, two large phase III clinical trials of semagacestat in patients with mild to moderate AD were prematurely interrupted because of the observation of detrimental effects on cognition and functionality in patients receiving the drug compared with those receiving placebo. These detrimental effects were mainly ascribed to the inhibition of Notch processing and to the accumulation of the neurotoxic precursor of Aβ (the C-terminal fragment of APP or CTFβ) resulting from the block of the γ-secretase cleavage activity on APP. Two large phase III studies in patients with mild AD with tarenflurbil (or R-flurbiprofen), which is a putative γ-secretase modulator, were also completely negative. The failure of tarenflurbil was ascribed to low potency and brain penetration. New Notch-sparing γ-secretase inhibitors and more potent and brain penetrant γ-secretase modulators are being developed with the hope of overcoming the previous setbacks.A potent γ-secretase inhibitor, BMS-708163 (avagacestat; Bristol-Myers Squibb, New York, NY, USA), was tested in a phase I clinical trial. After 18 days, BMS-708163 caused a decrease in CSF Aβ40 and Aβ42 of 30% following a daily dose of 100mg as well as a decrease of 60% at a daily dose of 150mg.

A phase II study is ongoing.α-Secretase potentiation Etazolate (EHT 0202; ExonHit Therapeutics, Paris, France) stimulates the neurotrophic α-secretase (nonamyloidogenic) pathway and inhibits Aβ-induced neuronal death, providing symptomatic relief and modifying disease progression. The recent pilot, randomized, double-blind, placebo-controlled, parallel group, multicentre, phase IIA study was conducted in 159 randomized patients with mild to moderate AD. EHT0202 was shown to be safe and generally well tolerated. These first encouraging safe results support further development of EHT0202 to assess its clinical efficacy and to confirm its tolerability in a larger cohort of patients with AD and for a longer period of time. ImmunotherapyImmunotherapy is one of the strategies being studied by most pharmaceutical companies. The mechanism behind amyloid clearance by immunotherapy has not been fully elucidated.

Drugs interfering with tau depositionMultiple compounds have been identified through cell culture or in vitro screens as tau aggregation inhibitors. A phenothiazine, methylene blue (MB) or methylthioninium chloride, has previously been used in humans and is currently being evaluated in AD trials. The problem with this drug is that urine is colored blue, resulting in a lack of blinding. However, promising results have emerged from a phase II clinical trial testing MB as a potential therapy for AD, as improvements in cognitive function of patients with AD after 6 months of MB administration have been reported.

Drugs interfering with tau phosphorylationThe intriguing link between phosphorylation and tau pathology has provided the boost to examine the role of kinase inhibitors as potential therapeutics targeting tau. Kinases induce the hyperphosphorylation of tau. Despite the large number of tau phosphorylation sites and the ability of multiple kinases to phosporylate individual sites, glycogen synthase kinase 3 (GSK3β) has emerged as a potential therapeutic target. The most studied compound able to inhibit GSK3 is lithium, but several other compounds are under development, including pyrazolopyrazines, pyrazolopyridines, the aminothiazole AR-A014418, and sodium valproate.

In recent studies, the effect of short-term treatment on cognitive and biological outcomes in people with amnestic MCI was shown and supports the notion that lithium has disease-modifying elements with potential clinical implications in the prevention of AD. Molecules addressing oxidative damagePotential antioxidants include mitoquinone, vitamin E, Ginkgo biloba, natural polyphenols such as green tea, wine, blueberries and curcumin, ω3 fatty acids, folate, vitamin B6 and vitamin B12 supplementation. A trial to determine whether the reduction of homocysteine levels with high-dose folate, vitamin B6 and vitamin B12 supplementation can slow the rate of cognitive decline in subjects with AD had no beneficial effect on the primary cognitive measure, the rate of change in ADAS-cog score over 18 months, or on any secondary measures, although the vitamin supplement regimen was effective in reducing homocysteine levels. Clinical trials with vitamin E and ω3 fatty acids did not show beneficial effects in patients with AD.More recent data have revealed that tumor necrosis factor (TNF), one of the few gliotransmitters, has strikingly acute effects on synaptic physiology.

These complex influences on neural health suggest that manipulation of this cytokine might have important impacts on diseases characterized by glial activation, cytokine-mediated neuroinflammation and synaptic dysfunction. Toward such manipulation in AD, a 6-month study was conducted with 15 patients with probable AD who were treated weekly with perispinal injection of etanercept, an FDA-approved TNF inhibitor that is now widely used for the treatment of rheumatoid arthritis and other systemic diseases associated with inflammation. The results demonstrated that perispinal administration of etanercept could provide sustained improvement in cognitive function for patients with AD. Additionally, the authors were impressed by the striking rapidity with which these improvements occurred in the study patients. Nevertheless, etanercept merits further study in RCTs. Modulation of cholesterol and vascular-related risk factorsA link between hypercholesterolemia, cardiovascular diseases and AD has also been suggested.

Additional vascular-related risk factors for AD include hypertension, atrial fibrillation, hyperhomocysteinemia, atherosclerosis and stroke. Epidemiological studies have indicated that patients treated for cardiovascular disease with cholesterol-lowering therapy (statins) showed a decreased prevalence of AD. The Lipitor’s Effect in Alzheimer’s Dementia (LEADe) study tested the hypothesis that a statin (atorvastatin 80mg daily) is beneficial to patients with mild to moderate AD receiving background therapy of donepezil 10mg daily. Despite a promising premise, there were no significant differences in the coprimary or secondary endpoints, although atorvastatin was generally well tolerated.Simvastatin metabolites are high-affinity 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reducing the quantity of mevalonic acid, a precursor of cholesterol. Cholesterol Lowering Agent (simvastatin) to Slow Progression (CLASP) of Alzheimer’s Disease Study is an ongoing randomized, double-blind, placebo-controlled, parallel-assignment phase III trial that investigates the safety and effectiveness of simvastatin in slowing down the progression of AD.

It has not yet published its results. However, a randomized, double-blind, placebo-controlled recent trial of simvastatin was conducted in individuals with mild to moderate AD and normal lipid levels. Simvastatin had no benefit on the progression of symptoms in individuals with mild to moderate AD despite significant lowering of cholesterol. Final remarksCurrently available treatments for AD (donepezil, rivastigmine, galantamine and memantine) are symptomatic and do not decelerate or prevent the progression of the disease.

However, these therapies demonstrate modest, but particularly consistent, benefit for cognition, global status and functional ability.The search for disease-modifying interventions has focused largely on compounds targeting the Aβ pathway.