Can statin therapy really reduce the risk of Alzheimer's disease and slow its progression?

PURPOSE OF REVIEW: Statins are the most used cholesterol-lowering agents worldwide. Earlier studies suggested that they may have preventive effects in Alzheimer's disease. However, prospective studies have questioned this hypothesis. RECENT FINDINGS: Statins regulate beta-amyloid metabolism and microglial activation. Pathologically, patients with Alzheimer's disease have more severe atherosclerosis in cerebral arteries than do controls. Such lesions may cause cerebral hypoperfusion, a risk factor for dementia and cognitive decline. Although most population-based studies have failed to show a beneficial effect of statins in Alzheimer's disease, two randomized controlled trials suggested that statins slow cognitive decline in mild to moderate Alzheimer's disease. SUMMARY: There is still some hope that statins reduce the incidence of Alzheimer's disease and slow its progression. Large-scale randomized controlled trials of simvastatin and atorvastatin for mild to moderate Alzheimer's disease are underway, which might provide more conclusive results than earlier studies.     

Immunology and immunotherapy of Alzheimer's disease

Although Alzheimer's disease is considered to be a degenerative brain disease, it is clear that the immune system has an important role in the disease process. As discussed in this Review, immune-based therapies that are designed to remove amyloid-beta peptide from the brain have produced positive results in animal models of the disease and are being tested in humans with Alzheimer's disease. Although immunotherapy holds great promise for the treatment of Alzheimer's disease, clinical trials of active amyloid-beta vaccination of patients with Alzheimer's disease were discontinued after some patients developed meningoencephalitis. New immunotherapies using humoral and cell-based approaches are currently being investigated for the treatment and prevention of Alzheimer's disease.     

The modulation of metal bio-availability as a therapeutic strategy for the treatment of Alzheimer's disease

The postmortem Alzheimer's disease brain is characterized histochemically by the presence of extracellular amyloid plaques and neurofibrillary tangles. Also consistent with the disease is evidence for chronic oxidative damage within the brain. Considerable research data indicates that these three critical aspects of Alzheimer's disease are interdependent, raising the possibility that they share some commonality with respect to the ever elusive initial factor(s) that triggers the development of Alzheimer's disease. Here, we discuss reports that show a loss of metal homeostasis is also an important event in Alzheimer's disease, and we identify how metal dyshomeostasis may contribute to development of the amyloid-beta, tau and oxidative stress biology of Alzheimer's disease. We propose that therapeutic agents designed to modulate metal bio-availability have the potential to ameliorate several of the dysfunctional events characteristic of Alzheimer's disease. Metal-based therapeutics have already provided promising results for the treatment of Alzheimer's disease, and new generations of pharmaceuticals are being developed. In this review, we focus on copper dyshomeostasis in Alzheimer's disease, but we also discuss zinc and iron.     

Decreased DNA repair in familial Alzheimer's disease

Alterations in the capacity of a cell to repair DNA lesions play an important role in a number of human diseases. We and others have demonstrated defective DNA repair of alkylation damage in cells from patients with Alzheimer's disease. It has been hypothesized that this defect is related to the cause of Alzheimer's disease and results in the accumulation of lesions in the central nervous system neurons. One prediction of this hypothesis is that in dominantly inherited Alzheimer's disease, the repair defect will be present in half of the offspring of affected patients long before they develop symptoms of the disease. In order to test the hypothesis that decreased DNA repair is responsible for familial Alzheimer's disease and their at-risk offspring we have studied DNA repair in these individuals after exposure of lymphoblasts to alkylating agents. Our results indicate that cell lines from affected patients repair significantly less damage in 3 h than cell lines from healthy controls. A small number of at-risk individuals were also studied and some of these had lower levels of repair, although more cell lines from individuals in this group must be studied. These findings provide further support for defective DNA repair playing a role in the pathogenesis of Alzheimer's disease.     

Beyond amyloid: the next generation of Alzheimer's disease therapeutics

The precise pathological events that cause cognitive deficits in Alzheimer's disease remain to be determined. The most widely held view is that accumulation of amyloid beta peptide initiates the disease process; however, with more than eighteen amyloid-based therapeutic candidates currently in clinical trials, the targeting of amyloid alone may not be sufficient to improve functional deficits over the course of the disease. Alternative targets, such as the tau protein and apolipoprotein E, have thus been increasingly investigated, and in the future, therapeutic strategies will likely address events that are upstream of a more broadly construed pathological cascade that includes but is not limited to the generation and accumulation of amyloid beta. Consideration of such events provides the basis for an "indirect amyloid hypothesis," for which data are beginning to emerge. Although it is clinically defined by simple post-mortem criteria, Alzheimer's disease likely has a complex etiology, and effective treatments for this disease will become ever more urgent as the world's population ages.     

Novel approaches for immunotherapeutic intervention in Alzheimer's disease

Immunotherapy can attenuate amyloid neuropathology and improve cognitive function in transgenic models of Alzheimer's disease. However, the first clinical trial was halted when 6% of the Alzheimer's patients developed aseptic meningoencephalitis. Postmortem analysis of two cases with meningoencephalitis showed robust glial activation, T-cell infiltration and sporadic clearance of Abeta. Interestingly, transgenic mouse models of Alzheimer's disease failed as predictors of these adverse inflammatory events. However there are now several studies with amyloid precursor protein transgenic mice that have reported an increased risk of microhemorrhages at sites of cerebrovascular amyloid deposits and because approximately 80% of Alzheimer's patient's have cerebrovascular pathology, there is concern regarding clinical trials using passive administration of humanized anti-Abeta antibodies. Although many studies have now been published on immunotherapy in mouse models, the mechanism(s) of antibody-mediated clearance of beta-amyloid from the brain, and the cause of the antibody-induced microhemorrhages remain unclear. In this review, we will discuss the most recent results from the first clinical trial, offer speculation on possible causes for the failure of the trial, review data on antibody-mediated clearance mechanisms, explore the role of complement and inflammation in the clearance of beta-amyloid, and suggest novel strategies for avoiding problems in future clinical trials. The central hypothesis being proposed in this review is that anti-Abeta antibodies delivered directly to the CNS at the sites of amyloid deposits will be far more effective at clearing Abeta and safer than active or passive immunization strategies where the majority of the antibodies are in the periphery.     

Molecular mechanisms for Alzheimer's disease: implications for neuroimaging and therapeutics

Alzheimer's disease is a progressive neurodegenerative disorder characterised by the gradual onset of dementia. The pathological hallmarks of the disease are beta-amyloid (Abeta) plaques, neurofibrillary tangles, synaptic loss and reactive gliosis. The current therapeutic effort is directed towards developing drugs that reduce Abeta burden or toxicity by inhibiting secretase cleavage, Abeta aggregation, Abeta toxicity, Abeta metal interactions or by promoting Abeta clearance. A number of clinical trials are currently in progress based on these different therapeutic strategies and they should indicate which, if any, of these approaches will be efficacious. Current diagnosis of Alzheimer's disease is made by clinical, neuropsychologic and neuroimaging assessments. Routine structural neuroimaging evaluation with computed tomography and magnetic resonance imaging is based on non-specific features such as atrophy, a late feature in the progression of the disease, hence the crucial importance of developing new approaches for early and specific recognition at the prodromal stages of Alzheimer's disease. Functional neuroimaging techniques such as functional magnetic resonance imaging, magnetic resonance spectroscopy, positron emission tomography and single photon emission computed tomography, possibly in conjunction with other related Abeta biomarkers in plasma and CSF, could prove to be valuable in the differential diagnosis of Alzheimer's disease, as well as in assessing prognosis. With the advent of new therapeutic strategies there is increasing interest in the development of magnetic resonance imaging contrast agents and positron emission tomography and single photon emission computed tomography radioligands that will permit the assessment of Abeta burden in vivo.     

Calcium channel blocking as a therapeutic strategy for Alzheimer's disease: the case for isradipine

Alzheimer's disease is the most devastating neurodegenerative disorder in the elderly, yet treatment options are severely limited. The drug development effort to modify Alzheimer's disease pathology by intervention at beta amyloid production sites has been largely ineffective or inconclusive. The greatest challenge has been to identify and define downstream mechanisms reliably predictive of clinical symptoms. Beta amyloid accumulation leads to dysregulation of intracellular calcium by plasma membrane L-type calcium channels located on neuronal somatodendrites and axons in the hippocampus and cortex. Paradoxically, L-type calcium channel subtype Ca(v)1.2 also promotes synaptic plasticity and spatial memory. Increased intracellular calcium modulates amyloid precursor protein processing and affects multiple downstream pathways including increased hyperphosphorylated tau and suppression of autophagy. Isradipine is a Federal Drug Administration-approved dihydropyridine calcium channel blocker that binds selectively to Ca(v)1.2 in the hippocampus. Our studies have shown that isradipine in vitro attenuates beta amyloid oligomer toxicity by suppressing calcium influx into cytoplasm and by suppressing Ca(v)1.2 expression. We have previously shown that administration of isradipine to triple transgenic animal model for Alzheimer's disease was well-tolerated. Our results further suggest that isradipine became bioavailable, lowered tau burden, and improved autophagy function in the brain. A better understanding of brain pharmacokinetics of calcium channel blockers will be critical for designing new experiments with appropriate drug doses in any future clinical trials for Alzheimer's disease. This review highlights the importance of Ca(v)1.2 channel overexpression, the accumulation of hyperphosphorylated tau and suppression of autophagy in Alzheimer's disease and modulation of this pathway by isradipine.     

The potential application of iron chelators for the treatment of neurodegenerative diseases

Many forms of neurodegenerative disease, for instance Alzheimer's disease, Parkinson's disease, Friedreich's ataxia, Hallervorden Spatz syndrome and macular degeneration, are associated with elevated levels of redox active metals in the brain and eye. A logical therapeutic approach therefore, is to remove the toxic levels of these metals, copper and iron in particular, by selective chelation. The increased number of iron-selective chelators now available for clinical use has enhanced interest in this type of therapy. This review summarises the recent developments in the design of chelators for treatment of neurodegenerative disease, identifies some of the essential properties for such molecules and suggests some future strategies.     

Structural imaging in early pre-states of dementia

In this review focus is on structural imaging in the Alzheimer's disease (AD) pre-states, particularly cognitively normal (CN) persons at future dementia risk. Findings in mild cognitive impairment (MCI) are described here only for comparison with CN. Cited literature evidence and commentary address issues of structural imaging alterations in CN that precede MCI and AD, regional patterns of such alterations, and the time relationship between structural imaging alterations and the appearance of symptoms of AD, issues relevant to the conduct of future AD prevention trials. This article is part of a Special Issue entitled: Imaging Brain Aging and Neurodegenerative disease.     

Neuronal expression of glutamine synthetase in Alzheimer's disease indicates a profound impairment of metabolic interactions with astrocytes

A considerable body of evidence indicates that the activity of glutamine synthetase is decreased in the cerebral cortices of brains affected by Alzheimer's disease. It is difficult to discern the reason for this decrease because it is not known whether the cellular distribution of glutamine synthetase is altered in Alzheimer's disease. Therefore the present study has used immunocytochemistry to compare the cellular distributions of glutamine synthetase in the inferior temporal cortices of six Alzheimer's diseased brains and six age-matched, non-demented brains. Double-label immunocytochemistry has been used to examine whether the distribution of cellular glutamine synthetase is influenced by the distribution of senile plaques. It was found that glutamine synthetase expression in astrocytes is diminished in Alzheimer's disease, particularly in the vicinity of senile plaques. The most striking finding of the present study was that glutamine synthetase was expressed in a subpopulation of pyramidal neurons in all six Alzheimer's diseased brains, whereas glutamine synthetase was not observed in any neurons from control brains. The changed expression of glutamine synthetase may be triggered by toxic agents in senile plaques, a reduced noradrenergic supply to the cerebral cortex, and increased brain ammonia levels. That such dramatic changes occur in the distribution of this critical, and normally stable enzyme, suggests that the glutamate-glutamine cycle is profoundly impaired in Alzheimer's disease. This is significant because impairments of the glutamate-glutamine cycle are known to cause alterations of mood and behaviour, disturbance of sleeping patterns, amnesia, confusion and reduced awareness. Since these behavioural changes are also seen in Alzheimer's disease, it is speculated that they might be attributable to the reduced expression of glutamine synthetase or to impairments of the glutamate-glutamine cycle.     

Monoclonal antibodies that target pathological assemblies of Abeta

Amyloid beta (Abeta) immunotherapy for Alzheimer's disease has shown initial success in mouse models of Alzheimer's disease and in human patients. However, because of meningoencephalitis in clinical trials of active vaccination, approaches using therapeutic antibodies may be preferred. As a novel antigen to generate monoclonal antibodies, the current study has used Abeta oligomers (amyloid beta-derived diffusible ligands, ADDLs), pathological assemblies known to accumulate in Alzheimer's disease brain. Clones were selected for the ability to discriminate Alzheimer's disease from control brains in extracts and tissue sections. These antibodies recognized Abeta oligomers and fibrils but not the physiologically prevalent Abeta monomer. Discrimination derived from an epitope found in assemblies of Abeta1-28 and ADDLs but not in other sequences, including Abeta1-40. Immunoneutralization experiments showed that toxicity and attachment of ADDLs to synapses in culture could be prevented. ADDL-induced reactive oxygen species (ROS) generation was also inhibited, establishing this response to be oligomer-dependent. Inhibition occurred whether ADDLs were prepared in vitro or obtained from Alzheimer's disease brain. As conformationally sensitive monoclonal antibodies that selectively immunoneutralize binding and function of pathological Abeta assemblies, these antibodies provide tools by which pathological Abeta assemblies from Alzheimer's disease brain might be isolated and evaluated, as well as offering a valuable prototype for new antibodies useful for Alzheimer's disease therapeutics.     

Non-steroidal anti-inflammatory drugs (NSAIDs) in Alzheimer's disease: old and new mechanisms of action

Alzheimer's disease (AD) is characterized by cerebral deposits of beta-amyloid (A beta) peptides and neurofibrillary tangles (NFT) which are surrounded by inflammatory cells. Epidemiological studies have shown that prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays the onset of the disease. It has been postulated that some NSAIDs target pathological hallmarks of AD by interacting with several pathways, including the inhibition of cyclooxygenases (COX) and activation of the peroxisome proliferator-activated receptor gamma. A variety of experimental studies indicate that a subset of NSAIDs such as ibuprofen, flurbiprofen, indomethacin and sulindac also possess A beta-lowering properties in both AD transgenic mice and cell cultures of peripheral, glial and neuronal origin. While COX inhibition occurs at low concentrations in vitro (nM-low microm range), the A beta-lowering activity is observed at high concentrations (< or = 50 microm). Nonetheless, studies with flurbiprofen or ibuprofen in AD transgenic mice show that the effects on A beta levels or deposition are attained at plasma levels similar to those achieved in humans at therapeutic dosage. Still, it remains to be assessed whether adequate concentrations are reached in the brain. This is a crucial aspect that will allow defining the dose-window and the length of treatment in future clinical trials. Here, we will discuss how the combination of anti-amyloidogenic and anti-inflammatory activities of certain NSAIDs may produce a profile potentially relevant to their clinical use as disease-modifying agents for the treatment of AD.     

RNA viruses as vectors for the expression of heterologous proteins

RNA viruses comprise a wide variety of infectious agents, some of which are the cause of disease in humans, animals, and plants. Recombinant DNA technology is now making it feasible to modify these genomes and engineer them to express heterologous proteins. Several different schemes are being employed that depend on the genome organization of the virus and on the strategy of replication of the particular virus. Several different examples are illustrated and potential uses as well as possible problems are discussed. In the future reverse genetics may convert some of these viruses from agents of disease to agents of cure.     

The diagnostic approach to early Alzheimer's disease. What are we talking about? Conceptual considerations

Progress in knowledge of the physiopathology of Alzheimer's disease over the last few decades has allowed much earlier diagnosis, even before the onset of clinical symptoms. Although the use of biomarkers is still far from being widespread and cannot be recommended outside research settings, their potential use has led to a review of the diagnostic criteria employed in the last few years. Among other criteria, asymptomatic and prodromal phases have been definitively incorporated into the spectrum of the disease and have been redefined. In future, the possibility of an earlier and more accurate diagnosis will allow the application of treatments acting in these phases, delaying progression to more advanced stages or even halting the disease before clinical manifestations develop. Currently, such treatments are still far from being a reality and interest in biomarkers centers on research since their detection could allow standardization of the samples used in clinical trials and exclusion of individuals showing signs of prodromal disease but who will never develop the disease.     

Therapeutic applications of antibodies in non-infectious neurodegenerative diseases

Neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease, Huntington's disease (HD) or amyotrophic lateral sclerosis (ALS) are all characterised histologically by the presence of deposits of misfolded proteins, tau and amyloid-β, α-synuclein, huntingtin or superoxide dismutase, respectively. Currently, these illnesses do not have any disease modifying treatment options. A novel therapeutic strategy that is being pursued is immunomodulation, which is using the body's immune system to target the self-proteins that are deposited. Most of these promising approaches are still in preclinical development while some have progressed to Phase III clinical trials. As new insights are gained, it is hoped that these immunotherapies will be effective tools at slowing the progression of these debilitating diseases.     

Alzheimer mechanisms and therapeutic strategies

There are still no effective treatments to prevent, halt, or reverse Alzheimer's disease, but research advances over the past three decades could change this gloomy picture. Genetic studies demonstrate that the disease has multiple causes. Interdisciplinary approaches combining biochemistry, molecular and cell biology, and transgenic modeling have revealed some of its molecular mechanisms. Progress in chemistry, radiology, and systems biology is beginning to provide useful biomarkers, and the emergence of personalized medicine is poised to transform pharmaceutical development and clinical trials. However, investigative and drug development efforts should be diversified to fully address the multifactoriality of the disease.     

Abnormal tau-containing filaments in neurodegenerative diseases

It has been known for some time that the neurofibrillary pathology in Alzheimer's disease consists of so-called paired helical and straight filaments made up of the microtubule-associated protein tau. The degree of dementia observed in the disease correlates better with the extent of neurofibrillary pathology than with the Abeta amyloid deposits, the other characteristic defining pathological fibrous deposit in Alzheimer's disease. However, no familial cases of Alzheimer's disease have been genetically linked to the tau protein locus. Recently a group of frontotemporal dementias with parkinsonism linked to chromosome 17 has been shown to be caused by mutations in the tau gene. Some are missense mutations giving altered tau proteins, whereas others affect the splicing of the pre-mRNA and change the balance between different tau isoforms. Histologically these diseases are all characterised by various kinds of filamentous tau protein deposits, mostly in the complete absence of Abeta deposits. The abnormal tau filaments show different morphologies, depending on the nature of the tau mutation. These diseases show that tau mutations can be a prime cause of inherited dementing illness and may throw some light on the pathological process in the much larger number of sporadic cases of Alzheimer's disease.     

Invertebrate models of Alzheimer's disease

The intensely studied model organisms Caenorhabditis elegans and Drosophila melanogaster have been employed to study a number of neurodegenerative diseases, including Alzheimer's disease (AD). Although worms and flies are phylogenetically distant from humans, results of both classic genetic analyses and transgenic manipulation of these invertebrates suggest they are valid models for at least some aspects of AD. This review describes the rationale for AD-relevant studies in worms and flies and discusses both what has been learned from these studies and what may be discovered in the future.