Global Alzheimer Research Summit

Abstract

We report here on the proceedings of the Global Alzheimer Summit that took place September 22–23, 2011 in Madrid, Spain. As Alzheimer disease (AD) is the leading cause of neurodegeneration in elderly individuals and as yet has no effective therapeutic option, it continues to stimulate global research interests. At the conference, leaders in the field of AD research provided insights into current developments in various areas of research, namely molecular mechanisms, genetics, novel aspects of AD research and translational research. Emphasis was also placed on the importance of biomarkers in the diagnosis of AD and development of current therapeutic strategies.

Keywords: :

• Alzheimer disease
• amyloid beta
• biomarkers
• clinical trials
• diagnosis
• neurodegeneration
• tau
• therapeutics
• β-secretase
• γ-secretase

Introduction

Alzheimer disease (AD) is the most prevalent form of dementia globally, affecting an excess of 36 million people, of which 7 million are found in Europe alone. Ten percent of individuals over 60 years of age and 50% of those over 85 years are afflicted with the disease.1 To date, there is no cure for this disease and there are few effective palliative therapies available. Research is thus critical for the further understanding of the molecular basis of AD and the development of therapeutic interventions.

The Global Alzheimer Research Summit was held on the September 22–23, 2011 at the Palacio de Congresos de Madrid in Madrid, Spain. The conference was organized by the Queen Sofia Foundation and the Pasqual Maragall Foundation. The aim of this conference was to bring together leading experts in the field of AD and provide a comprehensive overview of the molecular mechanisms and genetics underlying this disease with the intent of providing a clear direction for future research into early diagnosis and therapeutic interventions.

The conference was divided into two sections: Health and Social Care Research (Learning to Live Better with Alzheimer Disease) and Basic and Clinical Research (Present and Future of Alzheimer Research), the latter of which will be the focus of this meeting report. There were five main areas of focus examined in this conference, namely molecular mechanisms, genetics, biomarkers, diagnosis and therapeutic advances, translational research and novel aspects of basic research in AD.

Molecular Mechanisms

The causative agent of AD is thought to be the 4 kDa neurotoxic amyloid β (Aβ) peptide. The proposed mechanism by which Aβ is generated involves the sequential proteolytic cleavage of the Amyloid Precursor Protein (APP) by β-secretase and the γ-secretase complex.2–4 Sangram Sisodia (University of Chicago) opened the conference with an elucidating overview on the function of presenilin (PS), the catalytic subunit of the γ-secretase complex, in health and disease. He presented findings aimed at describing the γ-secretase complex and its function, as well as the importance of PS in autophagy. The differentiation and proliferation of neuronal progenitor cells was shown to be impaired in Familial AD (FAD)—linked PS1 variants suggesting a link between PS1 and neurogenesis.

Christian Haass (Ludwig-Maximilians University Munich) emphasized the unique role of the GxGD motif with regards to PS1 activity, drawing a parallel between this catalytic subunit and intramembrane cleaving aspartyl proteases. He further illustrated functional commonalities between the two in terms of their sequential substrate cleaving activities and the autoactivation which is a result thereof. γ-secretase modulation, as opposed to inhibition, was suggested as a means to prevent unwanted modifications of the essential Notch signaling pathway. First generation γ-secretase modulators (GSMs) have failed to prove effective in clinical trials, but second generation GSMs have been shown to reduce Aβ₄₂ production in cases exhibiting PS1 and PS2 mutations. Moreover, genome-wide RNA interference (RNAi) screening is being employed to identify endogenous GSMs.

Neurofibrillary tangles (NFTs) are one of the major pathological hallmarks of AD. The main constituent of these NFTs are paired helical filaments (PHF), which are assembled from the hyperphosphorylated microtubule associated protein, tau.5 Virginia Lee (University of Pennsylvania) hypothesized that the amount of normal tau available for microtubule stabilization would therefore be reduced and axonal transport compromised, leading to the neurodegeneration associated with AD. Lee focused her talk on targeting tau as a therapeutic tool for the treatment of AD, specifically focusing on Paclitaxel and Epothilone D. Animal trials employing Epothilone D have indicated its potential use in treating AD and other tauopathies.

Jesus Avila (Universidad de Autonoma de Madrid) discussed the role of glycogen synthase kinase 3 (GSK3), the enzyme responsible for the hyperphosphorylation of tau, in the impairment of neurogenesis and memory loss associated with AD. Avila suggested that the depletion of dentate gyrus (DG) stem cells within the hippocampus could be a cause for the inhibition of memory and learning associated with AD. The elevated Aβ levels observed in AD are thought to possibly promote the activation of GSK3. Adult neurogenesis was impaired in transgenic mice overexpressing GSK3 at the DG, and this correlated with a decrease in DG volume and hindered memory. Avila further illustrated that these memory impairments could be reversed so long as neuronal stem cells were present at the DG. It is therefore speculated that this could be a possible molecular mechanism underlying episodic memory loss as is noted in AD patients.

In the keynote lecture presented by the esteemed Dennis Selkoe (Harvard Medical School), the pathological effects of neuronal derived Aβ oligomers (as opposed to synthetic Aβ assemblies) were highlighted. Soluble Aβ oligomers, at nanomolar concentrations, were shown to not only inhibit long-term potentiation (LTP) but also induce long-term synaptic depression (LTD) while decreasing dendritic spine density in the hippocampus of normal rodent models. The administration of anti-Aβ antibodies directed against the N-terminus of Aβ prevented the aforementioned effects on LTP and LTD. Since the amyloid plaque cores themselves did not influence LTP or LTD, it was concluded that the soluble Aβ dimers and other low oligomeric number (low-n) Aβ species are the synaptotoxic species. Selkoe also discussed the ongoing phase III clinical trials of the anti-Aβ vaccine, Bapineuzumab.

Genetics

The apolipoprotein E (APOE) allele was the first major risk factor identified for the sporadic form of AD. However, despite our advances in the understanding of the genetics underlying this disease, over 50% of AD cases have no known genetic risk factors or components. Alison Goate (Washington University School of Medicine) and Sandra Barral (Columbia University) elaborated on their findings from several genome-wide association studies (GWAS) aimed at discovering novel risk factors by comparing AD cases to non-demented elderly controls. Nine novel risk factors (CLU, PICALM, CR1, BIN1, MS4A4A cluster, ABCA7, CD2AP, CD33 and EPHA1) were identified, which increase the risk for late onset Alzheimer disease (LOAD) by 10–15%. These novel risk factors are believed to play roles in a number of cellular pathways including lipid metabolism, the immune system and endocytosis. Barral further elaborated on the risk factors associated with LOAD, hypothesizing that multiple common variants underlie the cause of AD. The APOE ε4 allele is considered to be the risk factor most commonly associated with LOAD and increases risk in a dose-dependent manner, while the APOE ε2 allele reduces the risk for AD. Goate also described the use of cerebro-spinal fluid (CSF) biomarkers, i.e., CSF Aβ and tau, as endophenotypes for genes which may influence the expression levels of these CSF proteins. These analyses revealed that risk factors associated with AD correlate to CSF Aβ levels, while CSF tau levels corresponded to the rate of disease progression as opposed to risk.

In a plenary talk given by Kenneth Kosik (University of California), entitled “Stalking an Alzheimer's gene in the Colombian countryside,” an interesting case was presented about a number of Colombian families residing in the state of Antioquia. These families, which include over 5,000 individuals, have been identified as carriers of one of the deadly mutations associated with early onset AD. This group of individuals presents an interesting opportunity for researchers and clinicians, through the use of genetic testing, to predict who will be afflicted with the disease and the possible age of onset. This scenario is ideal for Alzheimer “trialists” who believe that treatment of pre-symptomatic AD will prove most beneficial in delaying the age of onset—past the expected mean of 47 years of age, which is the case in this Colombian population.

Biomarkers, Diagnosis and Therapeutic Advances

Bruno Dubois (University of Paris) provided insight into new diagnostic criteria as proposed by the International Working Group for New Research Criteria for the Diagnosis of AD in 2007, moving away from the original criteria outlined by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer Disease and Related Disorders Association (NINCDS-ADRDA) in 1984. According to these new criteria, a clinician can make a clinical diagnosis of AD based on one major clinical criterion (e.g., episodic memory test with cued recall measures) and the presence of one or more biomarkers. This new classification system allows for the early diagnosis of AD at the prodromal stage. In terms of biomarkers, structural alterations, such as atrophy of the medial temporal lobe, can be assessed by Magnetic Resonance Imaging (MRI), while biological changes can be recorded by CSF analyses of tau and Aβ. Functional or molecular changes can be examined using neuro-imaging patterns or amyloid ligand retention on Positron Emission Tomography (PET) such as the Pittsburgh compound B (PiB-PET).

Dale Schenk (Elan Pharmaceuticals and Janssen Alzheimer Immunotherapy, LLC) and Jeffery Cummings (University of California) both highlighted the use of biomarkers, such as low CSF Aβ₄₂ and elevated CSF tau levels, as possible endpoints for clinical trials. The observed reduction in CSF Aβ₄₂ levels or an increase in PiB staining could be used as an indicator for dementia later in life, while a decrease in CSF tau levels correlates well with treatment efficacy. The use of such biomarkers in Phase II clinical trials can effectively increase the accuracy of reported therapeutic benefits using a smaller sample size, while reducing the potential risk of entering into Phase III trials. As a representative of Elan Pharmaceuticals, South San Fransisco, Schenk also briefly spoke about Bapineuzumab and the ongoing Phase III trials.

Kaj Blennow (University of Gothenberg) further highlighted the use of biomarkers for monitoring the pathophysiological mechanisms central to AD. He reported on numerous studies that suggest that CSF biomarkers, including total tau reflecting neuronal degeneration, Aβ₄₂ reflecting plaque pathology and phosphorylated tau reflecting tau phosphorylation state and tangle pathology, have clinical use in the accurate diagnosis of prodromal AD. Blennow further elaborated on many of the same themes raised by Shenk and Cummings, suggesting the use of biomarkers in clinical trials to enhance patient selection for the trials and possibly increase the likelihood of identifying any significant clinical effects of the drugs in question. He further raised attention to the use of the shorter Aβ isoforms, namely Aβ_1–15 and Aβ_1–16 for the monitoring of γ-secretase inhibitor treatment, a biomarker found to be more sensitive compared with CSF Aβ₄₂ for monitoring this particular treatment option.

Mony de Leon (New York University School of Medicine) emphasized the combined use of both imaging and biomarkers in the pre-symptomatic diagnosis and identification of new mechanisms of AD. His team discovered two emergent AD related mechanisms: first, higher amyloid plaque load in the brain and reduced glucose metabolism was noted in pre-symptomatic patients whose mothers had a positive AD diagnosis and, second, higher plasma Aβ₄₀ levels were correlated with alterations in CO₂-linked hippocampal vasoreactivity. These findings suggest inherited maternal mutations in mitochondrial DNA could contribute to an increased AD risk and provide a vascular mechanism for the basis of Aβ-induced neurodegeneration.

Khalid Iqbal (New York State Institute for Basic Research in Developmental Disabilities) focused on the multifactoral nature of AD, suggesting that an inability to accurately identify various subgroups of AD and the assignment of these groups to specific clinical trials has hampered the development of effective AD therapies. It is his belief that the treatment of AD should not only target the inhibition of neurodegeneration but also stimulate neurogenesis and neuronal plasticity, and suggests that a careful balance between these two factors is necessary to reverse the cognitive damage inflicted by AD.

Bengt Winblad (Karolinska Institutet Alzheimer Disease Research Center) believes that we have achieved a partial degree of success in terms of the development of palliative therapies for the treatment of AD, but emphasizes a need for disease modifying drugs. He highlighted the ongoing clinical trials, many of which are based on the amyloid hypothesis of AD, but also acknowledged that a single therapy for AD is improbable. Winblad agreed with Iqbal in that multiple drugs targeting various pathways of AD will be needed to effectively manage this disease.

Although many clinical trials for BACE1 inhibitors have failed thus far, Martin Citron (Eli Lilly and Company) provided evidence for the fact that “BACE1 is druggable.” The first orally available non-peptidic BACE1 (β-secretase) inhibitor, namely LY2811376, was recently generated using a fragment based chemistry strategy. LY2811376 was shown to significantly lower Aβ production in animal models, an effect which persists in humans. LY2811376 development was however terminated due to toxicology findings in preclinical studies. Citron's studies proved that BACE1 inhibition is a plausible therapeutic approach for the treatment of AD.

Translational Research

Oxidative and mitochondrial abnormalities were discussed in detail by George Perry (University of Texas at San Antonio). Impairments in mitochondrial function, fission and fusion events develop in the early stages of AD. A decrease in the expression levels as well as altered distribution of fission/fusion proteins DLP1, OPA1, Mfn1 and Mfn2C were reported in AD neurons, while a significant increase in Fis1 was noted. Moreover, APP and Aβ were found to be responsible for these changes in expression levels. The result thereof is a reduction in mitochondrial density, which consequently manifests as a decrease in spine numbers. Various structural changes are also evident in AD vulnerable neurons and include a reduction in the number and increase in the average size of mitochondria. However, it should be noted that the mitochondrial changes in AD are not solely from nor demonstrated to be the result of Aβ/APP alone as a similar effect of oxidative stress independent of Aβ is seen.

Lennart Mucke (Gladstone Institute of Neurological Diseases and University of California) discussed the key role of tau in Aβ induced changes in neuronal and cognitive function as well as intracellular transport. A reduction in tau effectively prevents neuronal dysfunction induced by Aβ oligomers in transgenic mouse models. Furthermore Aβ, tau and Fyn (a src family kinase) were found to function co-dependently. The receptor tyrosine kinase EphB2 is targeted for proteosomal degradation upon interacting with Aβ oligomers; this in turn affects NMDA-type glutamate receptors and ultimately results in synaptic deficits and memory and learning impairments.

Novel Aspects of Basic Research in AD

Eduardo Soriano (University of Barcelona) elucidated the intriguing link between Reelin (an extracellular matrix protein which functions in neuronal development) and AD. Reelin was shown to be an important protein in the brain controlling adult neurogenisis, glutamatergic neurotransmission and structural and functional properties of dendritic spines. This protein was found to regulate tau phosphorylation through GSK3 activity. Moreover, Reelin was shown not only to delay the accumulation of Aβ plaques but also to sequester the pathogenic oligomeric Aβ species within these plaques, preventing cognitive impairment. The Reelin-Aβ association disrupts the Reelin signaling cascade thus impairing the essential neuroprotective function of Reelin in the brain and leading to neurodegeneration.

The importance of side-chain oxidized oxysterol in AD pathogenesis was discussed by Angel Cedazo-Minguez (Karolinska Institutet Alzheimer Disease Research Center). It was hypothesized that these oxysterol compounds were not by-products in cholesterol metabolism but rather play an important pathological role in the development of AD. Further he provided evidence linking hypercholesterolemia and hypertension to AD via disturbances in cholesterol metabolism and the overactivation of the brain rennin-angiotensin system ultimately resulting in disruptions in long-term potentiation (LTP).

Javier DeFelipe (Universidad Politecnica de Madrid) focused his talk on the dendritic spine alterations associated with AD. DeFelipe's group used powerful micro-anatomical tools to investigate the effects of tau aggregation on dendritic spines. It was found that non-aggregated pre-tangle tau proteins did not alter pyramidal neuron dendrites, as opposed to aggregated forms, which result in dendritic atrophy and spinal loss.

The Future of AD Research

Since Alois Alzheimer first described the disease in 1907,6 our understanding of AD and its underlying molecular mechanisms has come a long way; however, many hurdles still remain. The continuing development of biomarkers and their use for not only the preclinical diagnosis of AD but also as endpoints for clinical trials will continue to change the face of AD research. It is now a reality that AD can be diagnosed in the prodromal stages. Numerous ongoing clinical trials offer hope to the millions of those afflicted by this devastating disease. The continued efforts of leading researchers in the field have offered a promising future for AD and its sufferers.

Disclosure of Potential Conflicts of Interest

Any opinions, findings and conclusions or recommendations expressed in this material are those of the authors and therefore the NRF do not accept any liability in regard thereto.

Financial Support

This work is based upon research supported by the National Research Foundation (NRF), Republic of South Africa and the University of the Witwatersrand Travel Award.