20th Anniversary Issue
Page 901
Foreword
George Perry, Jesus Avila, Massimo Tabaton, Xiongwei Zhu
Birth of JAD: 20 Years Later
Pages 903-911
Review
Benedetta Nacmias, Silvia Bagnoli, Irene Piaceri, Sandro Sorbi
Genetic Heterogeneity of Alzheimer’s Disease: Embracing Research Partnerships
Abstract: Studies on the genetics of Alzheimer’s disease (AD) have revealed the complexity and heterogeneity of the disease. All our studies have supported this evidence and contribute to the current understanding of the genetic architecture of AD. This report reviews the success of our investigations, focusing on the implications and importance of the genetics of AD, and demonstrates the relevance of research strategies embracing partnerships.
Pages 913-932
Review
Chiara Fenoglio, Elio Scarpini, Maria Serpente, Daniela Galimberti
Role of Genetics and Epigenetics in the Pathogenesis of Alzheimer’s Disease and Frontotemporal Dementia
Abstract: Alzheimer’s disease (AD) and frontotemporal dementia (FTD) represent the first cause of dementia in senile and pre-senile population, respectively. A percentage of cases have a genetic cause, inherited with an autosomal dominant pattern of transmission. The majority of cases, however, derive from complex interactions between a number of genetic and environmental factors. Gene variants may act as risk or protective factors. Their combination with a variety of environmental exposures may result in increased susceptibility to these diseases or may influence their course. The scenario is even more complicated considering the effect of epigenetics, which encompasses mechanisms able to alter the expression of genes without altering the DNA sequence. In this review, an overview of the current genetic and epigenetic progresses in AD and FTD will be provided, with particular focus on 1) causative genes, 2) genetic risk factors and disease modifiers, and 3) epigenetics, including methylation, non-coding RNAs and chromatin remodeling.
Pages 933-942
Review
Chengxuan Qiu, Laura Fratiglioni
Aging without Dementia is Achievable: Current Evidence from Epidemiological Research
Abstract: Both the incidence and the prevalence of dementia increase exponentially with increasing age. This raises the question of whether dementia is an inevitable consequence of aging or whether aging without dementia is achievable. In this review article, we sought to summarize the current evidence from epidemiological and neuropathological studies that investigated this topic. Epidemiological studies have shown that dementia could be avoided even at extreme old ages (e.g., centenarians or supercentenarians). Furthermore, clinico-neuropathological studies found that nearly half of centenarians with dementia did not have sufficient brain pathology to explain their cognitive symptoms, while intermediate-to-high Alzheimer pathology was present in around one-third of very old people without dementia or cognitive impairment. This suggests that certain compensatory mechanisms (e.g., cognitive reserve or resilience) may play a role in helping people in extreme old ages escape dementia syndrome. Finally, evidence has been accumulating in recent years indicating that the incidence of dementia has declined in Europe and North America, which supports the view that the risk of dementia in late life is modifiable. Evidence has emerged that intervention strategies that promote general health, maintain vascular health, and increase cognitive reserve are likely to help preserve cognitive function till late life, thus achieving the goal of aging without dementia.
Pages 943-963
Review
Christian Griñán-Ferré, Rubén Corpas, Dolors Puigoriol-Illamola, Verónica Palomera-Ávalos, Coral Sanfeliu, Mercè Pallàs
Understanding Epigenetics in the Neurodegeneration of Alzheimer's Disease: SAMP8 Mouse Model
Abstract: Epigenetics is emerging as the missing link among genetic inheritance, environmental influences, and body and brain health status. In the brain, specific changes in nucleic acids or their associated proteins in neurons and glial cells might imprint differential patterns of gene activation that will favor either cognitive enhancement or cognitive loss for more than one generation. Furthermore, derangement of age-related epigenetic signaling is appearing as a significant risk factor for illnesses of aging, including neurodegeneration and Alzheimer's disease (AD). In addition, better knowledge of epigenetic mechanisms might provide hints and clues in the triggering and progression of AD. Intense research in experimental models suggests that molecular interventions for modulating epigenetic mechanisms might have therapeutic applications to promote cognitive maintenance through an advanced age. The SAMP8 mouse is a senescence model with AD traits in which the study of epigenetic alterations may unveil epigenetic therapies against the AD.
Pages 965-992
Review
Ralph N. Martins, Victor Villemagne, Hamid R. Sohrabi, Pratishtha Chatterjee, Tejal M. Shah, Giuseppe Verdile, Paul Fraser, Kevin Taddei, Veer B. Gupta, Stephanie R. Rainey-Smith, Eugene Hone, Steve Pedrini, Wei Ling Lim, Ian Martins, Shaun Frost, Sunil Gupta, Sid O'Bryant, Alan Rembach, David Ames, Kathryn Ellis, Stephanie J. Fuller, Belinda Brown, Samantha L. Gardener, Binosha Fernando, Prashant Bharadwaj, Samantha Burnham, Simon M. Laws, Anna M. Barron, Kathryn Goozee, Eka J. Wahjoepramono, Prita R. Asih, James D. Doecke, Olivier Salvado, Ashley I. Bush, Christopher C. Rowe, Samuel E. Gandy, Colin L. Masters
Alzheimer's Disease: A Journey from Amyloid Peptides and Oxidative Stress, to Biomarker Technologies and Disease Prevention Strategies-Gains from AIBL and DIAN Cohort Studies
Abstract: Worldwide there are over 46 million people living with dementia, and this number is expected to double every 20 years reaching about 131 million by 2050. The cost to the community and government health systems, as well as the stress on families and carers is incalculable. Over three decades of research into this disease have been undertaken by several research groups in Australia, including work by our original research group in Western Australia which was involved in the discovery and sequencing of the amyloid-β peptide (also known as Aβ or A4 peptide) extracted from cerebral amyloid plaques. This review discusses the journey from the discovery of the Aβ peptide in Alzheimer's disease (AD) brain to the establishment of pre-clinical AD using PET amyloid tracers, a method now serving as the gold standard for developing peripheral diagnostic approaches in the blood and the eye. The latter developments for early diagnosis have been largely achieved through the establishment of the Australian Imaging Biomarker and Lifestyle research group that has followed 1,100 Australians for 11 years. AIBL has also been instrumental in providing insight into the role of the major genetic risk factor apolipoprotein E ε4, as well as better understanding the role of lifestyle factors particularly diet, physical activity and sleep to cognitive decline and the accumulation of cerebral Aβ.
Pages 993-1012
Review
Francesco Panza*, Madia Lozupone*, Vincenzo Solfrizzi, Rodolfo Sardone, Vittorio Dibello, Luca Di Lena, Francesca D’Urso, Roberta Stallone, Massimo Petruzzi, Gianluigi Giannelli, Nicola Quaranta, Antonello Bellomo, Antonio Greco, Antonio Daniele, Davide Seripa, Giancarlo Logroscino *These authors contributed equally to this work.
Different Cognitive Frailty Models and Health- and Cognitive-related Outcomes in Older Age: From Epidemiology to Prevention
Abstract: Frailty, a critical intermediate status of the aging process that is at increased risk for negative health-related events, includes physical, cognitive, and psychosocial domains or phenotypes. Cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (MCI), with two proposed subtypes: potentially reversible cognitive frailty (physical frailty/MCI) and reversible cognitive frailty (physical frailty/pre-MCI subjective cognitive decline). In the present article, we reviewed the framework for the definition, different models, and the current epidemiology of cognitive frailty, also describing neurobiological mechanisms, and exploring the possible prevention of the cognitive frailty progression. Several studies suggested a relevant heterogeneity with prevalence estimates ranging 1.0-22.0% (10.7-22.0% in clinical-based settings and 1.0-4.4% in population-based settings). Cross-sectional and longitudinal population-based studies showed that different cognitive frailty models may be associated with increased risk of functional disability, worsened quality of life, hospitalization, mortality, incidence of dementia, vascular dementia, and neurocognitive disorders. The operationalization of clinical constructs based on cognitive impairment related to physical causes (physical frailty, motor function decline, or other physical factors) appears to be interesting for dementia secondary prevention given the increased risk for progression to dementia of these clinical entities. Multidomain interventions have the potential to be effective in preventing cognitive frailty. In the near future, we need to establish more reliable clinical and research criteria, using different operational definitions for frailty and cognitive impairment, and useful clinical, biological, and imaging markers to implement intervention programs targeted to improve frailty, so preventing also late-life cognitive disorders.
Pages 1013-1022
Review
Milan Fiala, Lucas Restrepo, Matteo Pellegrini
Immunotherapy of Mild Cognitive Impairment by ω-3 Supplementation: Why Are Amyloid-β Antibodies and ω-3 Not Working in Clinical Trials?
Abstract: This article reviews the basic tenets of a clinical approach to effective immunotherapy of Alzheimer’s disease (AD) in patients with mild cognitive impairment (MCI). Although one randomized controlled study in early MCI patients by fish-derived omega-3 fatty acids (ω-3) showed slowing of disease progression, large clinical trials with different products have failed to show cognitive effects. Macrophages of healthy subjects phagocytize and degrade amyloid-β1-42 (Aβ) in the brain tissues, whereas macrophages of patients with AD and MCI are functionally defective. ω-3 and ω-3-derived specialized proresolving mediators (SPMs), such as resolvin D1, have powerful biochemical and immunological effects, which may repair the functions of MCI patients’ macrophages in the brain’s clearance of Aβ. Unfortunately, ω-3 products on the market have a variable quality. Nutritional supplementation with a combination drink called Smartfish with an emulsion of ω-3 and other fatty acids, antioxidants, 1,25-dihydroxy vitamin D3, and resveratrol improved the innate immune system of MCI patients by modulation of macrophage type to the pro-phagocytic M1-M2 type with an effective unfolded protein response against endoplasmic reticulum stress. Some MCI patients maintained their initial cognitive status for three years on Smartfish supplementation. Future randomized clinical trials should investigate the immune effects of ω-3, 1,25-dihydroxy vitamin D3, and SPMs on macrophage type, function, and biochemistry in parallel with cognitive effects.
Pages 1023-1047
Perspective
Isidro Ferrer
Sisyphus in Neverland
Abstract: The study of life and living organisms and the way in which these interact and organize to form social communities have been central to my career. I have been fascinated by biology, neurology, and neuropathology, but also by history, sociology, and art. Certain current historical, political, and social events, some occurring proximally but others affecting people in apparently distant places, have had an impact on me. Epicurus, Seneca, and Camus shared their philosophical positions which I learned from. Many scientists from various disciplines have been exciting sources of knowledge as well. I have created a world of hypothesis and experiments but I have also got carried away by serendipity following unexpected observations. It has not been an easy path; errors and wanderings are not uncommon, and opponents close to home much more abundant than one might imagine. Ambition, imagination, resilience, and endurance have been useful in moving ahead in response to setbacks. In the end, I have enjoyed my dedication to science and I am grateful to have glimpsed beauty in it. These are brief memories of a Spanish neuropathologist born and raised in Barcelona.
Pages 1049-1057
Perspective
Thomas B. Shea
While I Still Remember: 30 Years of Alzheimer’s Disease Research
Abstract: Turns out I have been a major contributor to the Journal of Alzheimer’s Disease over its 20-year history. As such, I was invited to provide a review of my work over the years. What follows is a retrospective of how the Alzheimer-related research of a Ph.D. (i.e., not an M.D.) transitioned from basic to clinical, and moved from bench to bedside and back again. I have included some of the more humorous and poignant twists along the way that some older players may find familiar and I hope might inspire some younger players to hang in there.
Pages 1059-1066
Review
Bruno Dubois
The Emergence of a New Conceptual Framework for Alzheimer’s Disease
Abstract: The New Criteria for the diagnosis of Alzheimer’s disease (AD), published by a group of experts in 2007, have resulted in a revolution in the comprehension of the disease. Before 2007, the diagnosis of AD dementia was done through a process of exclusion: it was considered in the case of patients with a dementia syndrome without identified etiologies. This traditional algorithm had three major limitations that penalize the disease: 1) a low accuracy of the performance which may share responsibility for negative results in clinical trials; 2) a late identification of the patients only when they reach the threshold of dementia which may delay the activation of optimal care; and last but not least, 3) an absence of clear recognition of AD as a disease because of the lack of specific arguments for its identification. Since 2007, the disease has gained a clear definition based on positive evidence: a specific clinical phenotype (the amnestic syndrome of the hippocampal type) and the presence of biomarkers, considered as a biological signature of the disease. Thanks to these positive arguments, AD is a clinically and biologically well-delineated disease, no longer defined as “probable”. It is now possible to certify that a given patient has or does not have the disease. Like diabetes, cancer, hyperthyroidism or any other disorder, AD has now a clear definition with well-defined borders. The disease has entered the world of medicine with identified diseases with a biological fingerprint. This is the story of this adventure that we will present now.
Pages 1067-1077
Review
José Luis Molinuevo, Carolina Minguillon, Lorena Rami, Juan Domingo Gispert
The Rationale Behind the New Alzheimer’s Disease Conceptualization: Lessons Learned During the Last Decades
Abstract: In the last decades, progress in neuroimaging techniques and cerebrospinal fluid assays has enabled the characterization of several Alzheimer’s disease (AD) biomarkers. This knowledge has shifted the conceptualization of AD from a clinical-pathological construct, where its diagnosis required the presence of dementia with distinct pathologic features, toward a clinical-biological one that recognizes AD as a pathological continuum with a clinical picture that ranges from normal cognition to a dementia stage. Specifically, AD is now divided into three stages: preclinical (abnormal biomarkers and no or only subtle cognitive impairment), mild cognitive impairment or prodromal AD (abnormal pathophysiological biomarkers and episodic memory impairment), and dementia (abnormal biomarkers and clear cognitive and functional impairment). The possibility of assessing AD pathophysiology in vivo before the onset of clinical symptoms in the preclinical stage provides the unprecedented opportunity to intervene at earlier stages of the continuum in secondary prevention trials. Currently, large cohort studies of cognitively healthy participants are undergoing with the main aim of disentangling the natural history of AD to identify individuals with an increased risk of developing AD in the near future to be recruited in these clinical trials. In this paper, we review how the concept of AD has changed over the years as well as discuss the implications of this conceptual change.
Pages 1079-1090
Review
Mercè Boada, Miguel A. Santos-Santos, Octavio Rodríguez-Gómez, Montserrat Alegret, Pilar Cañabate, Asunción Lafuente, Carla Abdelnour, Mar Buendía, Maria José de Dios, América Morera, Ángela Sanabria, Laura Campo, Agustín Ruiz, Lluis Tárraga
Patient Engagement: The Fundació ACE Framework for Improving Recruitment and Retention in Alzheimer's Disease Research
Abstract: Alzheimer's disease (AD) research is at a critical time. The global society is increasingly aware of the frightening rate of growth of the human and financial burden caused by this condition and of the urgent need to halt its progression. Consequently, the scientific community holds great responsibility to quickly put in place and optimize the machinery necessary for testing new treatments or interventions. In this context demand for participants for AD research is at an all-time high. In this review, we will focus on a methodological factor that is increasingly recognized as a key factor that shapes trial populations and affects validity of results in clinical trials: patient engagement, recruitment, and retention. We outline specific problems relevant to patient engagement in AD including recruiting enough participants, difficulties in participant retention, ensuring the recruited sample is representative of the general AD population, the burden of screening failures, and new challenges related to recruiting in preclinical disease. To address the urgent need for more research studying the applicability and cost-effectiveness of different recruitment strategies across different settings and nationalities, we describe the Models of Patient Engagement for Alzheimer's Disease (MOPEAD) project, a public-private partnership promoted by the Innovative Medicine Initiative (IMI), which will provide a large multinational quantitative analysis comparing different innovative recruitment models. We also discuss strategies that address each problem and draw on the experience of Fundació Ace to argue that focusing resources on comprehensive AD centers that offer coordinated clinical and social care and participate in basic and clinical research, is an effective and efficient way of implementing many of the discussed strategies.
Pages 1091-1111
Review
Wiesje M. van der Flier, Philip Scheltens
Amsterdam Dementia Cohort: Performing Research to Optimize Care
Abstract: The Alzheimer center of the VU University Medical Center opened in 2000 and was initiated to combine both patient care and research. Together, to date, all patients forming the Amsterdam Dementia Cohort number almost 6,000 individuals. In this cohort profile, we provide an overview of the results produced based on the Amsterdam Dementia Cohort. We describe the main results over the years in each of these research lines: 1) early diagnosis, 2) heterogeneity, and 3) vascular factors. Among the most important research efforts that have also impacted patients’ lives and/or the research field, we count the development of novel, easy to use diagnostic measures such as visual rating scales for MRI and the Amsterdam IADL Questionnaire, insight in different subgroups of AD, and findings on incidence and clinical sequelae of microbleeds. Finally, we describe in the outlook how our research endeavors have improved the lives of our patients.
Pages 1113-1123
Review
Barbara Borroni, Alberto Benussi, Enrico Premi, Antonella Alberici, Elena Marcello, Fabrizio Gardoni, Monica Di Luca, Alessandro Padovani
Biological, Neuroimaging, and Neurophysiological Markers in Frontotemporal Dementia: Three Faces of the Same Coin
Abstract: Frontotemporal dementia (FTD) is a heterogeneous clinical, genetic, and neuropathological disorder. Clinical diagnosis and prediction of neuropathological substrates are hampered by heterogeneous pictures. Diagnostic markers are key in clinical trials to differentiate FTD from other neurodegenerative dementias. In the same view, identifying the neuropathological hallmarks of the disease is key in light of future disease-modifying treatments. The aim of the present review is to unravel the progress in biomarker discovery, discussing the potential applications of available biological, imaging, and neurophysiological markers.
Pages 1125-1140
Review
Kaj Blennow, Henrik Zetterberg
The Past and the Future of Alzheimer’s Disease Fluid Biomarkers
Abstract: Following the development of the first methods to measure the core Alzheimer’s disease (AD) cerebrospinal fluid (CSF) biomarkers—total-tau (T-tau), phosphorylated tau (P-tau) and the 42 amino acid form of amyloid-β (Aβ42), there has been an enormous expansion of this scientific research area. Today, it is generally acknowledged that these biochemical tests reflect several central pathophysiological features of AD and contribute diagnostically relevant information, also for prodromal AD. In this article in the 20th anniversary issue of the Journal of Alzheimer’s Disease, we review the AD biomarkers, from early assay development to their entrance into diagnostic criteria. We also summarize the long journey of standardization and the development of assays on fully automated instruments, where we now have high precision and stable assays that will serve as the basis for common cut-off levels and a more general introduction of these diagnostic tests in clinical routine practice. We also discuss the latest expansion of the AD CSF biomarker toolbox that now also contains synaptic proteins such as neurogranin, which seemingly is specific for AD and predicts rate of future cognitive deterioration. Last, we are at the brink of having blood biomarkers that may be implemented as screening tools in the early clinical management of patients with cognitive problems and suspected AD. Whether this will become true, and whether it will be plasma Aβ42, the Aβ42/40 ratio, or neurofilament light, or a combination of these, remains to be established in future clinical neurochemical studies.
Pages 1141-1179
Review
Kurt A. Jellinger
Multiple System Atrophy: An Oligodendroglioneural Synucleinopathy
Abstract: Multiple system atrophy (MSA) is an orphan, fatal, adult-onset neurodegenerative disorder of uncertain etiology that is clinically characterized by various combinations of parkinsonism, cerebellar, autonomic, and motor dysfunction. MSA is an α-synucleinopathy with specific glioneuronal degeneration involving striatonigral, olivopontocerebellar, and autonomic nervous systems but also other parts of the central and peripheral nervous systems. The major clinical variants correlate with the morphologic phenotypes of striatonigral degeneration (MSA-P) and olivopontocerebellar atrophy (MSA-C). While our knowledge of the molecular pathogenesis of this devastating disease is still incomplete, updated consensus criteria and combined fluid and imaging biomarkers have increased its diagnostic accuracy. The neuropathologic hallmark of this unique proteinopathy is the deposition of aberrant α-synuclein in both glia (mainly oligodendroglia) and neurons forming glial cytoplasmic inclusions and neuronal cytoplasmic inclusions that cause cell dysfunction and demise. In addition, there is widespread demyelination, the pathogenesis of which is not fully understood. The pathogenesis of MSA is characterized by propagation of misfolded α-synuclein from neurons to oligodendroglia and cell-to-cell spreading in a “prion-like” manner, oxidative stress, proteasomal and mitochondrial dysfunction, dysregulation of myelin lipids, decreased neurotrophic factors, neuroinflammation, and energy failure. The combination of these mechanisms finally results in a system-specific pattern of neurodegeneration and a multisystem involvement that are specific for MSA. Despite several pharmacological approaches in MSA models, addressing these pathogenic mechanisms, no effective neuroprotective nor disease-modifying therapeutic strategies are currently available. Multidisciplinary research to elucidate the genetic and molecular background of the deleterious cycle of noxious processes, to develop reliable biomarkers and targets for effective treatment of this hitherto incurable disorder is urgently needed.
Pages 1181-1198
Review
Liu Shi, Alison L. Baird, Sarah Westwood, Abdul Hye, Richard Dobson, Madhav Thambisetty, Simon Lovestone
A Decade of Blood Biomarkers for Alzheimer’s Disease Research: An Evolving Field, Improving Study Designs, and the Challenge of Replication
Abstract: Blood-based biomarkers represent a less invasive and potentially cheaper approach for aiding Alzheimer’s disease (AD) detection compared with cerebrospinal fluid and some neuroimaging biomarkers. Acknowledging that many in the field have made great progress, here we review some of the work that our group has pursued to identify and validate blood-based proteomic biomarkers through both case control and AD pathology endophenotype-based approaches. Our focus is primarily to identify a minimally invasive and hopefully cost-effective blood-based biomarker to reduce screen failure in clinical trials where participants have prodromal or even pre-clinical disease. We summarize some of the key findings and approaches taken in these biomarker studies, while addressing the main challenges, including that of limited replication in the field, and discuss opportunities for biomarker development.
Pages 1199-1209
Review
Maria Bjerke, Sebastiaan Engelborghs
Cerebrospinal Fluid Biomarkers for Early and Differential Alzheimer’s Disease Diagnosis
Abstract: An accurate and early diagnosis of Alzheimer’s disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future.
Pages 1211-1218
Review
Narjes Baazaoui and Khalid Iqbal
A Novel Therapeutic Approach to Treat Alzheimer’s Disease by Neurotrophic Support During the Period of Synaptic Compensation
Abstract: Alzheimer’s disease (AD), at present, is considered an incurable disease and a major dilemma with no drug to stop or slow down its progression. Drugs that are currently available in the market are able to only transiently improve the clinical symptoms. The repeated failures in developing an effective drug has led to the suggestion that the medical intervention was probably too late to be effective since the pathology starts many years before the appearance of the clinical symptoms. Probably, at the time of the appearance of clinical symptoms the brain has undergone major neuronal and synaptic loss. Because of the uncertainty on when to use a prevention therapy, especially targeting amyloid-β (Aβ) and tau pathologies, interventions that rely on the regenerative capacity of the brain such as the modulation of the inherent neurogenesis and neuronal plasticity represents a promising therapeutic strategy. Such an approach can act both at early as well as late stages of the disease and remove the barrier of the time of intervention. In this article, we review studies mainly from our laboratory that show the merit of early intervention during the synaptic and neuronal compensation period where the brain still has the capacity to self-repair by offering neurotrophic support in reversing cognitive impairment, neuronal and synaptic deficits, Aβ, and tau pathologies and decreasing mortality in a transgenic mouse model of AD.
Pages 1219-1222
Review
Patrick L. McGeer, Jian Ping Guo, Moonhee Lee, Krista Kennedy, Edith G. McGeer
Alzheimer’s Disease Can Be Spared by Nonsteroidal Anti-Inflammatory Drugs
Abstract: Alzheimer’s disease (AD) is characterized by deposits of amyloid-β protein (Aβ) in brain which become foci of inflammation. Neurons are destroyed by this inflammatory process, leading to the cognitive deficits which define AD clinical onset. Epidemiological studies indicate that nonsteroidal anti-inflammatory drugs (NSAIDs) can ameliorate this destructive process if they are started well before clinical signs develop. Biomarker studies indicate that the disease process starts at least a decade before cognitive deficits appear. This pre-clinical onset explains the NSAID effect. It also opens a window of opportunity for preventive treatment that can be met with a simple diagnostic test. Salivary levels of Aβ42 may fulfill that need. They can be measured by a simple ELISA test we have developed using commercially available reagents. By this ELISA test, normal controls, who are not at risk for AD, have levels of Aβ42 close to 20 pg/ml. AD cases, as well as high level controls, secrete levels in the range of 40-85 pg/ml. Widespread application of this test by high level controls, followed by NSAID consumption, could substantially reduce the prevalence of AD.
Pages 1223-1240
Review
Jaume Folch, Oriol Busquets, Miren Ettcheto, Elena Sánchez-López, Ruben Dario Castro-Torres, Ester Verdaguer, Maria Luisa Garcia, Jordi Olloquequi, Gemma Casadesús, Carlos Beas-Zarate, Carme Pelegri, Jordi Vilaplana, Carme Auladell, Antoni Camins
Memantine for the Treatment of Dementia: A Review on its Current and Future Applications
Abstract: Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the presence in the brain of extracellular amyloid-β protein (Aβ) and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. The N-Methyl-D-aspartate receptors (NMDAR), ionotropic glutamate receptor, are essential for processes like learning and memory. An excessive activation of NMDARs has been associated with neuronal loss. The discovery of extrasynaptic NMDARs provided a rational and physiological explanation between physiological and excitotoxic actions of glutamate. Memantine (MEM), an antagonist of extrasynaptic NMDAR, is currently used for the treatment of AD jointly with acetylcholinesterase inhibitors. It has been demonstrated that MEM preferentially prevents the excessive continuous extrasynaptic NMDAR disease activation and therefore prevents neuronal cell death induced by excitotoxicity without disrupting physiological synaptic activity. The problem is that MEM has shown no clear positive effects in clinical applications while, in preclinical stages, had very promising results. The data in preclinical studies suggests that MEM has a positive impact on improving AD brain neuropathology, as well as in preventing Aβ production, aggregation, or downstream neurotoxic consequences, in part through the blockade of extrasynaptic NMDAR. Thus, the focus of this review is primarily to discuss the efficacy of MEM in preclinical models of AD, consider possible combinations of this drug with others, and then evaluate possible reasons for its lack of efficacy in clinical trials. Finally, applications in other pathologies are also considered.
Pages 1241-1245
Review
Elena Tamagno, Michela Guglielmotto, Debora Monteleone, Giusi Manassero, Valeria Vasciaveo, Massimo Tabaton
The Unexpected Role of Aβ1-42 Monomers in the Pathogenesis of Alzheimer’s Disease
Abstract: Amyloid-β (Aβ) has been proposed as a biomarker and a drug target for the therapy of Alzheimer’s disease (AD). The neurotoxic entity and relevance of each conformational form of Aβ to AD pathology is still under debate; Aβ oligomers are considered the major killer form of the peptide whereas monomers have been proposed to be involved in physiological process. Here we reviewed some different effects mediated by monomers and oligomers on mechanisms involved in AD pathogenesis such as autophagy and tau aggregation. Data reported in this review demonstrate that Aβ monomers could have a major role in sustaining the pathogenesis of AD and that AD therapy may be focused not only in the removal of oligomers but also of monomers.
Pages 1247-1259
Review
Giuseppe Di Fede, Giorgio Giaccone, Mario Salmona, Fabrizio Tagliavini
Translational Research in Alzheimer’s and Prion Diseases
Abstract: Translational neuroscience integrates the knowledge derived by basic neuroscience with the development of new diagnostic and therapeutic tools that may be applied to clinical practice in neurological diseases. This information can be used to improve clinical trial designs and outcomes that will accelerate drug development, and to discover novel biomarkers which can be efficiently employed to early recognize neurological disorders and provide information regarding the effects of drugs on the underlying disease biology. Alzheimer’s disease (AD) and prion disease are two classes of neurodegenerative disorders characterized by incomplete knowledge of the molecular mechanisms underlying their occurrence and the lack of valid biomarkers and effective treatments. For these reasons, the design of therapies that prevent or delay the onset, slow the progression, or improve the symptoms associated to these disorders is urgently needed. During the last few decades, translational research provided a framework for advancing development of new diagnostic devices and promising disease-modifying therapies for patients with prion encephalopathies and AD. In this review, we provide present evidence of how supportive can be the translational approach to the study of dementias and show some results of our preclinical studies which have been translated to the clinical application following the ‘bed-to-bench-and-back’ research model.
Pages 1261-1276
Review
Gianluigi Forloni, Claudia Balducci
Alzheimer’s Disease, Oligomers, and Inflammation
Abstract: The production of soluble amyloid-β oligomers (AβOs) and the activation of inflammation are two important early steps in the pathogenesis of Alzheimer's disease (AD). The central role of oligomers as responsible for the neuronal dysfunction associated with the clinical features has been extended to the other protein misfolding disorders definable, on this basis, as oligomeropathies. In AD, recent evidence indicates that the mechanism of inflammation as a consequence of neurodegeneration must be assessed in favor of a more direct role of glial activation in the alteration of synaptic function. Our own experimental models demonstrate the efficacy of anti-inflammatory treatments in preventing the cognitive deficits induced acutely by AβOs applied directly in the brain. Moreover, some promising clinical tools are based on immunological activation reducing the presence of cerebral Aβ deposits. However, the strategies based on the control of inflammatory factors as well as the amyloid aggregation show poor or non-therapeutic efficacy. Numerous studies have examined inflammatory factors in biological fluids as possible markers of the neuroinflammation in AD. In some cases, altered levels of cytokines or other inflammatory markers in cerebrospinal fluid correlate with the severity of the disease. Here we propose, according to the precision medicine principles, innovative therapeutic approaches to AD based on the patient’s inflammatory profile/state. The earlier intervention and a multifactor approach are two other elements considered essential to improve the chances of effective therapy in AD.
Pages 1277-1285
Review
Jesús Avila
Our Working Point of View of Tau Protein
Abstract: Tau protein, which was discovered in Prof. Kirschner’s laboratory in 1975, has been the focus of my research over the last 40 years. In this issue of the Journal of Alzheimer's Disease commemorating its 20th year of publication, I will provide a short review of some of the features of my relationship with tau.
Pages 1287-1303
Review
Claude M. Wischik, Björn O. Schelter, Damon J. Wischik, John M. D. Storey, Charles R. Harrington
Modeling Prion-Like Processing of Tau Protein in Alzheimer’s Disease for Pharmaceutical Development
Abstract: Following the discovery of a fragment from the repeat domain of tau protein as a structural constituent of the PHF-core in Alzheimer’s disease (AD), we developed an assay that captured several key features of the aggregation process. Tau-tau binding through the core tau fragment could be blocked by the same diaminophenothiazines found to dissolve proteolytically stable PHFs isolated from AD brain. We found that the PHF-core tau fragment is inherently capable of auto-catalytic self-propagation in vitro, or “prion-like processing”, that has now been demonstrated for several neurodegenerative disorders. Here we review the findings that led to the first clinical trials to test tau aggregation inhibitor therapy in AD as a way to block this cascade. Although further trials are still needed, the results to date suggest that a treatment targeting the prion-like processing of tau protein may have a role in both prevention and treatment of AD.
Pages 1305-1317
Review
Ying Yang, Jian-Zhi Wang
Nature of Tau-Associated Neurodegeneration and the Molecular Mechanisms
Abstract: Neurodegeneration is defined as the progressive loss of structure or function of the neurons. As the nature of degenerative cell loss is currently not clear, there is no specific molecular marker to measure neurodegeneration. Therefore, researchers have been using apoptotic markers to measure neurodegeneration. However, neurodegeneration is completely different from apoptosis by morphology and time course. Lacking specific molecular marker has been the major hindrance in research of neurodegenerative disorders. Alzheimer’s disease (AD) is the most common neurodegenerative disorder, and tau accumulation forming neurofibrillary tangles is a hallmark pathology in the AD brains, suggesting that tau must play a critical role in AD neurodegeneration. Here we review part of our published papers on tau-related studies, and share our thoughts on the nature of tau-associated neurodegeneration in AD.
Pages 1319-1335
Review
Patrizia Mecocci, Virginia Boccardi, Roberta Cecchetti, Patrizia Bastiani, Michela Scamosci, Carmelinda Ruggiero, Marta Baroni
A Long Journey into Aging, Brain Aging, and Alzheimer’s Disease Following the Oxidative Stress Tracks
Abstract: The Editors of the Journal of Alzheimer’s Disease invited Professor Patrizia Mecocci to contribute a review article focused on the importance and implications of her research on aging, brain aging, and senile dementias over the last years. This invitation was based on an assessment that she was one of the journal’s top authors and a strong supporter of the concept that oxidative stress is a major contributor to several alterations observed in age-related conditions (sarcopenia, osteoporosis) and, more significantly, in brain aging suggesting a pivotal role in the pathogenesis and progression of one of the most dramatic age-related diseases, Alzheimer’s disease (AD). Her first pioneering research was on the discovery of high level of 8-hydroxy-2'-deoxyguanosine (OH8dG), a marker of oxidation in nucleic acids, in mitochondrial DNA isolated from cerebral cortex. This molecule increases progressively with aging and more in AD brain, supporting the hypothesis that oxidative stress, a condition of unbalance between the production of reactive oxygen species and antioxidants, gives a strong contribution to the high incidence of AD in old age subjects. OH8dG also increases in peripheral lymphocyte from AD subjects, suggesting that AD is not only a cerebral but also a systemic disease. The role of antioxidants, particularly vitamin E and zinc, were also studied in longevity and in cognitive decline and dementia. This review shows the main findings from Mecocci’s laboratory related to oxidative stress in aging, brain aging, and AD and discusses the importance and implications of some of the major achievements in this field of research.
Pages 1337-1344
Review
Antonio Di Meco, Jian-Guo Li, Domenico Praticò
Dissecting the Role of 5-Lipoxygenase in the Homocysteine-Induced Alzheimer’s Disease Pathology
Abstract: Alzheimer’s disease (AD) affects over 40 million patients around the world and poses a huge economic burden on society since no effective therapy is available yet. While the cause(s) for the most common sporadic form of the disease are still obscure, lifestyle and different environmental factors have emerged as modulators of AD susceptibility. Hyperhomocysteinemia (HHCY), a condition of high circulating levels of homocysteine, is an independent but modifiable risk factor for AD. Studies in AD mouse models have linked HHCY with memory impairment, amyloidosis, tau pathology, synaptic dysfunction, and neuroinflammation. However, the exact mechanism by which HHCY affects AD pathogenesis is unclear. The 5-lipoxygenase (5LO) is a protein upregulated in postmortem AD brains and plays a functional role in AD pathogenesis. Recently, in vitro and in vivo studies showed that HHCY effects on amyloid- and tau pathology, synapse and memory impairments are dependent on the activation of the 5LO enzymatic pathway, since its genetic absence or pharmacological inhibition prevents them. HHCY induces 5LO gene upregulation by lowering the methylation of its promoter, which results in increased translation and transcription of its mRNA. Based on these findings, we propose that epigenetic modification of 5LO represents the missing biological link between HHCY and AD pathogenesis, and for this reason it represents a viable therapeutic target to prevent AD development in individuals bearing this risk factor.
Pages 1345-1367
Review
D. Allan Butterfield, Debra Boyd-Kimball
Oxidative Stress, Amyloid-β Peptide, and Altered Key Molecular Pathways in the Pathogenesis and Progression of Alzheimer’s Disease
Abstract: Oxidative stress is implicated in the pathogenesis and progression of Alzheimer’s disease (AD) and its earlier stage, amnestic mild cognitive impairment (aMCI). One source of oxidative stress in AD and aMCI brains is that associated with amyloid-β peptide, Aβ1-42 oligomers. Our laboratory first showed in AD elevated oxidative stress occurred in brain regions rich in Aβ1-42, but not in Aβ1-42-poor regions, and was among the first to demonstrate Aβ peptides led to lipid peroxidation (indexed by HNE) in AD and aMCI brains. Oxidatively modified proteins have decreased function and contribute to damaged key biochemical and metabolic pathways in which these proteins normally play a role. Identification of oxidatively modified brain proteins by the methods of redox proteomics was pioneered in the Butterfield laboratory. Four recurring altered pathways secondary to oxidative damage in brain from persons with AD, aMCI, or Down syndrome with AD are interrelated and contribute to neuronal death. This “Quadrilateral of Neuronal Death” includes altered: glucose metabolism, mTOR activation, proteostasis network, and protein phosphorylation. Some of these pathways are altered even in brains of persons with preclinical AD. We opine that targeting these pathways pharmacologically and with lifestyle changes potentially may provide strategies to slow or perhaps one day, prevent, progression or development of this devastating dementing disorder. This invited review outlines both in vitro and in vivo studies from the Butterfield laboratory related to Aβ1-42 and AD and discusses the importance and implications of some of the major achievements of the Butterfield laboratory in AD research.
Pages 1369-1379
Review
Paul A. Adlard, Ashley I. Bush
Metals and Alzheimer’s Disease: How Far Have We Come in the Clinic?
Abstract: It is estimated that by the year 2050 there will be more than 1.5 billion people globally over the age of 65 years. Aging is associated with changes to a number of different cellular processes which are driven by a variety of factors that contribute to the characteristic decline in function that is seen across multiple physiological domains/tissues in the elderly (including the brain). Importantly, aging is also the primary risk factor for the development of neurodegenerative disorders such as Alzheimer’s disease. As such, there is an urgent need to provide a greater understanding of both the pathogenesis and treatment of these devastating neurodegenerative disorders. One of the key cellular processes that becomes dysregulated with age and participates both directly and indirectly in age-related dysfunction, is metal homeostasis and the neurochemistry of metalloproteins, the basic science of which has been extensively reviewed in the past. In this review, we will focus on the human clinical intervention trials that have been conducted over approximately the last four decades that have attempted to establish the efficacy of targeting metal ions in the treatment of AD.
Pages 1381-1390
Review
Suzanne M. de la Monte, Ming Tong, Jack R. Wands
The 20-Year Voyage Aboard the Journal of Alzheimer’s Disease: Docking at ‘Type 3 Diabetes’, Environmental/Exposure Factors, Pathogenic Mechanisms, and Potential Treatments
Abstract: The Journal of Alzheimer’s Disease (JAD), founded in 1998, played a pivotal role in broadening the field of research on Alzheimer’s disease (AD) by publishing a diverse range of clinical, pathological, molecular, biochemical, epidemiological, experimental, and review articles from its birth. This article recounts my own journey as an author who contributed articles to JAD over the 20 years of the journal’s existence. In retrospect, it seems remarkable that a considerable body of work that originated from our group marks a trail that began with studies of vascular, stress, and mitochondrial factors in AD pathogenesis, exploded into the concept of ‘Type 3 Diabetes’, and continued with the characterization of how environmental, exposure, and lifestyle factors promote neurodegeneration and which therapeutic strategies could reverse the neurodegeneration cascade.
Pages 1391-1401
Review
Paula I. Moreira
Sweet Mitochondria: A Shortcut to Alzheimer’s Disease
Abstract: A growing body of evidence supports a clear association between Alzheimer’s disease and diabetes and several mechanistic links have been revealed. This paper is mainly devoted to the discussion of the role of diabetes-associated mitochondrial defects in the pathogenesis of Alzheimer’s disease. The research experience and views of the author on this subject will be highlighted.
Pages 1403-1416
Review
Russell H. Swerdlow
Mitochondria and Mitochondrial Cascades in Alzheimer’s Disease
Abstract: Decades of research indicate mitochondria from Alzheimer’s disease (AD) patients differ from those of non-AD individuals. Initial studies revealed structural differences, and subsequent studies showed functional deficits. Observations of structure and function changes prompted investigators to consider the consequences, significance, and causes of AD-related mitochondrial dysfunction. Currently, extensive research argues mitochondria may mediate, drive, or contribute to a variety of AD pathologies. The perceived significance of these mitochondrial changes continues to grow, and many currently believe AD mitochondrial dysfunction represents a reasonable therapeutic target. Debate continues over the origin of AD mitochondrial changes. Some argue amyloid-β (Aβ) induces AD mitochondrial dysfunction, a view that does not challenge the amyloid cascade hypothesis and that may in fact help explain that hypothesis. Alternatively, data indicate mitochondrial dysfunction exists independent of Aβ, potentially lies upstream of Aβ deposition, and suggest a primary mitochondrial cascade hypothesis that assumes mitochondrial pathology hierarchically supersedes Aβ pathology. Mitochondria, therefore, appear at least to mediate or possibly even initiate pathologic molecular cascades in AD. This review considers studies and data that inform this area of AD research.
Pages 1417-1441
Review
Anders Wallin*, Gustavo C. Román*, Margaret Esiri, Petronella Kettunen, Johan Svensson, George P. Paraskevas, Elisabeth Kapaki *These authors contributed equally to this work.
Update on Vascular Cognitive Impairment Associated with Subcortical Small-Vessel Disease
Abstract: Subcortical small-vessel disease (SSVD) is a disorder well characterized from the clinical, imaging, and neuropathological viewpoints. SSVD is considered the most prevalent ischemic brain disorder, increasing in frequency with age. Vascular risk factors include hypertension, diabetes, hyperlipidemia, elevated homocysteine, and obstructive sleep apnea. Ischemic white matter lesions are the hallmark of SSVD; other pathological lesions include arteriolosclerosis, dilatation of perivascular spaces, venous collagenosis, cerebral amyloid angiopathy, microbleeds, microinfarcts, lacunes, and large infarcts. The pathogenesis of SSVD is incompletely understood but includes endothelial changes and blood-brain barrier alterations involving metalloproteinases, vascular endothelial growth factors, angiotensin II, mindin/spondin, and the mammalian target of rapamycin pathway. Metabolic and genetic conditions may also play a role but hitherto there are few conclusive studies. Clinical diagnosis of SSVD includes early executive dysfunction manifested by impaired capacity to use complex information, to formulate strategies, and to exercise self-control. In comparison with Alzheimer’s disease (AD), patients with SSVD show less pronounced episodic memory deficits. Brain imaging has advanced substantially the diagnostic tools for SSVD. With the exception of cortical microinfarcts, all other lesions are well visualized with MRI. Diagnostic biomarkers that separate AD from SSVD include reduction of cerebrospinal fluid amyloid-β (Aβ)42 and of the ratio Aβ42/Aβ40 often with increased total tau levels. However, better markers of small-vessel function of intracerebral blood vessels are needed. The treatment of SSVD remains unsatisfactory other than control of vascular risk factors. There is an urgent need of finding targets to slow down and potentially halt the progression of this prevalent, but often unrecognized, disorder.
Pages 1443-1466
Review
Patrick Gavin Kehoe
The Coming of Age of the Angiotensin Hypothesis in Alzheimer's Disease: Progress Toward Disease Prevention and Treatment?
Abstract: There is wide recognition of a complex association between midlife hypertension and cardiovascular disease and later development of Alzheimer's disease (AD) and cognitive impairment. While significant progress has been made in reducing rates of mortality and morbidity due to cardiovascular disease over the last thirty years, progress towards effective treatments for AD has been slower. Despite the known association between hypertension and dementia, research into each disease has largely been undertaken in parallel and independently. Yet over the last decade and a half, the emergence of converging findings from pre-clinical and clinical research has shown how the renin angiotensin system (RAS), which is very important in blood pressure regulation and cardiovascular disease, warrants careful consideration in the pathogenesis of AD. Numerous components of the RAS have now been found to be altered in AD such that the multifunctional and potent vasoconstrictor angiotensin II, and similarly acting angiotensin III, are greatly altered at the expense of other RAS signaling peptides considered to contribute to neuronal and cognitive function. Collectively these changes may contribute to many of the neuropathological hallmarks of AD, as well as observed progressive deficiencies in cognitive function, while also linking elements of a number of the proposed hypotheses for the cause of AD. This review discusses the emergence of the RAS and its likely importance in AD, not only because of the multiple facets of its involvement, but also perhaps fortuitously because of the ready availability of numerous RAS-acting drugs, that could be repurposed as interventions in AD.
Pages 1467-1480
Review
John R. Hodges, Olivier Piguet
Progress and Challenges in Frontotemporal Dementia Research: A 20-Year Review
Abstract: The landscape of frontotemporal dementia (FTD) has evolved remarkably in recent years and is barely recognizable from two decades ago. Knowledge of the clinical phenomenology, cognition, neuroimaging, genetics, pathology of the different subtypes of FTD, and their relations to other neurodegenerative conditions, has increased rapidly, due in part, to the growing interests into these neurodegenerative brain conditions. This article reviews the major advances in the field of FTD over the past 20 years, focusing primarily on the work of Frontier, the frontotemporal dementia clinical research group, based in Sydney, Australia. Topics covered include clinical presentations (cognition, behavior, neuroimaging), pathology, genetics, and disease progression, as well as interventions and carer directed research. This review demonstrates the improvement in diagnostic accuracy and capacity to provide advice on genetic risks, prognosis, and outcome. The next major challenge will be to capitalize on these research findings to develop effective disease modifying drugs, which are currently lacking.
