Journal of Alzheimer's Disease - Volume 64, issue s1

Authors: Perry, George | Avila, Jesús | Moreira, Paula I. | Sorensen, Aaron A. | Tabaton, Massimo

Article Type: Other

DOI: 10.3233/JAD-179945

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S1-S1, 2018

Authors: Cummings, Jeffrey | Ritter, Aaron | Zhong, Kate

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) has no currently approved disease-modifying therapies (DMTs), and treatments to prevent, delay the onset, or slow the progression are urgently needed. A delay of 5 years if available by 2025 would decrease the total number of patients with AD by 50% in 2050. To meet the definition of DMT, an agent must produce an enduring change in the course of AD; clinical trials of DMTs have the goal of demonstrating this effect. AD drug discovery entails target identification followed by high throughput screening and lead optimization of drug-like compounds. Once an optimized agent is available and has …been assessed for efficacy and toxicity in animals, it progresses through Phase I testing with healthy volunteers, Phase II learning trials to establish proof-of-mechanism and dose, and Phase III confirmatory trials to demonstrate efficacy and safety in larger populations. Phase III is followed by Food and Drug Administration review and, if appropriate, market access. Trial populations include cognitively normal at-risk participants in prevention trials, mildly impaired participants with biomarker evidence of AD in prodromal AD trials, and subjects with cognitive and functional impairment in AD dementia trials. Biomarkers are critical in trials of DMTs, assisting in participant characterization and diagnosis, target engagement and proof-of-pharmacology, demonstration of disease-modification, and monitoring side effects. Clinical trial designs include randomized, parallel group; delayed start; staggered withdrawal; and adaptive. Lessons learned from completed trials inform future trials and increase the likelihood of success. Show more

Keywords: Alzheimer’s disease, biomarkers, clinical trials, disease modifying therapies, proof-of-concept, target engagement

DOI: 10.3233/JAD-179901

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S3-S22, 2018

Authors: Gauthier, Serge | Ng, Kok Pin | Pascoal, Tharick A. | Zhang, Hua | Rosa-Neto, Pedro

Article Type: Review Article

Abstract: Cautious optimism is appropriate for a near future (five years) time frame for a number of drugs acting on the different pathophysiological components of Alzheimer’s disease (amyloid deposition, tau hyperphosphorylation, neuroinflammation, vascular changes, to name the most important known so far). Since the relative weight of these components will be different between individuals and will even change over time for each individual, a ‘one drug fit for all’ approach is no longer defensible. Precision medicine using biomarkers in the diagnosis and treatment of Alzheimer’s disease is the new strategy.

Keywords: Alzheimer’s disease, biomarkers, brain imaging, database analysis, diagnosis, human volunteer cohorts, precision medicine, translational research, treatment

DOI: 10.3233/JAD-179924

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S23-S31, 2018

Authors: Quinn, Joseph F.

Article Type: Review Article

Abstract: Efforts over the past two decades to develop effective disease-modifying treatments for Alzheimer’s disease have been disappointing, while parallel efforts in another chronic neurologic disease, multiple sclerosis, have been remarkably productive. In an effort to advance development of therapeutics for Alzheimer’s disease, these two fields are contrasted in terms of the utility of animal models, definition of study populations, and utility of biomarkers. Possible solutions are suggested, and the review concludes with description of some active peer-reviewed, publicly funded clinical studies which address some of the identified weaknesses in past clinical trials for age-related dementia.

Keywords: Alzheimer’s disease, animal models, clinical trials

DOI: 10.3233/JAD-179930

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S33-S39, 2018

Authors: Wimo, Anders

Article Type: Research Article

Abstract: Although there have been so many failures in Alzheimer’s disease (AD) modifying trials, there are still many compounds in the pipeline and the hope still remains that the entrance of disease-modifying treatment (DMT) for AD will positively and dramatically change the whole situation of AD treatment. However, if DMT does enter the market, it will be the beginning of a great number of challenges and problems. The current infrastructure for diagnostics of early (pre-dementia) AD does not have the capacity to meet the demands and expectations of the population. Neither is there capacity for treatment monitoring and follow-ups. If screening …is considered, there will be a great risk for false positive cases and a great number of people who will have to undergo diagnostics. There will be high costs for diagnostics and treatment initially, while potential benefits will occur much later in other sectors than where the payers for treatment are. Although there are great hopes that prevention of cardiovascular risk factors and changes in lifestyle might impact the risk for dementia, there is still no consensus that this is the case. Finally, the relevance of different AD paradigms such as amyloid and tau is still a matter of discussion, particularly regarding the oldest old. Show more

Keywords: Alzheimer’s disease, costs, diagnosis, disease modifying treatment, economic simulation, predictive values, prevention, reimbursement

DOI: 10.3233/JAD-179905

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S41-S46, 2018

Authors: Hampel, Harald | Toschi, Nicola | Babiloni, Claudio | Baldacci, Filippo | Black, Keith L. | Bokde, Arun L.W. | Bun, René S. | Cacciola, Francesco | Cavedo, Enrica | Chiesa, Patrizia A. | Colliot, Olivier | Coman, Cristina-Maria | Dubois, Bruno | Duggento, Andrea | Durrleman, Stanley | Ferretti, Maria-Teresa | George, Nathalie | Genthon, Remy | Habert, Marie-Odile | Herholz, Karl | Koronyo, Yosef | Koronyo-Hamaoui, Maya | Lamari, Foudil | Langevin, Todd | Lehéricy, Stéphane | Lorenceau, Jean | Neri, Christian | Nisticò, Robert | Nyasse-Messene, Francis | Ritchie, Craig | Rossi, Simone | Santarnecchi, Emiliano | Sporns, Olaf | Verdooner, Steven R. | Vergallo, Andrea | Villain, Nicolas | Younesi, Erfan | Garaci, Francesco | Lista, Simone

Article Type: Research Article

Abstract: The Precision Neurology development process implements systems theory with system biology and neurophysiology in a parallel, bidirectional research path : a combined hypothesis-driven investigation of systems dysfunction within distinct molecular, cellular, and large-scale neural network systems in both animal models as well as through tests for the usefulness of these candidate dynamic systems biomarkers in different diseases and subgroups at different stages of pathophysiological progression. This translational research path is paralleled by an “omics”-based, hypothesis-free, exploratory research pathway, which will collect multimodal data from progressing asymptomatic, preclinical, and clinical neurodegenerative disease (ND) populations, within the wide continuous biological and clinical …spectrum of ND, applying high-throughput and high-content technologies combined with powerful computational and statistical modeling tools, aimed at identifying novel dysfunctional systems and predictive marker signatures associated with ND. The goals are to identify common biological denominators or differentiating classifiers across the continuum of ND during detectable stages of pathophysiological progression, characterize systems-based intermediate endophenotypes, validate multi-modal novel diagnostic systems biomarkers, and advance clinical intervention trial designs by utilizing systems-based intermediate endophenotypes and candidate surrogate markers. Achieving these goals is key to the ultimate development of early and effective individualized treatment of ND, such as Alzheimer’s disease. The Alzheimer Precision Medicine Initiative (APMI) and cohort program (APMI-CP), as well as the Paris based core of the Sorbonne University Clinical Research Group “Alzheimer Precision Medicine” (GRC-APM) were recently launched to facilitate the passageway from conventional clinical diagnostic and drug development toward breakthrough innovation based on the investigation of the comprehensive biological nature of aging individuals. The APMI movement is gaining momentum to systematically apply both systems neurophysiology and systems biology in exploratory translational neuroscience research on ND. Show more

Keywords: Alzheimer’s disease, biomarkers, integrative disease modeling, pathophysiology, precision medicine, precision neurology, systems biology, systems neurophysiology, systems pharmacology, systems theory

DOI: 10.3233/JAD-179932

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S47-S105, 2018

Authors: Gong, Cheng-Xin | Liu, Fei | Iqbal, Khalid

Article Type: Research Article

Abstract: The amyloid cascade hypothesis has been dominating drug discovery for Alzheimer’s disease (AD) for the last two decades. The failure of the development of effective drugs for slowing down or reversing the progression of AD warrants the AD field to consider out-of-the-box thinking and therapeutic approaches. We propose the multifactorial hypothesis of AD, emphasizing that AD is caused by multiple etiological factors, which may result in common brain pathology and functional consequences through several separate but integrated molecular pathways. More than one etiological factor and mechanistic pathway may be involved in a single individual with sporadic AD, and different individuals …may have different etiological factors, involving different mechanisms/pathways. We urge the recognition of the multifactorial nature of AD and the paradigm shift of AD drug development from a single target to multiple targets, either with the multitarget-directed ligands approach or the cocktail therapy approach. We believe that patient stratification and the use of the precision medicine model will also benefit AD drug discovery. Show more

Keywords: Alzheimer’s disease, cocktail therapy, multifactorial hypothesis, multitarget-directed ligands, patient stratification, precision medicine model

DOI: 10.3233/JAD-179921

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S107-S117, 2018

Authors: Hunter, Sally | Smailagic, Nadja | Brayne, Carol

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is a clinicopathologically defined syndrome leading to cognitive impairment. Following the recent failures of amyloid-based randomized controlled trials to change the course of AD, there are growing calls for a re-evaluation of basic AD research. Epidemiology offers one approach to integrating the available evidence. Here we examine relationships between evidence from population-based, clinicopathological studies of brain aging and a range of hypotheses from all areas of AD research. We identify various problems, including a lack of systematic approach to measurement of clinical and neuropathological factors associated with dementia in experimental and clinical settings, poor understanding of the …strengths and weaknesses of different observational and experimental designs, a lack of clarity in relation to disease definitions from the clinical, neuropathological, and molecular perspectives, inadequate characterization of brain aging in the human population, difficulties in translation between laboratory-based and population-based evidence bases, and a lack of communication between different sections of the dementia research community. Population studies highlight complexity and predict that therapeutic approaches based on single disease features will not be successful. Better characterization of brain aging in the human population is urgently required to select biomarkers and therapeutic targets that are meaningful to human disease. The generation of detailed and reliable evidence must be addressed before progress toward therapeutic interventions can be made. Show more

Keywords: Age, Alzheimer’s disease, amyloid-β protein, amyloid-β protein precursor, experimental design, population study, risk factors

DOI: 10.3233/JAD-179927

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S119-S143, 2018

Authors: Wolters, Frank J. | Adams, Hieab H.H. | Bos, Daniel | Licher, Silvan | Ikram, M. Arfan

Article Type: Review Article

Abstract: The most commonly encountered opening sentence in scientific publications about dementia undoubtedly relates to the overwhelming burden of disease. Finding an effective preventive or therapeutic intervention against dementia has been considered the most important unmet need in contemporary medicine. While efforts on tackling this devastating disease have increased exponentially, it is difficult to imagine that in the 1980s and early-1990s, the disease did not feature prominently on any public health report. Yet, it was already then that epidemiologists recognized the growing societal burden of dementia and rationalized that dementia is not necessarily part of aging. Indeed, the conviction that dementia …is pathologically distinct from aging led to various efforts in search of unravelling its risk factors and understanding its pre-clinical phase. Among the early pioneers, the population-based Rotterdam Study was initiated in 1990 clearly aiming on chronic diseases including dementia, and among this Alzheimer’s disease, as one of its focus points. Ever since, the Rotterdam Study has been an important cornerstone in increasing our knowledge about dementia from an epidemiological perspective. Here, we summarize the main findings originating from this study, and put these into perspective with previous and current work in the field. With an expanding scope of the Rotterdam Study over the years, we discuss findings on occurrence, modifiable risk factors, imaging, and its genetic underpinnings. Importantly, we conclude with recommendations— or, perhaps better stated, a wish list— for future research which may help us reach our finish line: finding an effective preventive or therapeutic intervention against dementia. Show more

Keywords: Alzheimer’s disease, cohort studies, dementia, epidemiologic methods, epidemiology, neurodegenerative diseases

DOI: 10.3233/JAD-179938

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S145-S159, 2018

Authors: Bennett, David A. | Buchman, Aron S. | Boyle, Patricia A. | Barnes, Lisa L. | Wilson, Robert S. | Schneider, Julie A.

Article Type: Review Article

Abstract: Background: The Religious Orders Study and Rush Memory and Aging Project are both ongoing longitudinal clinical-pathologic cohort studies of aging and Alzheimer’s disease (AD). Objectives: To summarize progress over the past five years and its implications for understanding neurodegenerative diseases. Methods: Participants in both studies are older adults who enroll without dementia and agree to detailed longitudinal clinical evaluations and organ donation. The last review summarized findings through the end of 2011. Here we summarize progress and study findings over the past five years and discuss new directions for how these studies can inform on aging …and AD in the future. Results: We summarize 1) findings on the relation of neurobiology to clinical AD; 2) neurobiologic pathways linking risk factors to clinical AD; 3) non-cognitive AD phenotypes including motor function and decision making; 4) the development of a novel drug discovery platform. Conclusion: Complexity at multiple levels needs to be understood and overcome to develop effective treatments and preventions for cognitive decline and AD dementia. Show more

Keywords: Alzheimer’s disease, cognitive decline, decision making, dementia, drug discovery, epidemiology, motor function, neuropathology, omics

DOI: 10.3233/JAD-179939

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S161-S189, 2018

Authors: Kulmala, Jenni | Ngandu, Tiia | Kivipelto, Miia

Article Type: Research Article

Abstract: During the last few years, dementia prevention based on modifiable lifestyle factors has gained increasing attention. Cohort studies with follow-ups extending up to decades have identified several risk and protective factors, and very recently new randomized controlled trials with multidomain approach have provided promising evidence by showing that modifying simultaneously several risk factors, it is possible to maintain and improve cognitive capacity among older at-risk persons. Several lifestyle-based multidomain trials are under preparation or ongoing and to facilitate international collaboration and effective worldwide dementia prevention, the World Wide FINGERS interdisciplinary network (http://wwfingers.com ) was recently initiated. Additionally, several new implementation …projects are taking the first steps from trial setting to real-life implementation of a dementia prevention program. This paper highlights the recent perspectives from the field of Alzheimer’s disease and reflects the implications and importance of current achievements. Finally, predictions for the future work especially in terms of global collaboration and implementation will be discussed. Show more

Keywords: Dementia, implementation, intervention, prevention, risk reduction

DOI: 10.3233/JAD-179919

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S191-S198, 2018

Authors: Chételat, Gaël

Article Type: Review Article

Abstract: Over the last ten years, we have conducted research in Alzheimer’s disease (AD) using multimodal neuroimaging techniques to improve diagnosis, further our understanding of the pathological mechanisms underlying the disease, and support the development of innovative non-pharmacological preventive strategies. Our works emphasized the interest of hippocampal subfield volumetry in early diagnosis and the need for further development in this field including optimization, standardization, and automatization of the techniques. Also, we conducted several studies in cognitively intact at-risk elderly (e.g., subjective cognitive decline patients and APOE4 carriers) to better identify biomarkers associated with increased risk of developing AD. Regarding the physiopathological …mechanisms, specific multimodal neuroimaging techniques allowed us to highlight the relevance of diaschisis, the mismatch between neurodegeneration and local Aβ deposition and the regional variation in the mechanisms underlying structural or functional alterations. Further works integrating other biomarkers known to play a role in the physiopathology of AD (tau, TDP-43, inflammation, etc.) in a longitudinal design would be useful to get a comprehensive understanding of their relative role, sequence, and causal relationships. Our works also highlighted the relevance of functional connectivity in further understanding the specificity of cognitive deficits in AD and how connectivity differentially influences the propagation of the different AD biomarkers. Finally, we conducted several studies on the links between lifestyle factors and neuroimaging biomarkers to unravel mechanisms of reserve. Further efforts are needed to better understand which lifestyle factor, or combination of factors, impact on AD pathology, and when, to help translating our knowledge to training programs that might prevent or delay brain and cognitive changes leading to AD dementia. Show more

Keywords: Aging, Alzheimer’s disease, diagnosis, disconnection, FDG-PET, lifestyle, meditation, multimodal neuroimaging, prevention, structural MRI

DOI: 10.3233/JAD-179920

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S199-S211, 2018

Authors: Vos, Stephanie J.B. | Visser, Pieter Jelle

Article Type: Review Article

Abstract: Increasing interest in clinical trials and clinical research settings to identify Alzheimer’s disease (AD) in the earliest stages of the disease has led to the concept of preclinical AD. Individuals with preclinical AD have AD pathology without clinical symptoms yet. Accumulating evidence has shown that biomarkers can identify preclinical AD and that preclinical AD is associated with a poor clinical outcome. Little is known yet about the role of vascular and lifestyle risk factors in the development of preclinical AD. In order to better understand preclinical AD pathology and clinical progression rates, there is a need to refine the concept …of preclinical AD. This will be of great value for advancements in future research, clinical trials, and eventually clinical practice. Show more

Keywords: Amyloid, biomarkers, clinical trials, cognition, diagnosis, lifestyle, neuronal injury, preclinical Alzheimer’s disease, prognosis, vascular risk

DOI: 10.3233/JAD-179943

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S213-S227, 2018

Authors: Solfrizzi, Vincenzo | Agosti, Pasquale | Lozupone, Madia | Custodero, Carlo | Schilardi, Andrea | Valiani, Vincenzo | Sardone, Rodolfo | Dibello, Vittorio | Di Lena, Luca | Lamanna, Angela | Stallone, Roberta | Bellomo, Antonello | Greco, Antonio | Daniele, Antonio | Seripa, Davide | Sabbà, Carlo | Logroscino, Giancarlo | Panza, Francesco

Article Type: Research Article

Abstract: The link diet-cognitive function/dementia has been largely investigated in observational studies; however, there was a lack of evidence from randomized clinical trials (RCTs) on the prevention of late-life cognitive disorders though dietary intervention in cognitively healthy older adults. In the present article, we systematically reviewed RCTs published in the last four years (2014–2017) exploring nutritional intervention efficacy in preventing the onset of late-life cognitive disorders and dementia in cognitively healthy subjects aged 60 years and older using different levels of investigation (i.e., dietary pattern changes/medical food/nutraceutical supplementation/multidomain approach and dietary macro- and micronutrient approaches) as well as possible underlying mechanisms …of nutritional prevention. From the 35 included RCTs, there was moderate evidence that intervention through dietary pattern changes, medical food/nutraceutical supplementation, and multidomain approach improved specific cognitive domains or cognitive-related blood biomarkers. There was high evidence that protein supplementation improved specific cognitive domains or functional status in prefrail older adults without effect Show more

Keywords: Alzheimer’s disease, dementia, dietary pattern, healthy diet, macronutrients, medical food, Mediterranean diet, micronutrients, mild cognitive impairment, nutraceuticals, prevention

DOI: 10.3233/JAD-179940

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S229-S254, 2018

Authors: Andrade, Andreia G. | Bubu, Omonigho M. | Varga, Andrew W. | Osorio, Ricardo S.

Article Type: Review Article

Abstract: Obstructive sleep apnea (OSA) and Alzheimer’s disease (AD) are highly prevalent conditions with growing impact on our aging society. While the causes of OSA are now better characterized, the mechanisms underlying AD are still largely unknown, challenging the development of effective treatments. Cognitive impairment, especially affecting attention and executive functions, is a recognized clinical consequence of OSA. A deeper contribution of OSA to AD pathogenesis is now gaining support from several lines of research. OSA is intrinsically associated with disruptions of sleep architecture, intermittent hypoxia and oxidative stress, intrathoracic and hemodynamic changes as well as cardiovascular comorbidities. All of these …could increase the risk for AD, rendering OSA as a potential modifiable target for AD prevention. Evidence supporting the relevance of each of these mechanisms for AD risk, as well as a possible effect of AD in OSA expression, will be explored in this review. Show more

Keywords: AD risk, Alzheimer’s disease, amyloid, obstructive sleep apnea, OSA phenotypes

DOI: 10.3233/JAD-179936

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S255-S270, 2018

Authors: Zetterberg, Henrik | Blennow, Kaj

Article Type: Review Article

Abstract: The past five years have seen an enormous development in the field of fluid biomarkers for Alzheimer’s disease (AD) and related disorders. The proteins that constitute the foundation for the cerebrospinal fluid (CSF) tests for the classical AD pathologies are now being explored as potential blood-based biomarkers, thanks to the recent implementation of ultrasensitive measurement technologies in academic and clinical laboratories worldwide. The current blood-derived data are still less clear than those obtained using CSF as the sample type, but independent research suggests that there are biomarker signals in blood that relate to plaque and tangle pathologies in AD, which …are relevant to explore further. Additionally, neurofilament light has emerged as the first robust blood-based biomarker for neurodegeneration in a broad range of central nervous system disorders, as well as for acute brain injuries. Here, we briefly recapitulate the first and second waves of fluid biomarker analysis in AD, i.e., the development and validation of established and novel CSF biomarkers for the disorder, followed by a focused discussion on blood-based biomarkers for AD, which we describe as the third wave of fluid biomarker analysis that hopefully will gain further momentum during the coming five years. Show more

Keywords: Alzheimer’s disease, amyloid, biomarkers, cerebrospinal fluid, plasma, serum, tau

DOI: 10.3233/JAD-179926

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S271-S279, 2018

Authors: Parnetti, Lucilla | Eusebi, Paolo

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the most common neurodegenerative disorder, affecting around 35 million people worldwide. Cerebrospinal fluid (CSF) biomarkers entered the diagnostic criteria as support for early diagnosis. The classical biochemical signature of AD includes total tau (T-tau), phosphorylated tau (P-tau), and the 42 amino acid peptide (Aβ42 ) of amyloid-β. Recent observations suggest that the use of CSF Aβ42 :Aβ40 ratio rather than CSF Aβ42 alone could contribute to reduce inter-laboratory variation in Aβ values and increasing diagnostic performance of the CSF AD biomarkers in routine practice. However, research efforts aimed at enriching the CSF biomarker panel …are ongoing. The CSF AD signature is also crucial for the design of clinical trials for AD, since it best guarantees AD pathology as the cause of cognitive impairment. Accordingly, CSF biomarkers have been now reported in the inclusion criteria of Phase I, Phase II, and Phase III clinical trials as enrichment strategy. So far, one of the most important reasons for the failure of AD clinical trials was the inclusion of participants with unlikely AD pathology. In order to implement the use of CSF biomarkers in AD routine diagnostic work-up and as accepted strategy for enriching trial populations, inter-laboratory variability should be minimized. Increasing efforts should also be devoted to promote data sharing practices, encouraging individual participant data meta-analyses. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, early diagnosis, tau

DOI: 10.3233/JAD-179910

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S281-S287, 2018

Authors: Kiddle, Steven J. | Voyle, Nicola | Dobson, Richard J.B.

Article Type: Review Article

Abstract: Ever since the discovery of APOE ɛ 4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimer’s disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have …seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed. Show more

Keywords: Alzheimer’s disease, blood proteins, blood tests, cohort studies, data reporting, genetics, gene expression, metabolomics, research design

DOI: 10.3233/JAD-179904

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S289-S297, 2018

Authors: Drummond, Eleanor | Goñi, Fernando | Liu, Shan | Prelli, Frances | Scholtzova, Henrieta | Wisniewski, Thomas

Article Type: Review Article

Abstract: There is growing genetic and proteomic data highlighting the complexity of Alzheimer’s disease (AD) pathogenesis. Greater use of unbiased “omics” approaches is being increasingly recognized as essential for the future development of effective AD research, that need to better reflect the multiple distinct pathway abnormalities that can drive AD pathology. The track record of success in AD clinical trials thus far has been very poor. In part, this high failure rate has been related to the premature translation of highly successful results in animal models that mirror only limited aspects of AD pathology to humans. We highlight our recent efforts …to increase use of human tissue to gain a better understanding of the AD pathogenesis subtype variety and to develop several distinct therapeutic approaches tailored to address this diversity. These therapeutic approaches include the blocking of the Aβ/apoE interaction, stimulation of innate immunity, and the simultaneous blocking of Aβ/tau oligomer toxicity. We believe that future successful therapeutic approaches will need to be combined to better reflect the complexity of the abnormal pathways triggered in AD pathogenesis. Show more

Keywords: Apolipoprotein E, chronic traumatic encephalopathy, immunomodulation, innate immunity, oligomer, prion, Toll-like receptor 9, unbiased proteomics

DOI: 10.3233/JAD-179909

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S299-S312, 2018

Authors: Selles, M. Clara | Oliveira, Mauricio M. | Ferreira, Sergio T.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, …eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver’s health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets. Show more

Keywords: Alzheimer, depression, amyloid- β, inflammation, microglia, TNF-α

DOI: 10.3233/JAD-179925

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S313-S327, 2018

Authors: Gutierrez, Antonia | Vitorica, Javier

Article Type: Research Article

Abstract: The continuing failure to develop an effective treatment for Alzheimer’s disease urges a better understanding of the pathogenic mechanisms and the improvement of current animal models to facilitate success for clinical interventions. The transgenic models have been so far designed to recapitulate one, or both, protein lesions found in the brain of patients, the extracellular amyloid plaques and the intraneuronal neurofibrillary tangles. However, in recent years, a third pathogenic component is gaining strength in the onset and progression of this disease, the neuroinflammatory response mediated primarily by the brain’s resident immune cells, microglia. This has been highlighted by the identification …of genes involved in innate immunity as risk factors to develop this neurodegenerative disease. Our current concept, mostly derived from amyloid-β producing models which show a robust microglial activation, supports an initial beneficial role of these glial cells followed by a pro-inflammatory cytotoxic function later on. This view is now challenged by emerging data in human postmortem samples. We have recently demonstrated that in the hippocampus of Braak V-VI individuals there is a prominent degenerative process of the microglial population, driven by phospho-tau, that might compromise neuronal homeostasis. This scenario of microglial dysfunction/degeneration should be taken into account for developing more reliable animal models of this disease and improve their predictive value for human drug efficacy testing. Finally, correcting dysregulated brain inflammatory responses might be a promising avenue to restore cognitive function. Show more

Keywords: Alzheimer’s disease, degeneration, inflammatory, innate immunity, microglia, transgenic models

DOI: 10.3233/JAD-179914

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S329-S338, 2018

Authors: Edison, Paul | Brooks, David J.

Article Type: Review Article

Abstract: Recent evidence suggests that neuroinflammation and immunity play a significant role in Alzheimer’s disease and other neurodegenerative diseases. It has also been observed that, independent of the presence of aggregated proteins, neuroinflammation could be present in different neurodegenerative diseases. It has also been suggested that neuroinflammation could occur well ahead of amyloid deposition in AD. Recent genetic studies and other preclinical studies specifically point to a role of neuroinflammation and, in this review, we evaluate the evidence of neuroinflammation in the Alzheimer’s disease trajectory and the different imaging modalities by which we could monitor neuroinflammation in vivo in humans.

Keywords: Alzheimer’s disease, astrocytes, microglia, neurodegeneration, neuroinflammation

DOI: 10.3233/JAD-179929

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S339-S351, 2018

Authors: Sahara, Naruhiko | Maeda, Jun | Ishikawa, Ai | Tokunaga, Masaki | Suhara, Tetsuya | Higuchi, Makoto

Article Type: Research Article

Abstract: Tauopathy is characterized by the fibrillar tau accumulation in neurons and glial cells. In order to advance our understanding of the causative mechanisms of tauopathy, neuroinflammation, which has been suggested to play important roles in disease progression, will require particular attention. Neuroinflammation is characterized predominantly by microglial activation. At present, it is still under debate whether microglial activation is a cause or a result of neurodegeneration. To search for a temporal relationship between neurodegeneration and neuroinflammation, our group demonstrated that in vivo imaging (e.g., tau-PET, TSPO-PET, and volumetric MRI) of tauopathy mice strongly supports the evidence of microglial activation …along with both pathological tau accumulation and brain atrophy. Both in vivo imaging and histochemical analysis confirmed that microglial TSPO accumulation was the late event during the pathogenesis of tauopathy. On the other hand, it is known that purinergic receptor P2Y12 as a marker of homeostatic microglia cells was reduced at an early stage of disease progression. In this review, we will introduce a phenotypic change of microglia in a mouse model of tauopathy and propose novel approaches to the establishment of imaging biomarkers, thereby targeting the early diagnosis of tauopathy. Show more

Keywords: Microglia, neuroinflammation, P2Y12 receptor, PET imaging, tauopathy, TSPO

DOI: 10.3233/JAD-179933

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S353-S359, 2018

Authors: McGeer, Patrick L. | McGeer, Edith

Article Type: Research Article

Abstract: The means are now at hand to conquer Alzheimer’s disease (AD). The method is to identify those at risk for the disease before clinical signs develop. That is followed by implementing measures that can effectively prevent disease development. Since biotechnology markers have shown that AD commences at least a decade before cognitive deficits set in, there is an extended window of opportunity to successfully prevent disease development. Methods of identifying those at risk include positron electron microscopy for AD senile plaques, blood or saliva analysis for elevation of the amyloid-β protein fragment terminating at position 42, and cerebrospinal fluid analysis …showing a decrease in content of this protein. Of the modalities available, saliva is by far the simplest and least invasive. Once identified, those at risk can prevent disease development through self treatment by consumption of non-steroidal anti-inflammatory drugs, adhering to a Mediterranean diet, and consuming antioxidants such as quercitin which is contained in coffee. Show more

Keywords: Aβ42 , coffee, Mediterranean diet, non-steroidal anti-inflammatory drugs, saliva

DOI: 10.3233/JAD-179913

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S361-S363, 2018

Authors: Martini, Alessandra C. | Forner, Stefania | Trujillo-Estrada, Laura | Baglietto-Vargas, David | LaFerla, Frank M.

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets. Here we highlight significant studies from our laboratory that have helped advance the AD field by elucidating key pathogenic processes operative in AD and exploring a variety of aspects of the disease which may yield novel therapeutic strategies for combatting this burdensome disease.

Keywords: 3xTg-AD, amyloid-β, animal models, comorbidities, inflammation, stem cell therapy, synaptic loss, tau

DOI: 10.3233/JAD-179917

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S365-S378, 2018

Authors: Lane, Darius J.R. | Ayton, Scott | Bush, Ashley I.

Article Type: Review Article

Abstract: Iron is a crucial transition metal for life and is the most abundant transition metal in the brain. However, iron’s biological utility as an effective redox cycling metal also endows it with the potential to catalyze production of noxious free radicals. This “Janus-faced” nature of iron demands a tight regulation of cellular its metabolism. This regulation is crucial in the CNS, where iron plays myriad keystone roles in CNS processes, including mitochondrial energy transduction, enzyme catalysis, mitochondrial function, myelination, neurotransmitter anabolism and catabolism. Aberrations in brain iron homeostasis can elevate levels of this redox-active metal, leading to mislocalization of the …metal and catastrophic oxidative damage to sensitive cellular and subcellular structures. Iron dyshomeostasis has been strongly linked to the pathogenesis of Alzheimer’s disease (AD), as well as other major neurodegenerative diseases. Despite the growing societal burden of AD, no disease-modifying therapy exists, necessitating continued investment into both drug-development and the fundamental science investigating the disease-causing mechanisms. Targeting iron dyshomeostasis in the brain represents a rational approach to treat the underlying disease. Here we provide an update on known and emerging iron-associated mechanisms involved in AD. We conclude with an overview of evidence suggesting that, in addition to apoptosis, neuronal loss in AD involves “ferroptosis”, a newly discovered iron- and lipid-peroxidation-dependent form of regulated necrosis. The ferroptosis field is rapidly progressing and may provide key insights for future drug-development with disease-modifying potential in AD. Show more

Keywords: Alzheimer’s disease, amyloid-β, amyloid-β protein precursor, apoptosis, astrocytes, ferroptosis, iron, lipid peroxidation, oxidative stress, neuroinflammation

DOI: 10.3233/JAD-179944

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S379-S395, 2018

Authors: Mecocci, Patrizia | Baroni, Marta | Senin, Umberto | Boccardi, Virginia

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) represents the most common form of dementia in old age subjects, and despite decades of studies, the underlying etiopathogenetic mechanisms remain unsolved. The definition of AD has changed over the past years, offering an ever more detailed definition of pre-morbid and pre-clinical status, but without a similar strong emphasis on the role of aging as the main risk factor. In fact, while early-onset AD is a clear consequence of gene mutations, late-onset AD is more likely due to a gradual accumulation of age-related damages. The pathogenetic amyloid cascade hypothesis has been recently questioned due to multiple clinical …failures. Furthermore, several studies reported that cognitively normal elderly have a high amyloid deposition in the brain comparable to the levels observed in old age subjects with AD. This suggests that amyloid accumulation enters into the normal process of aging and what really triggers neuronal death and clinical manifestation in late-onset AD still needs further explanation. In this context, ‘normal brain aging’ and AD might represent a different pathway of successful or failed capability to adapt brain structures and cerebral functions. Cellular senescence and age-related changes affecting the brain may be considered as biologic manifestations of increasing entropy. Bioenergetic deficits due to mitochondrial dysfunction may lead to progressive neuronal death and clinical expression of dementia. So, increased amyloid in the brain of old age subjects may represent the downstream event expression of a biological system that is cooling down because of its exhaustion and not the core causative factor of late-onset dementia. Show more

Keywords: Aging, Alzheimer’s disease, amyloid, energy, entropy, mitochondria, old age

DOI: 10.3233/JAD-179903

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S397-S404, 2018

Authors: Clarke, Julia R. | Ribeiro, Felipe C. | Frozza, Rudimar L. | De Felice, Fernanda G. | Lourenco, Mychael V.

Article Type: Review Article

Abstract: Clinical trials have extensively failed to find effective treatments for Alzheimer’s disease (AD) so far. Even after decades of AD research, there are still limited options for treating dementia. Mounting evidence has indicated that AD patients develop central and peripheral metabolic dysfunction, and the underpinnings of such events have recently begun to emerge. Basic and preclinical studies have unveiled key pathophysiological mechanisms that include aberrant brain stress signaling, inflammation, and impaired insulin sensitivity. These findings are in accordance with clinical and neuropathological data suggesting that AD patients undergo central and peripheral metabolic deregulation. Here, we review recent basic and clinical …findings indicating that metabolic defects are central to AD pathophysiology. We further propose a view for future therapeutics that incorporates metabolic defects as a core feature of AD pathogenesis. This approach could improve disease understanding and therapy development through drug repurposing and/or identification of novel metabolic targets. Show more

Keywords: Alzheimer’s disease, hormones, memory, metabolism, therapy

DOI: 10.3233/JAD-179911

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S405-S426, 2018

Authors: Lee, Jung Hyun | Jahrling, Jordan B. | Denner, Larry | Dineley, Kelly T.

Article Type: Review Article

Abstract: Insulin resistance can occur when the body is unable to respond to insulin even in excess. In the brain, insulin manages glucose metabolism in regions such as the hippocampus and plays a key role in directly regulating ERK, a kinase required for the type of memory compromised in early Alzheimer’s disease (AD). Human imaging studies show that brain glucose utilization declines with age and is notably impaired in subjects with early AD. Likewise, animal models of AD or insulin resistance, or both, demonstrate that dysfunctional insulin signaling and insulin resistance in the brain have reciprocity with neuroinflammation and aberrant accumulation …of amyloid-β (Aβ), pathological hallmarks in AD. As such, the association between brain insulin activity and AD has led to clinical trials testing the efficacy of insulin and insulin-sensitizing drugs to intervene in AD. Based on recent inquiries to ClinicalTrials.gov, we evaluated thirty-three clinical studies related to AD and insulin. The search filtered for interventional clinical trials to test FDA-approved drugs or substances that impinge upon the insulin signaling pathway. Insulin, metformin, and thiazolidinediones were the three main interventions assessed. Overall, these strategies are expected to negate the effects of brain insulin resistance by targeting insulin signaling pathways involved in neuroinflammation, metabolic homeostasis, synaptic functional and structural integrity. The goal of this review is to provide an update on insulin and ERK signaling in relation to memory, its decline in early AD, and provide an overview of clinical trials related to insulin for early AD intervention. Show more

Keywords: Alzheimer’s disease, animal model, clinical trials, ERK, insulin resistance, learning and memory, metabolism, mitochondria, PPARγ

DOI: 10.3233/JAD-179923

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S427-S453, 2018

Authors: Stockburger, Carola | Eckert, Schamim | Eckert, Gunter P. | Friedland, Kristina | Müller, Walter E.

Article Type: Review Article

Abstract: Because of the failure of all amyloid-β directed treatment strategies for Alzheimer’s disease (AD), the concept of mitochondrial dysfunction as a major pathomechanism of the cognitive decline in aging and AD has received substantial support. Accordingly, improving mitochondrial function as an alternative strategy for new drug development became of increasing interest and many different compounds have been identified which improve mitochondrial function in preclinical in vitro and in vivo experiments. However, very few if any have been investigated in clinical trials, representing a major drawback of the mitochondria directed drug development. To overcome these problems, we used a …top-down approach by investigating several older antidementia drugs with clinical evidence of therapeutic efficacy. These include EGb761® (standardized ginkgo biloba extract), piracetam, and Dimebon. All improve experimentally many aspects of mitochondrial dysfunction including mitochondrial dynamics and also improve cognition and impaired neuronal plasticity, the functionally most relevant consequences of mitochondrial dysfunction. All partially inhibit opening events of the mitochondrial permeability transition pore (mPTP) which previously has mainly been discussed as a mechanism relevant for the induction of apoptosis. However, as more recent work suggests the mPTP as a master regulator of many mitochondrial functions, our data suggest the mPTP as a possible relevant drug target within the love triangle between mPTP regulation, mitochondrial dynamics, and mitochondrial function including regulation of neuronal plasticity. Drugs interfering with mPTP function will improve not only mitochondrial impairment in aging and AD but also will have beneficial effects on impaired neuronal plasticity, the pathomechanism which correlates best with functional deficits (cognition, behavior) in aging and AD. Show more

Keywords: Antidementia drugs, inhibition of mitochondrial permeability transition pore function, mitochondrial dysfunction, therapeutic efficacy

DOI: 10.3233/JAD-179915

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S455-S467, 2018

Authors: Butterfield, D. Allan

Article Type: Review Article

Abstract: Oxidative stress, an overproduction of free radicals or a diminution of free radical scavenging ability relative to those of cognitively aged-matched controls, is widely recognized as a critical component of the pathogenesis and progression of Alzheimer’s disease (AD). This recognition arose in significant part from the work in the author’s laboratory, complemented by research from others’ laboratories. The Butterfield laboratory discovered the oxidative stress associated with oligomeric amyloid-β peptide manifested primarily as elevated oxidative modification of proteins and peroxidation of lipids. Such oxidative damage caused neuronal death, which undoubtedly underlies the progressive loss of cognition in AD. Identification of specific …oxidatively modified brain proteins in subjects with AD or amnestic mild cognitive impairment was achieved by the methods of redox proteomics, pioneered in the author’s laboratory. The importance and significance of the research emanating from the Butterfield laboratory rest on the paradigm shift of thinking regarding the roles of oxidative stress and resulting damage to key proteins and biochemical pathways in the pathogenesis and progression of AD. Predictions of future research directions also are presented. Given the enormous financial and personal burden placed upon citizens (and governments) of the US from AD, and the surety that the number of AD patients will greatly increase over the next 20–30 years, greater understanding of the molecular basis of pathogenesis and progression of AD is essential. Our laboratory is privileged to have contributed to better understanding of AD and provided rationales to identify effective therapeutic targets for this devastating dementing disorder. Show more

Keywords: Alzheimer’s disease, lipid peroxidation, neuronal death, oxidative stress, pathogenesis, predictions, progression, protein oxidation, redox proteomics

DOI: 10.3233/JAD-179912

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S469-S479, 2018

Authors: Lauretti, Elisabetta | Praticò, Domenico

Article Type: Review Article

Abstract: Tauopathies belong to a large group of neurodegenerative diseases characterized by progressive accumulation of hyperphosphorylated tau. Tau is a microtubule binding protein which is necessary for their assembly and stability. However, tau affinity for microtubules mainly depends on its phosphorylation status, which is the result of a delicate balance between kinases and phosphatases activity. Any significant changes in this equilibrium can promote tau fibrillation, aggregation, neuronal dysfunction, and ultimately neuronal loss. Despite intensive research, the molecular mechanism(s) leading to tau hyperphosphorylation are still unknown and there is no cure for these diseases. Development of an effective strategy that successfully prevents …tau excessive phosphorylation and/or tau aggregation may offer a real therapeutic opportunity for these less investigated neurodegenerative conditions. Beside tau, chronic brain inflammation is a common feature of all tauopathies and 5-lipoxygenase, an inflammatory enzyme, is upregulated in brain regions affected by tau pathology. Recently, in vitro studies and preclinical investigations with animal models of tauopathy have implicated 5-lipoxygenase in the regulation of tau phosphorylation through activation of the cyclin-dependent kinase 5 pathway, supporting the novel hypothesis that this protein is a promising therapeutic target for the treatment of tauopathies. In this article, we will discuss the contribution of the 5-lipoxygenase signaling pathway in the development of tau neuropathology, and the promising potential that drugs targeting this enzyme activation hold as a novel disease-modifying therapeutic approach for tauopathies. Show more

Keywords: 5-lipoxygenase, phosphorylation, tau protein, tauopathies

DOI: 10.3233/JAD-179931

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S481-S489, 2018

Authors: Thordardottir, Steinunn | Graff, Caroline

Article Type: Review Article

Abstract: This is a brief summary of the findings from the Swedish study on familial Alzheimer’s disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in …preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems. Show more

Keywords: Alzheimer’s disease, biomarkers, cerebrospinal fluid, genetics, neuroimaging, neuropsychology

DOI: 10.3233/JAD-179922

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S491-S496, 2018

Authors: Teixeira, Catia M. | Pallas-Bazarra, Noemí | Bolós, Marta | Terreros-Roncal, Julia | Ávila, Jesús | Llorens-Martín, María

Article Type: Review Article

Abstract: Neurogenesis occurs in a limited number of brain regions during adulthood. Of these, the hippocampus has attracted great interest due to its involvement in memory processing. Moreover, both the hippocampus and the main area that innervates this structure, namely the entorhinal cortex, show remarkable atrophy in patients with Alzheimer’s disease (AD). Adult hippocampal neurogenesis is a process that continuously gives rise to newborn granule neurons in the dentate gyrus. These cells coexist with developmentally generated granule neurons in this structure, and both cooperative and competition phenomena regulate the communication between these two types of cells. Importantly, it has been revealed …that GSK-3β and tau proteins, which are two of the main players driving AD pathology, are cornerstones of adult hippocampal neurogenesis regulation. We have shown that alterations either promoting or impeding the actions of these two proteins have detrimental effects on the structural plasticity of granule neurons. Of note, these impairments occur both under basal conditions and in response to detrimental and neuroprotective stimuli. Thus, in order to achieve the full effectiveness of future therapies for AD, we propose that attention be turned toward identifying the pathological and physiological actions of the proteins involved in the pathogenesis of this condition. Show more

Keywords: Adult hippocampal neurogenesis, Alzheimer’s disease, granule neuron, GSK-3β, morphology, neuroprotection, tau

DOI: 10.3233/JAD-179918

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S497-S505, 2018

Authors: Alonso, Alejandra D. | Cohen, Leah S.

Article Type: Review Article

Abstract: The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer’s disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P-tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on …tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing. Show more

Keywords: Hyperphosphorylation, microtubules, neurodegeneration, tau, tau mouse model

DOI: 10.3233/JAD-179906

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S507-S516, 2018

Authors: Nisbet, Rebecca M. | Götz, Jürgen

Article Type: Review Article

Abstract: Accumulation of the peptide amyloid-β (Aβ) and the protein tau in Alzheimer’s disease (AD) brains is a gradual process that involves the post-translational modification and assembly of monomeric forms into larger structures that eventually form fibrillar inclusions. This process is thought to both drive and initiate AD. However, why the axonally enriched tau in the course of AD accumulates in the somatodendritic domain is not fully understood. We discuss new data that provide a possible explanation that involves de novo protein synthesis, induced by Aβ and mediated through the kinase Fyn. We further discuss how in a pathological state, …tau, being a scaffolding protein, impairs nuclear and mitochondrial functions and reduces action potential generation at the axon initial segment. Pathological tau can further be packaged into exosomes, released by one neuron and taken up by another, contributing to its pathogenicity. We also present our new work that suggests ultrasound as a new treatment modality to clear pathological Aβ and tau. We put this work into perspective, discussing current vaccination strategies and improved brain delivery methods involving antibody engineering and viral approaches. We propose that rather than reducing post-translational modifications of tau, its levels and de novo synthesis need to be reduced. We anticipate a surge in combinatorial strategies, simultaneously targeting multiple pathologies, and an improved drug delivery to the brain facilitated by emerging technologies such as ultrasound. Show more

Keywords: Alzheimer’s disease, amyloid, axon initial segment, focused ultrasound, fyn kinase, microtubule-associated protein tau, non-invasive, phosphorylation, spreading, vaccination

DOI: 10.3233/JAD-179907

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S517-S527, 2018

Authors: Hernández, Félix | Llorens-Martín, María | Bolós, Marta | Pérez, Mar | Cuadros, Raquel | Pallas-Bazarra, Noemí | Zabala, Juan C. | Avila, Jesús

Article Type: Review Article

Abstract: Alzheimer’s disease (AD) is characterized by the presence of two aberrant structures: namely senile plaques, composed of amyloid-β peptide (Aβ), and neurofibrillary tangles, composed of tau protein. In this regard, Aβ and tau protein have been widely studied in research efforts aiming to find a therapy for AD. Aβ and tau pathologies do not always overlap. The precursor of Aβ is expressed in peripheral tissues and in the central nervous system (CNS), whereas tau is mainly a neuronal protein. Since AD is a disease of the CNS, it has been proposed that Aβ may initiate the disease process, with tau …being the executor. In this review, we will focus on future studies of tau pathology, although we will comment on new beginnings for AD, as other molecules other than Aβ and tau may be involved in the onset of dementia. Show more

Keywords: Extracellular tau, MAPs, tau functions, tauopathies

DOI: 10.3233/JAD-179916

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S529-S534, 2018

Authors: Novak, Petr | Cehlar, Ondrej | Skrabana, Rostislav | Novak, Michal

Article Type: Review Article

Abstract: Tau protein plays a major role in the pathogenesis of Alzheimer’s disease. Despite many decades of intensive research, the cause of the conformational switch that leads to the remodeling of the highly flexible conformational ensemble of intrinsically disordered protein tau into insoluble filaments is still elusive. We show here that truncation of tau may play a causative role in this conformational change, as evidenced by results obtained from in vitro experiments and from transgenic animal models. This conformational change is a common denominator of pathological tau protein assemblies, and a salient drug target. The long-running research of truncated tau …has led to the generation of the first active tau vaccine that has entered clinical trials. Show more

Keywords: Aggregation, Alzheimer’s disease, conformational ensemble, immunotherapy, tau protein, truncation

DOI: 10.3233/JAD-179942

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S535-S546, 2018

Authors: Bhat, Ratan V. | Andersson, Ulf | Andersson, Shalini | Knerr, Laurent | Bauer, Udo | Sundgren-Andersson, Anna K.

Article Type: Review Article

Abstract: Spanning over three decades of extensive drug discovery research, the efforts to develop a potent and selective GSK3 inhibitor as a therapeutic for the treatment of type 2 diabetes, Alzheimer’s disease (AD), bipolar disorders and cancer have been futile. Since its initial discovery in 1980 and subsequent decades of research, one cannot underscore the importance of the target and the promise of a game changing disease modifier. Several pharmaceutical companies, biotech companies, and academic institutions raged in a quest to unravel the biology and discover potent and selective GSK3 inhibitors, some of which went through clinical trials. However, the …conundrum of what happened to the fate of the AstraZeneca’s GSK3 inhibitors and the undertaking to find a therapeutic that could control glycogen metabolism and aberrant tau hyperphosphorylation in the brain, and rescue synaptic dysfunction has largely been untold. AstraZeneca was in the forefront of GSK3 drug discovery research with six GSK3 drug candidates, one of which progressed up to Phase II clinical trials in the quest to untangle the tau hypothesis for AD. Analysis of key toxicity issues, serendipitous findings and efficacy, and biomarker considerations in relation to safety margins have limited the potential of small molecule therapeutics as a way forward. To guide future innovation of this important target, we reveal the roller coaster journey comprising of two decades of preclinical and clinical GSK3 drug discovery at AstraZeneca; the understanding of which could lead to improved GSK3 therapies for disease. These learnings in combination with advances in achieving kinase selectivity, different modes of action as well as the recent discovery of novel conjugated peptide technology targeting specific tissues have potentially provided a venue for scientific innovation and a new beginning for GSK3 drug discovery. Show more

Keywords: Alzheimer’s disease, drug targeting, tau

DOI: 10.3233/JAD-179934

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S547-S554, 2018

Authors: Sigurdsson, Einar M.

Article Type: Review Article

Abstract: Tau immunotherapies have now advanced from proof-of-concept studies to Phase II clinical trials. This review briefly outlines developments in the field and discusses how these therapies may work, which involves multiple variables that are connected in complex ways. These various factors are likely to define therapeutic success in humans and have not been thoroughly investigated, at least based on published reports.

Keywords: Alzheimer’s disease, antibodies, clinical trials, immunotherapies, mechanisms, tau, tauopathy

DOI: 10.3233/JAD-179937

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S555-S565, 2018

Authors: Cline, Erika N. | Bicca, Maíra Assunção | Viola, Kirsten L. | Klein, William L.

Article Type: Review Article

Abstract: The amyloid-β oligomer (AβO) hypothesis was introduced in 1998. It proposed that the brain damage leading to Alzheimer’s disease (AD) was instigated by soluble, ligand-like AβOs. This hypothesis was based on the discovery that fibril-free synthetic preparations of AβOs were potent CNS neurotoxins that rapidly inhibited long-term potentiation and, with time, caused selective nerve cell death (Lambert et al., 1998). The mechanism was attributed to disrupted signaling involving the tyrosine-protein kinase Fyn, mediated by an unknown toxin receptor. Over 4,000 articles concerning AβOs have been published since then, including more than 400 reviews. AβOs have been shown to accumulate in …an AD-dependent manner in human and animal model brain tissue and, experimentally, to impair learning and memory and instigate major facets of AD neuropathology, including tau pathology, synapse deterioration and loss, inflammation, and oxidative damage. As reviewed by Hayden and Teplow in 2013, the AβO hypothesis “has all but supplanted the amyloid cascade.” Despite the emerging understanding of the role played by AβOs in AD pathogenesis, AβOs have not yet received the clinical attention given to amyloid plaques, which have been at the core of major attempts at therapeutics and diagnostics but are no longer regarded as the most pathogenic form of Aβ. However, if the momentum of AβO research continues, particularly efforts to elucidate key aspects of structure, a clear path to a successful disease modifying therapy can be envisioned. Ensuring that lessons learned from recent, late-stage clinical failures are applied appropriately throughout therapeutic development will further enable the likelihood of a successful therapy in the near-term. Show more

Keywords: Alzheimer’s disease, amyloid-β peptide, diagnostics, etiology, model systems, oligomers, prions, receptors, structure-function, tau, therapeutics

DOI: 10.3233/JAD-179941

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S567-S610, 2018

Authors: Gulisano, Walter | Maugeri, Daniele | Baltrons, Marian A. | Fà, Mauro | Amato, Arianna | Palmeri, Agostino | D’Adamio, Luciano | Grassi, Claudio | Devanand, D.P. | Honig, Lawrence S. | Puzzo, Daniela | Arancio, Ottavio

Article Type: Review Article

Abstract: The “Amyloid Cascade Hypothesis” has dominated the Alzheimer’s disease (AD) field in the last 25 years. It posits that the increase of amyloid-β (Aβ) is the key event in AD that triggers tau pathology followed by neuronal death and eventually, the disease. However, therapeutic approaches aimed at decreasing Aβ levels have so far failed, and tau-based clinical trials have not yet produced positive findings. This begs the question of whether the hypothesis is correct. Here we have examined literature on the role of Aβ and tau in synaptic dysfunction, memory loss, and seeding and spreading of AD, highlighting important parallelisms …between the two proteins in all of these phenomena. We discuss novel findings showing binding of both Aβ and tau oligomers to amyloid-β protein precursor (AβPP), and the requirement for the presence of this protein for both Aβ and tau to enter neurons and induce abnormal synaptic function and memory. Most importantly, we propose a novel view of AD pathogenesis in which extracellular oligomers of Aβ and tau act in parallel and upstream of AβPP. Such a view will call for a reconsideration of therapeutic approaches directed against Aβ and tau, paving the way to an increased interest toward AβPP, both for understanding the pathogenesis of the disease and elaborating new therapeutic strategies. Show more

Keywords: Amyloid-β peptide, amyloid-β protein precursor, oligomers, synaptic dysfunction, tau

DOI: 10.3233/JAD-179935

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S611-S631, 2018

Authors: Mormino, Elizabeth C. | Papp, Kathryn V.

Article Type: Review Article

Abstract:  The aberrant accumulation of the amyloid protein is a critical and early event in the Alzheimer’s disease (AD) cascade. Given the early involvement of this pathological process, it is not surprising that many clinically normal (CN) older individuals demonstrate evidence of abnormal Aβ at postmortem examination and in vivo using either CSF or PET imaging. Converging evidence across multiple research groups suggests that the presence of abnormal Aβ among CN individuals is associated with elevated risk of future clinical impairment and cognitive decline. Amyloid positivity in conjunction with biomarkers of neuronal injury offers further insight into which CN are …most at risk for short-term decline. Although in its infancy, tau PET has demonstrated early increases among Aβ+ that will likely be an important indicator of risk among CN. Overall, the detection of early Aβ among CN individuals has provided an important opportunity to understand the contributions of this pathology to age-related cognitive decline and to explore early intervention with disease modifying strategies. Show more

Keywords: Aging, amyloid, biomarkers, cognitive decline, early detection, memory, PET

DOI: 10.3233/JAD-179928

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S633-S646, 2018

Authors: Santana, Isabel | Baldeiras, Inês | Santiago, Beatriz | Duro, Diana | Freitas, Sandra | Pereira, Miguel Tábuas | Almeida, Maria Rosário | Oliveira, Catarina Resende

Article Type: Research Article

Abstract: The amyloid cascade hypothesis proposes amyloid-β (Aβ) as the earliest and key pathological hallmark of Alzheimer’s disease (AD), but this mandatory “amyloid-first pathway” has been contested. Longitudinal studies of mild cognitive impairment (MCI) patients represent an opportunity to investigate the intensity of underlying biological processes (amyloidosis versus neurodegeneration) and their relevance for progression to AD. We re-examined our cohort of amnestic MCI, grouped according to cerebrospinal fluid (CSF) biomarkers, aiming at establishing their prognostic value for Alzheimer-type dementia and testing the hypothetical model of biomarkers sequence, based on the amyloid cascade. Our baseline population consisted of 217 MCI patients, 63% …with neurodegeneration markers and 47% with amyloidosis. Within the longitudinal study-group (n  = 165), 85 progressed to AD and 80 remained cognitively stable. Age, CSF Aβ42 , and t-Tau were identified as the best single predictors of conversion to AD. Regarding MCI classification according to the NIA-AA criteria, the high-AD-likelihood group (HL-both amyloid and neurodegeneration markers) was the most frequent (42%); followed by the Suspected Non-Alzheimer Pathophysiology group (SNAP-26%), the low-AD-likelihood group (LL-negative biomarkers-22%), and the Isolated Amyloid Pathology group (IAP-10%). Risk of progression to AD was higher in HL in relation to the LL group (HR = 6.1, 95% CI = 2.1–18.0, p  = 0.001). SNAP and IAP groups were equivalent in terms of risk of progression to AD (IAP: HR = 2.6, 95% CI = 0.7–9.3, p  = 0.141; SNAP: HR = 3.1, 95% CI = 1.1–9.6; p  = 0.046), but only SNAP was significantly different from the LL group. These results support different neurobiological pathways to AD beyond the amyloid hypothesis, highlighting the alternative “neurodegeneration-first pathway” for further investigation. Show more

Keywords: Alzheimer’s disease, amyloid, cerebrospinal fluid biomarkers, mild cognitive impairment, neurodegeneration

DOI: 10.3233/JAD-179908

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S647-S657, 2018

Authors: Nguyen, Phuong H. | del Castillo-Frias, Maria P. | Berthoumieux, Olivia | Faller, Peter | Doig, Andrew J. | Derreumaux, Philippe

Article Type: Research Article

Abstract: Targeting the early oligomers formed by the amyloid-β (Aβ) peptide of 40 and 42 amino acids is considered one promising therapeutic approach for Alzheimer’s disease (AD). In vitro experiments and computer simulations are often used in synergy to reveal the modes of interactions of drugs. In this account, we present our contribution to understanding how small molecules bind to Aβ40 /Aβ42 peptides, based either on extensive coarse-grained and all-atom simulations, or a variety of experimental techniques. We conclude by offering several perspectives on the future of this field to design more efficient drugs.

Keywords: Aβ oligomers, all-atom/coarse-grained models, Alzheimer’s disease, amyloid simulations, cell-based assays, drugs, in vitro studies

DOI: 10.3233/JAD-179902

Citation: Journal of Alzheimer's Disease, vol. 64, no. s1, pp. S659-S672, 2018