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