Ebook: Alzheimer's Disease: New Beginnings

Alzheimer's Disease: New Beginnings focuses on the future promise for therapeutic breakthroughs in light of notable clinical trial failures. We used a combination of scientometric evaluations to determine the most promising new approaches as well as soliciting insights from leaders in each of the major areas of Alzheimer's disease research. By combining these two approaches, we recruited authors from the entire outlook spectrum of those who feel an elusive breakthrough might still be a few, well-placed tweaks away to those who feel that they are launching entirely new investigative paradigms. These scholars present an open-eyed path forward. Now is the most exciting period of a generation in our field as old dogmas make way for new insight, whether it be new approaches to clinical trials, improved biomarker-based diagnostics, population-based studies, prevention, metabolism, or further refinement of the role of inflammation, genetics, tau, and amyloid-β.

Editors:

George Perry

Jesús Avila

Paula I. Moreira

Aaron A. Sorensen

Massimo Tabaton

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.

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, neuroin-flammation, 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 on cognitive function. For fatty acid supplementation, mainly long-chain polyunsaturated fatty acids, there was emerging evidence suggesting an impact of this approach in improving specific cognitive domains, magnetic resonance imaging (MRI) findings, and/or cognitive-related biomarkers also in selected subgroups of older subjects, although some results were conflicting. There was convincing evidence of an impact of non-flavonoid polyphenol and flavonoid supplementations in improving specific cognitive domains and/or MRI findings. Finally, there was only low evidence suggesting efficacy of intervention with homocysteine-related and antioxidant vitamins in improving cognitive functions, dementia incidence, or cognitive-related biomarkers in cognitively healthy older subjects.

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.

Th epast 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.

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.

Ever since the discovery of APOE ε4 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.

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.

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.

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.

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.

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.

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.

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.