Back to the future: Alzheimer's disease heterogeneity revisited

Alzheimer's research & therapy, 2013

Alzheimer's research & therapy, 2017

Basic research advances in recent years have furthered our understanding of the natural history of Alzheimer's disease (AD). It is now recognized that pathophysiological changes begin many years prior to clinical manifestations of disease and the spectrum of AD spans from clinically asymptomatic to severely impaired. Defining AD purely by its clinical presentation is thus artificial and efforts have been made to recognize the disease based on both clinical and biomarker findings. Advances with biomarkers have also prompted a shift in how the disease is considered as a clinico-pathophysiological entity, with an increasing appreciation that AD should not only be viewed with discrete and defined clinical stages, but as a multifaceted process moving along a seamless continuum. Acknowledging this concept is critical to understanding the development process for disease-modifying therapies, and for initiating effective diagnostic and disease management options. In this article, we disc...

Progress in Neurobiology, 2011

Alzheimer's disease (AD) is a fast growing worldwide epidemic. AD is a genetically complex, slowly progressive, and irreversible neurodegenerative disease of the brain. During decades of asymptomatic progression multiple interactive systems, pathways and molecular mechanisms (e.g. protein processing, aberrant signaling, inflammation and immune system, lipid transport, endocytosis, apoptosis, oxidative damage and response to stress, tau pathology, neuron and synapse loss, energy metabolism), contribute to the development of the early clinical prodromal stage with episodic memory deficits and to further decline and loss of general cognitive functioning during the final syndromal dementia stage. The non-mendelian genetically complex ''sporadic'' AD type is the most common form of dementia affecting people usually over the age of 65. Despite considerable progress of AD research in recent years and evolving paradigm shifts in both pathophysiological concepts as well as in diagnostic criteria fundamental challenges have not yet been resolved. The strong age-related incidence, the recent failure and complete lack of disease-modifying or preventive therapy that may delay onset or substantially affect the pathophysiology of AD, result in an enormous burden posed both on individuals, their families and care givers, and the societies at large, and these call for urgent concerted worldwide measures. Based on the meeting of the German Task Force on Alzheimer's Disease (GTF-AD) in Paris on July 19th 2011, the present position paper provides an overview on the current state and future developments in epidemiology, pathophysiology, disease conceptualization, diagnostic criteria and their use in research and clinical practice, as well as preventive and symptomatic therapeutic approaches. Particular emphasis is placed on a discussion of the different approaches to diagnostics and therapy taken by preventive/public health medicine, methodologically advanced academic research propagating the use of sophisticated biomarkers, and everyday clinical practice focusing on patient-centered care. During the next 10 years, major advances both in early detection as well as in therapy and comprehensive AD care seem mandatory. These still unmet needs call for ever more concerted and focused efforts in research across the world to combat the erupting and as yet uncontrolled epidemic of AD.

Neurologic Clinics, 2016

Alzheimer disease represents one of the greatest medical challenges that face this century; the condition is becoming increasingly prevalent worldwide and as yet, no effective treatments have been developed for this terminal disease. Since the disease manifests at a late stage after a long period of clinically silent neurodegeneration, knowledge of the modifiable risk factors and the implementation of biomarkers is crucial in the primary prevention of the disease and presymptomatic detection of AD, respectively. This review discusses the growing epidemic of AD and antecedent risk factors in the disease process. Disease biomarkers are discussed and the implications that this may have for the treatment of this currently incurable disease.

Annals of Clinical and Translational Neurology, 2015

Frontiers in Neuroscience, 2019

The repeated unsuccessful clinical trials on the amyloid-beta targeting medications and the pessimistic calculations of the cost burden of Alzheimer's disease (AD) will have an impact in the next few decades, posing serious challenges for humanity with severe social implications. To date, holistic solution for the disease has yet to be identified, although quite a few alternative diagnostic and treatment procedures have been presented during the past years, considering the latest Alzheimer's classification. The range of scientific fields actively involved in the race for a cure for AD has been impressively extended, allowing the combination of creative ideas using modern technology with innovative therapeutic agents and traditional pharmaceutical practices. In this way, common etiologies and mechanisms in other related disorders or aspects of neurodegeneration could be identified. This Research Topic titled ‘Alzheimer's disease as a current challenge’ offers a contribution of 38 innovative papers on the multidimensional and crucial social problem of AD management. A total of 284 authors presented their different perspectives, research updates and studies in several sections of the Frontiers journals, describing methods on potential diagnosis and treatment.

Continuum (Minneapolis, Minn.), 2010

Alzheimer disease (AD) is a progressive neurodegenerative disorder affecting more than 37 million people worldwide and increasing in incidence based on its primary risk factor, advancing age. A growing body of knowledge regarding amyloid and tau neuropathology, genetic and environmental risk modifiers, early and atypical clinical presentations, and the use of symptom-modifying medical and psychosocial therapies is available to aid in the diagnosis and management of patients with AD. Exciting recent advances in neurobiology render the areas of genetic susceptibility, biomarkers for early disease detection and assessment of disease progression, and novel therapeutic strategies to modify the natural history of the disease compelling, but in need of further study before implementation into routine clinical practice is feasible.

Biomolecules

Old age increases the risk of Alzheimer’s disease (AD), the most common neurodegenerative disease, a devastating disorder of the human mind and the leading cause of dementia. Worldwide, 50 million people have the disease, and it is estimated that there will be 150 million by 2050. Today, healthcare for AD patients consumes 1% of the global economy. According to the amyloid cascade hypothesis, AD begins in the brain by accumulating and aggregating Aβ peptides and forming β-amyloid fibrils (Aβ42). However, in clinical trials, reducing Aβ peptide production and amyloid formation in the brain did not slow cognitive decline or improve daily life in AD patients. Prevention studies in cognitively unimpaired people at high risk or genetically destined to develop AD also have not slowed cognitive decline. These observations argue against the amyloid hypothesis of AD etiology, its development, and disease mechanisms. Here, we look at other avenues in the research of AD, such as the presenilin...

2011

There is an urgent need to find effective presymptomatic Alzheimer's disease (AD) treatments that reduce the risk of AD symptoms or prevent them completely. It currently takes too many healthy people, too much money and too many years to evaluate the range of promising presymptomatic treatments using clinical endpoints. We have used brain imaging and other measurements to track some of the earliest changes associated with the predisposition to AD. We have proposed the Alzheimer's Prevention Initiative (API) to evaluate investigational amyloid-modifying treatments in healthy people who, based on their age and genetic background, are at the highest imminent risk of developing symptomatic AD using brain imaging, cerebrospinal fluid (CSF), and cognitive endpoints. In one trial, we propose to study AD-causing presenilin 1 [PS1] mutation carriers from the world's largest early-onset AD kindred in Antioquia, Colombia, close to their estimated average age at clinical onset. In another trial, we propose to study apolipoprotein E (APOE)ε4 homozygotes (and possibly heterozygotes) close to their estimated average age at clinical onset. The API has several goals: 1) to evaluate investigational AD-modifying treatments sooner than otherwise possible; 2) to determine the extent to which the treatment's brain imaging and other biomarker effects predict a clinical benefit-information needed to help qualify biomarker endpoints for use in pivotal prevention trials; 3) to provide a better test of the amyloid hypothesis than clinical trials in symptomatic patients, when these treatments may be too little too late to exert their most profound effect; 4) to establish AD prevention registries needed to support these