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[Disease-modifying treatment approaches for Alzheimer's disease].

ABSTRACT: Alzheimer's disease is one the major common diseases but so far only with symptomatic treatment options. New insights define the disease as a slowly progressive continuum with very long preclinical and early symptomatic phases. Innovative molecular treatment strategies are based on an improved understanding of the molecular neurobiology of the disease, opening up a variety of therapeutic targets. For the first time, an anti-amyloid antibody has been approved in the USA in 2021 as a disease-modifying treatment for Alzheimer's disease, representing a first highly controversial step towards a molecular, cause-oriented treatment. This review presents the most advanced molecular treatment strategies and discusses the implications of the approved antibody treatment for the clinical practice. The special features of this long-term treatment with i.v. infusions in a particularly vulnerable population and a special side effect profile will impose significant challenges for implementation in the practice and will require a high degree of cooperation within the healthcare system. The future of Alzheimer's treatment with a multimodal therapeutic approach with different classes of drugs will probably reinforce these trends.

SUBMITTER: Frolich L

PROVIDER: S-EPMC8648638 | biostudies-literature |

REPOSITORIES: biostudies-literature

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[Disease-modifying treatment approaches in Huntington disease : Past and future].

Project description:Huntington disease (HD) is the most frequent monogenetic neurodegenerative disease and can be unequivocally diagnosed even in the preclinical stage, at least in all individuals in whom the CAG expansion mutation in the huntingtin gene (HTT) is in the range of full penetrance. Therefore, important preconditions for an intervention early in the disease process are met, rendering modification of the course of the disease in a clinically meaningful way possible. In this respect, HD can be viewed as a model disorder for exploring neuroprotective treatment approaches. In the past emphasis was placed on the compensation of a suspected neurotransmitter deficit (GABA) analogous to Parkinson's disease and on classical neuroprotective strategies to influence hypothetical common pathways in neurodegenerative diseases (e.g., excitotoxicity, mitochondrial dysfunction, oxidative stress). With the discovery of the causative HTT mutation in 1993, therapeutic research increasingly focused on intervening as proximally as possible in the chain of pathophysiological events. Currently, an important point of intervention is the HTT mRNA with the aim of reducing the continued production of mutant huntingtin gene products and thus relieving the body of their detrimental actions. To this end, various treatment modalities (single-stranded DNA and RNA, divalent RNA and zinc finger repressor complexes, orally available splice modulators) were developed and are currently in clinical trials (phases I-III) or in late stages of preclinical development. In addition, there is the notion that it may be possible to modify the length of the somatically unstable CAG mutation, i.e. its increase in the brain during the lifetime, thereby slowing the progression of HD.

| S-EPMC8825394 | biostudies-literature

Disease-modifying drugs in Alzheimer's disease.

Project description:Alzheimer's disease (AD) is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques) and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition.

| S-EPMC3862506 | biostudies-other

New pharmacological strategies for treatment of Alzheimer's disease: focus on disease modifying drugs.

Project description:Current approved drug treatments for Alzheimer disease (AD) include cholinesterase inhibitors (donepezil, rivastigmine, galantamine) and the NMDA receptor antagonist memantine. These drugs provide symptomatic relief but poorly affect the progression of the disease. Drug discovery has been directed, in the last 10 years, to develop 'disease modifying drugs' hopefully able to counteract the progression of AD. Because in a chronic, slow progressing pathological process, such as AD, an early start of treatment enhances the chance of success, it is crucial to have biomarkers for early detection of AD-related brain dysfunction, usable before clinical onset. Reliable early biomarkers need therefore to be prospectively tested for predictive accuracy, with specific cut off values validated in clinical practice. Disease modifying drugs developed so far include drugs to reduce ? amyloid (A?) production, drugs to prevent A? aggregation, drugs to promote A? clearance, drugs targeting tau phosphorylation and assembly and other approaches. Unfortunately none of these drugs has demonstrated efficacy in phase 3 studies. The failure of clinical trials with disease modifying drugs raises a number of questions, spanning from methodological flaws to fundamental understanding of AD pathophysiology and biology. Recently, new diagnostic criteria applicable to presymptomatic stages of AD have been published. These new criteria may impact on drug development, such that future trials on disease modifying drugs will include populations susceptible to AD, before clinical onset. Specific problems with completed trials and hopes with ongoing trials are discussed in this review.

| S-EPMC3376428 | biostudies-literature

Novel Approaches for the Treatment of Alzheimer's and Parkinson's Disease.

Project description:Neurodegenerative disorders affect around one billion people worldwide. They can arise from a combination of genomic, epigenomic, metabolic, and environmental factors. Aging is the leading risk factor for most chronic illnesses of old age, including Alzheimer's and Parkinson's diseases. A progressive neurodegenerative process and neuroinflammation occur, and no current therapies can prevent, slow, or halt disease progression. To date, no novel disease-modifying therapies have been shown to provide significant benefit for patients who suffer from these devastating disorders. Therefore, early diagnosis and the discovery of new targets and novel therapies are of upmost importance. Neurodegenerative diseases, like in other age-related disorders, the progression of pathology begins many years before the onset of symptoms. Many efforts in this field have led to the conclusion that exits some similar events among these diseases that can explain why the aging brain is so vulnerable to suffer neurodegenerative diseases. This article reviews the current knowledge about these diseases by summarizing the most common features of major neurodegenerative disorders, their causes and consequences, and the proposed novel therapeutic approaches.

| S-EPMC6386829 | biostudies-literature

Neurotechnological Approaches to the Diagnosis and Treatment of Alzheimer's Disease.

Project description:Alzheimer's disease (AD) is the most common cause of dementia in the elderly, clinically defined by progressive cognitive decline and pathologically, by brain atrophy, neuroinflammation, and accumulation of extracellular amyloid plaques and intracellular neurofibrillary tangles. Neurotechnological approaches, including optogenetics and deep brain stimulation, have exploded as new tools for not only the study of the brain but also for application in the treatment of neurological diseases. Here, we review the current state of AD therapeutics and recent advancements in both invasive and non-invasive neurotechnologies that can be used to ameliorate AD pathology, including neurostimulation via optogenetics, photobiomodulation, electrical stimulation, ultrasound stimulation, and magnetic neurostimulation, as well as nanotechnologies employing nanovectors, magnetic nanoparticles, and quantum dots. We also discuss the current challenges in developing these neurotechnological tools and the prospects for implementing them in the treatment of AD and other neurodegenerative diseases.

| S-EPMC8989850 | biostudies-literature

Preparedness of the Brazilian health-care system to provide access to a disease-modifying Alzheimer's disease treatment.

Project description:BackgroundWhile the majority of patients with Alzheimer's disease resides in low and middle-income countries, little is known of their preparedness for emerging disease-modifying treatments. We analyze the preparedness of Brazil, one of the most populous middle-income countries, from a capacity and institutional preparedness perspective.MethodsDesk research and 12 interviews for background and capacity data. Markov model to estimate wait times for access to treatment.FindingsBrazil has no national dementia strategy or established pathway for evaluation of cognitive concerns, and dementia is typically diagnosed late if at all. While members of private health plans have ready access to elective specialty care, wait times in the public sector are long. Assuming potentially treatment-eligible patients are referred from primary to specialty care based on a brief cognitive exam and a blood test for the Alzheimer's pathology, available capacity will not be sufficient to match the projected demand. The biggest obstacle is availability of dementia specialist visits, and the effect of population growth and ageing means that the wait list for specialist appointment will continue to grow from around 400,000 in 2022 to over 2.2 million in 2040. We do not project substantial wait times for confirmatory biomarker testing and treatment delivery but note that this is a consequence of patients waiting for their specialist appointments. These queues will result in estimated persistent wait times for treatment of around two years on average with substantial differences between the public and private sectors, as capacity growth is insufficient to keep up with increasing demand.DiscussionOur findings suggest that Brazil is ill-prepared to provide timely access to an Alzheimer's treatment with predicted wait times of about two years, largely because of a limited number of dementia specialists.

| S-EPMC10087834 | biostudies-literature

CDNF: An innovative actor in disease-modifying approaches for Parkinson's disease.

Project description: Not available

| S-EPMC8417500 | biostudies-literature

Disease-Modifying Therapies for Alzheimer's Disease: More Questions than Answers.

Project description:Scientific advances over the last four decades have steadily infused the Alzheimer's disease (AD) field with great optimism that therapies targeting Aβ, amyloid, tau, and innate immune activation states in the brain would provide disease modification. Unfortunately, this optimistic scenario has not yet played out. Though a recent approval of the anti-Aβ aggregate binding antibody, Aduhelm (aducanumab), as a "disease-modifying therapy for AD" is viewed by some as a breakthrough, many remain unconvinced by the data underlying this approval. Collectively, we have not succeeded in changing AD from a largely untreatable, inevitable, and incurable disease to a treatable, preventable, and curable one. Here, I will review the major foci of the AD "disease-modifying" therapeutic pipeline and some of the "open questions" that remain in terms of these therapeutic approaches. I will conclude the review by discussing how we, as a field, might adjust our approach, learning from our past failures to ensure future success.

| S-EPMC8885119 | biostudies-literature

Projecting the long-term societal value of a disease-modifying treatment for Alzheimer's disease in the United States.

Project description:IntroductionWe estimate societal value of a disease-modifying Alzheimer's disease (AD) treatment that reduces progression by 30% in early stages.MethodsUsing the International Society for Pharmacoeconomics and Outcomes Research value flower as framework, we estimate gross societal value, that is, not including treatment cost, from avoided medical and social care costs, productivity and quality-adjusted life-years (QALY) gains for patients and caregivers, adjusting for severity of disease, value of financial insurance, and value of insurance for currently unafflicted adults with a Markov model.ResultsPredicted societal value from 2021 until 2041 is $2.62 trillion for the overall afflicted US population and $986 billion for the 2021 prevalent cohort or $134,418 per person, with valuation of patients' QALY gains (63%) and avoided nursing-home costs (20%) as largest components. Delays in access because of health system capacity constraints could reduce realized value between 52% and 69%. The value of insurance for the unafflicted is $4.52 trillion or $18,399 on average per person.DiscussionWith a total of $5.5 trillion, the projected gross societal value of a hypothetical AD treatment is substantial, which may help to put the cost of treatment into perspective.

| S-EPMC9303743 | biostudies-literature

New therapeutic approaches for type 1 diabetes: Disease-modifying therapies.

Project description:It has been 100 years since the first successful clinical use of insulin, yet it remains the only treatment option for type 1 diabetes mellitus (T1DM) patients. Advances in diabetes care, such as insulin analogue therapies and new devices, including continuous glucose monitoring with continuous subcutaneous insulin infusion have improved the quality of life of patients but have no impact on the pathogenesis of the disease. They do not eliminate long-term complications and require several lifestyle sacrifices. A more ideal future therapy for T1DM, instead of supplementing the insufficient hormone production (a consequence of β-cell destruction), would also aim to stop or slow down the destructive autoimmune process. The discovery of the autoimmune nature of type 1 diabetes mellitus has presented several targets by which disease progression may be altered. The goal of disease-modifying therapies is to target autoimmune mechanisms and prevent β-cell destruction. T1DM patients with better β-cell function have better glycemic control, reduced incidence of long-term complications and hypoglycemic episodes. Unfortunately, at the time symptomatic T1DM is diagnosed, most of the insulin secreting β cells are usually lost. Therefore, to maximize the salvageable β-cell mass by disease-modifying therapies, detecting autoimmune markers in an early, optimally presymptomatic phase of T1DM is of great importance. Disease-modifying therapies, such as immuno- and regenerative therapies are expected to take a relevant place in diabetology. The aim of this article was to provide a brief insight into the pathogenesis and course of T1DM and present the current state of disease-modifying therapeutic interventions that may impact future diabetes treatment.

| S-EPMC9606789 | biostudies-literature

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