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Signal Transduction and Targeted Therapy Jun 2023Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of... (Review)
Review
Amyloid β protein (Aβ) is the main component of neuritic plaques in Alzheimer's disease (AD), and its accumulation has been considered as the molecular driver of Alzheimer's pathogenesis and progression. Aβ has been the prime target for the development of AD therapy. However, the repeated failures of Aβ-targeted clinical trials have cast considerable doubt on the amyloid cascade hypothesis and whether the development of Alzheimer's drug has followed the correct course. However, the recent successes of Aβ targeted trials have assuaged those doubts. In this review, we discussed the evolution of the amyloid cascade hypothesis over the last 30 years and summarized its application in Alzheimer's diagnosis and modification. In particular, we extensively discussed the pitfalls, promises and important unanswered questions regarding the current anti-Aβ therapy, as well as strategies for further study and development of more feasible Aβ-targeted approaches in the optimization of AD prevention and treatment.
Topics: Humans; Amyloid beta-Peptides; Alzheimer Disease; Plaque, Amyloid
PubMed: 37386015
DOI: 10.1038/s41392-023-01484-7 -
Cell Oct 2023Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it... (Review)
Review
Alzheimer's disease (AD) research has entered a new era with the recent positive phase 3 clinical trials of the anti-Aβ antibodies lecanemab and donanemab. Why did it take 30 years to achieve these successes? Developing potent therapies for reducing fibrillar amyloid was key, as was selection of patients at relatively early stages of disease. Biomarkers of the target pathologies, including amyloid and tau PET, and insights from past trials were also critical to the recent successes. Moving forward, the challenge will be to develop more efficacious therapies with greater efficiency. Novel trial designs, including combination therapies and umbrella and basket protocols, will accelerate clinical development. Better diversity and inclusivity of trial participants are needed, and blood-based biomarkers may help to improve access for medically underserved groups. Incentivizing innovation in both academia and industry through public-private partnerships, collaborative mechanisms, and the creation of new career paths will be critical to build momentum in these exciting times.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Amyloidogenic Proteins; Antibodies, Monoclonal; Biomarkers; Clinical Trials as Topic; Drug Development
PubMed: 37848035
DOI: 10.1016/j.cell.2023.09.023 -
Trends in Endocrinology and Metabolism:... Aug 2023Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E... (Review)
Review
Dysregulation of lipid metabolism has emerged as a central component of many neurodegenerative diseases. Variants of the lipid transport protein, apolipoprotein E (APOE), modulate risk and resilience in several neurodegenerative diseases including late-onset Alzheimer's disease (LOAD). Allelic variants of the gene, APOE, alter the lipid metabolism of cells and tissues and have been broadly associated with several other cellular and systemic phenotypes. Targeting APOE-associated metabolic pathways may offer opportunities to alter disease-related phenotypes and consequently, attenuate disease risk and impart resilience to multiple neurodegenerative diseases. We review the molecular, cellular, and tissue-level alterations to lipid metabolism that arise from different APOE isoforms. These changes in lipid metabolism could help to elucidate disease mechanisms and tune neurodegenerative disease risk and resilience.
Topics: Humans; Neurodegenerative Diseases; Lipid Metabolism; Apolipoproteins E; Phenotype; Alzheimer Disease
PubMed: 37357100
DOI: 10.1016/j.tem.2023.05.002 -
Cell Metabolism Oct 2023Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the...
Circadian disruptions impact nearly all people with Alzheimer's disease (AD), emphasizing both their potential role in pathology and the critical need to investigate the therapeutic potential of circadian-modulating interventions. Here, we show that time-restricted feeding (TRF) without caloric restriction improved key disease components including behavioral timing, disease pathology, hippocampal transcription, and memory in two transgenic (TG) mouse models of AD. We found that TRF had the remarkable capability of simultaneously reducing amyloid deposition, increasing Aβ42 clearance, improving sleep and memory, and normalizing daily transcription patterns of multiple genes, including those associated with AD and neuroinflammation. Thus, our study unveils for the first time the pleiotropic nature of timed feeding on AD, which has far-reaching effects beyond metabolism, ameliorating neurodegeneration and the misalignment of circadian rhythmicity. Since TRF can substantially modify disease trajectory, this intervention has immediate translational potential, addressing the urgent demand for accessible approaches to reduce or halt AD progression.
Topics: Mice; Animals; Humans; Alzheimer Disease; Mice, Transgenic; Disease Models, Animal; Circadian Rhythm; Brain; Amyloid beta-Peptides
PubMed: 37607543
DOI: 10.1016/j.cmet.2023.07.014 -
European Journal of Neurology Feb 2024Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid-β. This is a joint statement of the European... (Review)
Review
Our aim is to review the most recent evidence on novel antibody therapies for Alzheimer's disease directed against amyloid-β. This is a joint statement of the European Association of Neurology and the European Psychiatric Association. After numerous unsuccessful endeavors to create a disease-modifying therapy for Alzheimer's disease, substantial and consistent evidence supporting the clinical effectiveness of monoclonal antibodies aimed at amyloid-β is finally emerging. The latest trials not only achieved their primary objective of slowing the progression of the disease over several months but also demonstrated positive secondary clinical outcomes and a decrease in amyloid-β levels as observed through positron emission tomography scans. Taken as a whole, these findings mark a significant breakthrough by substantiating that reducing amyloid-β yields tangible clinical benefits, beyond mere changes in biomarkers. Concurrently, the regular utilization of the new generation of drugs will determine whether statistical efficacy translates into clinically meaningful improvements. This may well signify the dawning of a new era in the development of drugs for Alzheimer's disease.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Treatment Outcome; Antibodies, Monoclonal; Positron-Emission Tomography; Cognitive Dysfunction; Biomarkers
PubMed: 37697714
DOI: 10.1111/ene.16049 -
Alzheimer's & Dementia : the Journal of... May 2024This article describes the public health impact of Alzheimer's disease (AD), including prevalence and incidence, mortality and morbidity, use and costs of care and the...
This article describes the public health impact of Alzheimer's disease (AD), including prevalence and incidence, mortality and morbidity, use and costs of care and the ramifications of AD for family caregivers, the dementia workforce and society. The Special Report discusses the larger health care system for older adults with cognitive issues, focusing on the role of caregivers and non-physician health care professionals. An estimated 6.9 million Americans age 65 and older are living with Alzheimer's dementia today. This number could grow to 13.8 million by 2060, barring the development of medical breakthroughs to prevent or cure AD. Official AD death certificates recorded 119,399 deaths from AD in 2021. In 2020 and 2021, when COVID-19 entered the ranks of the top ten causes of death, Alzheimer's was the seventh-leading cause of death in the United States. Official counts for more recent years are still being compiled. Alzheimer's remains the fifth-leading cause of death among Americans age 65 and older. Between 2000 and 2021, deaths from stroke, heart disease and HIV decreased, whereas reported deaths from AD increased more than 140%. More than 11 million family members and other unpaid caregivers provided an estimated 18.4 billion hours of care to people with Alzheimer's or other dementias in 2023. These figures reflect a decline in the number of caregivers compared with a decade earlier, as well as an increase in the amount of care provided by each remaining caregiver. Unpaid dementia caregiving was valued at $346.6 billion in 2023. Its costs, however, extend to unpaid caregivers' increased risk for emotional distress and negative mental and physical health outcomes. Members of the paid health care and broader community-based workforce are involved in diagnosing, treating and caring for people with dementia. However, the United States faces growing shortages across different segments of the dementia care workforce due to a combination of factors, including the absolute increase in the number of people living with dementia. Therefore, targeted programs and care delivery models will be needed to attract, better train and effectively deploy health care and community-based workers to provide dementia care. Average per-person Medicare payments for services to beneficiaries age 65 and older with AD or other dementias are almost three times as great as payments for beneficiaries without these conditions, and Medicaid payments are more than 22 times as great. Total payments in 2024 for health care, long-term care and hospice services for people age 65 and older with dementia are estimated to be $360 billion. The Special Report investigates how caregivers of older adults with cognitive issues interact with the health care system and examines the role non-physician health care professionals play in facilitating clinical care and access to community-based services and supports. It includes surveys of caregivers and health care workers, focusing on their experiences, challenges, awareness and perceptions of dementia care navigation.
Topics: Humans; Alzheimer Disease; United States; Caregivers; Aged; COVID-19; Prevalence; Incidence; Health Care Costs; Aged, 80 and over
PubMed: 38689398
DOI: 10.1002/alz.13809 -
Biomedicine & Pharmacotherapy =... Sep 2023Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to... (Review)
Review
Alzheimer's disease (AD) is the most common neurodegenerative disease, resulting in the loss of cognitive ability and memory. However, there is no specific treatment to mechanistically inhibit the progression of Alzheimer's disease, and most drugs only provide symptom relief and do not fundamentally reverse AD. Current studies show that triggering receptor expressed on myeloid cells 2 (TREM2) is predominantly expressed in microglia of the central nervous system (CNS) and is involved in microglia proliferation, survival, migration and phagocytosis. The current academic view suggests that TREM2 and its ligands have CNS protective effects in AD. Specifically, TREM2 acts by regulating the function of microglia and promoting the clearance of neuronal toxic substances and abnormal proteins by microglia. In addition, TREM2 is also involved in regulating inflammatory response and cell signaling pathways, affecting the immune response and regulatory role of microglia. Although the relationship between TREM2 and Alzheimer's disease has been extensively studied, its specific mechanism of action is not fully understood. The purpose of this review is to provide a comprehensive analysis of the research of TREM2, including its regulation of the inflammatory response, lipid metabolism and phagocytosis in microglia of CNS in AD, and to explore the potential application prospects as well as limitations of targeting TREM2 for the treatment of AD.
Topics: Humans; Alzheimer Disease; Microglia; Neurodegenerative Diseases; Central Nervous System; Phagocytosis; Membrane Glycoproteins; Receptors, Immunologic
PubMed: 37517293
DOI: 10.1016/j.biopha.2023.115218 -
Nature Communications Oct 2023Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether...
Plasma amyloid-β (Aβ)42, phosphorylated tau (p-tau)181, and neurofilament light chain (NfL) are promising biomarkers of Alzheimer's disease (AD). However, whether these biomarkers can predict AD in Chinese populations is yet to be fully explored. We therefore tested the performance of these plasma biomarkers in 126 participants with preclinical AD and 123 controls with 8-10 years of follow-up from the China Cognition and Aging Study. Plasma Aβ42, p-tau181, and NfL were significantly correlated with cerebrospinal fluid counterparts and significantly altered in participants with preclinical AD. Combining plasma Aβ42, p-tau181, and NfL successfully discriminated preclinical AD from controls. These findings were validated in a replication cohort including 51 familial AD mutation carriers and 52 non-carriers from the Chinese Familial Alzheimer's Disease Network. Here we show that plasma Aβ42, p-tau181, and NfL may be useful for predicting AD 8 years before clinical onset in Chinese populations.
Topics: Humans; Alzheimer Disease; Amyloid beta-Peptides; Biomarkers; East Asian People; tau Proteins
PubMed: 37875471
DOI: 10.1038/s41467-023-42596-6 -
Cellular and Molecular Neurobiology Oct 2023The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological... (Review)
Review
The Apolipoprotein E ε4 (ApoE ε4) allele, encoding ApoE4, is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD). Emerging epidemiological evidence indicated that ApoE4 contributes to AD through influencing β-amyloid (Aβ) deposition and clearance. However, the molecular mechanisms of ApoE4 involved in AD pathogenesis remains unclear. Here, we introduced the structure and functions of ApoE isoforms, and then we reviewed the potential mechanisms of ApoE4 in the AD pathogenesis, including the effect of ApoE4 on Aβ pathology, and tau phosphorylation, oxidative stress; synaptic function, cholesterol transport, and mitochondrial dysfunction; sleep disturbances and cerebrovascular integrity in the AD brains. Furthermore, we discussed the available strategies for AD treatments that target to ApoE4. In general, this review overviews the potential roles of ApoE4 in the AD development and suggests some therapeutic approaches for AD. ApoE4 is genetic risk of AD. ApoE4 is involved in the AD pathogenesis. Aβ deposition, NFT, oxidative stress, abnormal cholesterol, mitochondrial dysfunction and neuroinflammation could be observed in the brains with ApoE4. Targeting the interaction of ApoE4 with the AD pathology is available strategy for AD treatments.
Topics: Humans; Alzheimer Disease; Apolipoprotein E4; Amyloid beta-Peptides; Apolipoproteins E; Brain
PubMed: 37227619
DOI: 10.1007/s10571-023-01365-1 -
Advances in Clinical and Experimental... Oct 2023Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the...
Recently, the U.S. Food and Drug Administration (FDA) approved 2 anti-amyloid monoclonal antibodies, aducanumab (June 7, 2021) and lecanemab (July 6, 2023), for the treatment of Alzheimer's disease (AD) patients, and will most likely also approve a 3rd one, donanemab, soon. While these antibodies have been shown to significantly reduce amyloid in the brain, there is little, if any, evidence that they provide clinically meaningful benefit for AD patients by slowing cognitive decline. I have said it before, and I say it again: the reported benefits of anti-amyloid antibodies observed in clinical trials are erroneous and based on misinterpretation of data and a trivial miscalculation. For example, Sims et al. (2023) reported in a phase III clinical trial that donanemab treatment of early symptomatic AD patients with amyloid and tau pathology provided 35% and 36% slowing of clinical progression and cognitive decline, respectively, as measured using the Integrated Alzheimer's Disease Rating Scale (iADRS) and Clinical Dementia Rating-Sum of Boxes (CDR-SB) psychometric tests. Here, in this editorial, I show that 2.5% and 9.6% would be better estimates for less cognitive impairment with donanemab treatment.
Topics: United States; Humans; Alzheimer Disease; Antibodies, Monoclonal
PubMed: 37831471
DOI: 10.17219/acem/172673