Why Alzheimer trials fail: removing soluble oligomeric beta amyloid is essential, inconsistent, and difficult
1VCU School of Medicine, Richmond, VA, USA; Icahn School of Medicine at Mt Sinai, Mt Sinai, NY, USA.
Neurobiology of Aging
|November 12, 2013
Summary
Toxic soluble amyloid-beta oligomers, not just plaques, drive cognitive decline. Current Alzheimer's trials may fail because they don't sufficiently reduce this soluble oligomer load.
Area of Science:
- Neuroscience
- Biochemistry
- Pathology
Background:
- Soluble oligomers of amyloid precursor protein (APP) peptides are neurotoxic and correlate with cognitive decline.
- Current Alzheimer's clinical trials targeting insoluble amyloid plaques have shown limited success.
- Existing treatments have not consistently reduced the soluble oligomer load.
Purpose of the Study:
- To investigate the role of soluble amyloid-beta (Aβ) oligomers in Alzheimer's disease pathogenesis.
- To evaluate the effectiveness of current therapeutic strategies in reducing soluble Aβ oligomer load.
- To propose a "triple therapy" approach targeting multiple stages of the amyloid cascade.
Main Methods:
- Analysis of autopsied human brains to measure soluble Aβ oligomer load.
- Review of clinical trial data focusing on cognitive outcomes and Aβ load reduction.
- Examination of the interrelationship between Aβ peptide synthesis, oligomer formation, and plaque deposition.
Main Results:
- Soluble Aβ oligomers are highly neurotoxic and their levels correlate with cognitive impairment.
- Clinical trials have failed to significantly reduce soluble oligomer load, contributing to lack of cognitive improvement.
- A "triple therapy" approach simultaneously targeting Aβ synthesis, oligomerization, and plaque formation may be necessary.
Conclusions:
- Failure of Alzheimer's clinical trials may stem from insufficient reduction of toxic soluble Aβ oligomers.
- Current therapeutic strategies need to address the entire amyloid cascade, including soluble oligomers.
- Autopsied brain analysis is crucial for evaluating trial outcomes and validating the amyloid hypothesis.
Related Concept Videos
01:26Alzheimer's Disease: Overview
1.7K
Alzheimer's Disease (AD) is a continually advancing neurodegenerative disorder, distinguished by escalating memory loss, cognitive dysfunction, and dementia. The disease unfolds in three stages: preclinical, mild cognitive impairment (MCI), and dementia. Its onset is insidious, and the progression gradual, with the cause not well explained by other disorders.
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
The clinical diagnosis of AD hinges on the presence of memory and other cognitive impairments. Biomarkers, such as changes in Aβ...
1.7K
01:22Alzheimer's Disease: Treatment
1.3K
Alzheimer's Disease (AD), a neurodegenerative disorder, is pathologically identified by amyloid plaques and neurofibrillary tangles composed of tau protein. AD pharmacotherapy aims to manage cognitive symptoms, delay disease progression, and treat behavioral symptoms. The treatment is primarily symptomatic and palliative, with no definitive disease-modifying therapy available. Cholinesterase inhibitors, including donepezil (Aricept), rivastigmine (Exelon), and galantamine (Razadyne), are...
1.3K
01:23Alzheimer Disease ll: Pathophysiology
42
Alzheimer disease involves structural changes in the brain that begin long before symptoms appear. The most distinctive features are extracellular neuritic plaques and intracellular neurofibrillary tangles.Neuritic plaques form in the cerebral cortex and around blood vessels. These plaques contain a dense core of beta-amyloid (Aβ)—a toxic protein fragment that clumps outside neurons. The core is surrounded by damaged neuronal extensions, as well as reactive astrocytes and...
42
03:03Amyloid Fibrils
10.3K
Amyloid fibrils are aggregates of misfolded proteins. Under most circumstances, misfolded proteins are either refolded by chaperone proteins or degraded by the proteasome. However, in the case of a mutation or a disease, these proteins can accumulate to form large clusters and often further assemble to form elongated fibers, called fibrils.
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
Amyloid deposits were observed as early as 1639 in the liver and the spleen. In 1854, Rudolph Virchow performed iodine staining,...
10.3K
01:29Alzheimer Disease l: Introduction
29
Alzheimer disease is a chronic, progressive, and irreversible neurodegenerative disorder and the most common cause of dementia in older adults. It leads to gradual neuronal loss, causing cognitive decline, behavioral changes, and loss of functional independence.Risk Factors and EtiologyThe disease is multifactorial. Age is the strongest risk factor, with prevalence doubling every 5 years after age 65. Genetic factors include mutations in genes such as APP, PSEN1, and PSEN2, which are associated...
29
01:22Dementia l: Introduction
35
Dementia is an acquired, progressive syndrome characterized by a decline in multiple cognitive domains severe enough to impair daily functioning and reduce independence. Although memory loss is a central feature, the diagnosis requires additional deficits involving language, executive function, visuospatial skills, judgment, calculation, or abstract reasoning. These cognitive impairments reflect underlying neurodegenerative or vascular processes that gradually disrupt neuronal networks...
35