Aducanumab (Marketed as Aduhelm) Approval Is Likely Based on Misinterpretation of PET Imaging Data

2021 ◽  
pp. 1-4
Author(s):  
Poul F. Høilund-Carlsen ◽  
Abass Alavi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Death ◽  
Advanced Disease ◽  
Amyloid Plaques ◽  
Imaging Data ◽  
Amyloid Deposits ◽  
Amyloid Accumulation ◽  
Apparent Reduction ◽  
Cerebral Amyloid

According to the FDA, aducanumab (Aduhelm), the recently approved anti-Alzheimer drug, reduces the level of cerebral amyloid plaques—a hallmark finding in patients with Alzheimer’s disease—and this will result in a reduction in clinical decline. The authors of this article are not convinced that amyloid deposits are a hallmark of Alzheimer’s disease and are of the opinion that the apparent reduction in amyloid accumulation following aducanumab treatment is likely instead a result of continued and advanced cerebral cell death and, thus, not a sign of improvement but of an even more advanced disease.

ASSOCIATION BETWEEN CEREBRAL AMYLOID ACCUMULATION AND SYNAPTIC DENSITY IN ALZHEIMER'S DISEASE: A MULTITRACER PET STUDY

2020 ◽  
Vol 28 (4) ◽  
pp. S123-S124
Author(s):  
Ryan O'Dell ◽  
Adam Mecca ◽  
Ming-Kai Chen ◽  
Tyler Godek ◽  
Joanna Harris ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Synaptic Density ◽  
Amyloid Accumulation ◽  
Cerebral Amyloid

Activated microglia and cerebral amyloid deposits in alzheimer's disease

1992 ◽  
Vol 143 (6) ◽  
pp. 646-649 ◽  
Author(s):  
J.M. Rozemuller ◽  
P. van der^Valk ◽  
P. Eikelenboom
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Activated Microglia ◽  
Amyloid Deposits ◽  
Cerebral Amyloid

scholarly journals Massive accumulation of luminal protease-deficient axonal lysosomes at Alzheimer’s disease amyloid plaques

2015 ◽  
Vol 112 (28) ◽  
pp. E3699-E3708 ◽  
Author(s):  
Swetha Gowrishankar ◽  
Peng Yuan ◽  
Yumei Wu ◽  
Matthew Schrag ◽  
Summer Paradise ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Spatial Relationship ◽  
Amyloid Plaques ◽  
Retrograde Transport ◽  
Amyloidogenic Processing ◽  
Amyloid Deposits ◽  
Neuronal Processes ◽  
Β Amyloid ◽  
Massive Accumulation

Through a comprehensive analysis of organellar markers in mouse models of Alzheimer’s disease, we document a massive accumulation of lysosome-like organelles at amyloid plaques and establish that the majority of these organelles reside within swollen axons that contact the amyloid deposits. This close spatial relationship between axonal lysosome accumulation and extracellular amyloid aggregates was observed from the earliest stages of β-amyloid deposition. Notably, we discovered that lysosomes that accumulate in such axons are lacking in multiple soluble luminal proteases and thus are predicted to be unable to efficiently degrade proteinaceous cargos. Of relevance to Alzheimer’s disease, β-secretase (BACE1), the protein that initiates amyloidogenic processing of the amyloid precursor protein and which is a substrate for these proteases, builds up at these sites. Furthermore, through a comparison between the axonal lysosome accumulations at amyloid plaques and neuronal lysosomes of the wild-type brain, we identified a similar, naturally occurring population of lysosome-like organelles in neuronal processes that is also defined by its low luminal protease content. In conjunction with emerging evidence that the lysosomal maturation of endosomes and autophagosomes is coupled to their retrograde transport, our results suggest that extracellular β-amyloid deposits cause a local impairment in the retrograde axonal transport of lysosome precursors, leading to their accumulation and a blockade in their further maturation. This study both advances understanding of Alzheimer’s disease brain pathology and provides new insights into the subcellular organization of neuronal lysosomes that may have broader relevance to other neurodegenerative diseases with a lysosomal component to their pathology.

Utilizing Advanced Imaging and Surrogate Markers Across the Spectrum of Alzheimer's Disease

CNS Spectrums ◽  
2005 ◽  
Vol 10 (S18) ◽  
pp. 13-16 ◽  
Author(s):  
Mark A. Mintun
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Pet Imaging ◽  
Amyloid Plaques ◽  
Pet Tracer ◽  
Positron Emission ◽  
Amyloid Deposits ◽  
Wide Range ◽  
Β Amyloid ◽  
The Brain

AbstractAlzheimer's disease is a degenerative neurological condition characterized by the presence of β-amyloid plaques and neurofibrillary tangles in the limbic and neocortical regions of the brain. Pittsburgh Compound-B (PIB), a benzothiazole analog, has recently been found to specifically label amyloid deposits in positron emission tomography (PET) studies of the brain, opening the door for a wide range of applications related to Alzheimer's disease. In this article, data demonstrating the specificity of PIB as a PET tracer for β-amyloid lesions are reviewed, and the potential clinical applications of PIB PET imaging is discussed. Because amyloid plaques are common even in elderly individuals who are not suffering from dementia, the primary diagnostic function of PIB PET imaging presumably would be to rule out, rather than definitively confirm, Alzheimer's diagnoses in elderly patients. Other possible uses include monitoring plaque loads in patients receiving anti-amyloid therapy for Alzheimer's disease, as well as assessing plaque formation in unaffected individuals as a means of evaluating future Alzheimer's disease.

scholarly journals Therapeutic Potential of Neu1 in Alzheimer’s Disease Via the Immune System

2021 ◽  
Vol 36 ◽  
pp. 153331752199614
Author(s):  
Aiza Khan ◽  
Sumit Das ◽  
Consolato Sergi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune System ◽  
Therapeutic Potential ◽  
Amyloid Plaques ◽  
Beta Amyloid ◽  
Underlying Mechanism ◽  
Amyloid Deposits ◽  
Potential Therapeutic Role

Alzheimer’s Disease (AD) is pathologically characterized by the accumulation of soluble oligomers causing extracellular beta-amyloid deposits in form of neuritic plaques and tau-containing intraneuronal neurofibrillary tangles in brain. One proposed mechanism explaining the formation of these proteins is impaired phagocytosis by microglia/macrophages resulting in defective clearance of soluble oligomers of beta-amyloid stimulating aggregation of amyloid plaques subsequently causing AD. However, research indicates that activating macrophages in M2 state may reduce toxic oligomers. NEU1 mutation is associated with a rare disease, sialidosis. NEU1 deficiency may also cause AD-like amyloidogenic process. Amyloid plaques have successfully been reduced using NEU1.Thus, NEU1 is suggested to have therapeutic potential for AD, with lysosomal exocytosis being suggested as underlying mechanism. Studies however demonstrate that NEU1 may activate macrophages in M2 state, which as noted earlier, is crucial to reducing toxic oligomers. In this review, authors discuss the potential therapeutic role of NEU1 in AD via immune system.

scholarly journals C99 selectively accumulates in vulnerable neurons in Alzheimer’s disease

2019 ◽  
Author(s):  
Maria V. Pulina ◽  
Maya Hopkins ◽  
Vahram Haroutunian ◽  
Paul Greengard ◽  
Victor Bustos
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cognitive Impairment ◽  
Amyloid Precursor Protein ◽  
Amyloid Plaques ◽  
Beta Amyloid ◽  
Sensitive Assay ◽  
Brain Areas ◽  
Amyloid Deposits ◽  
The Brain

ABSTRACTIntroductionThe levels and distribution of amyloid deposits in the brain does not correlate well with Alzheimer’s disease (AD) progression. Therefore, it is likely that Amyloid-precursor-protein proteolytic fragments other than beta-amyloid contribute to the onset of AD.MethodsWe developed a sensitive assay adapted to the detection of C99, the direct precursor of beta-amyloid. Three postmortem groups were studied: control with normal and stable cognition; subjects with moderate AD, and individuals with severe AD. The amount of C99 and beta-amyloid was quantified and correlated with the severity of AD.ResultsC99 accumulates in vulnerable neurons, and its levels correlate with the degree of cognitive impairment in patients suffering from AD. In contrast, beta-amyloid levels are increased in both vulnerable and resistant brain areas.DiscussionThese results raise the possibility that C99, rather than beta-amyloid plaques, is responsible for the death of nerve cells in Alzheimer’s disease.

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