Amyloid PET: A Questionable Single Primary Surrogate Efficacy Measure on Alzheimer Immunotherapy Trials

Abstract

Using amyloid PET imaging as a single primary surrogate efficacy measure in Alzheimer’s disease immunotherapy trials, as happened when the FDA granted accelerated approval of aducanumab, is unjustified. In vivo evidence indicates that PET quantification of amyloid deposition is distorted and misrepresents effects of anti-amyloid treatments due to lack of specificity of the PET imaging probe, effects of amyloid-related imaging abnormalities, spill-over from high white matter signals, and questionable quantification models. Before granting approval to other immunotherapy candidates, the FDA should require rigorous evidence of all imaging claims and irrefutable documentation that proposed treatments are clinically effective and harmless to patients.

FDG PET (and MRI) for Monitoring Immunotherapy in Alzheimer Disease

“…The few images published as evidence of therapy-related amyloid removal show a large PET signal in the white matter, 8,17 which decreases during treatment, whereas the thin gray matter is almost invisible. We are concerned that what is seen is more likely an initial large nonspecific white matter signal, which decreases during treatment because of increased cell damage 27,34 . This belief is more consistent with the dose-dependent increase in ARIAs 9,16,18 and the increased loss of brain volume in treated patients compared with placebo patients as demonstrated by MRI in some of these trials 16,35,36 …”

“…This raises doubts not only about the validity of the amyloid hypothesis but also about the validity of the measurement methods used. The amyloid tracers are highly unspecific 25–27 . They accumulate in inflammatory processes, 28,29 whether due to neurodegeneration or antibody-antigen reactions, and in the skull 30 and the white matter, 31 all of which make quantification of gray matter uptake virtually impossible 26,32 .…”

“…The amyloid tracers are highly unspecific. [25][26][27] They accumulate in inflammatory processes, 28,29 whether due to neurodegeneration or antibody-antigen reactions, and in the skull 30 and the white matter, 31 all of which make quantification of gray matter uptake virtually impossible. 26,32 Add to this that white matter uptake of 18 F-florbetapir is myelin-related and associated with large-caliber axon degeneration.…”

Nicotinic acetylcholine receptors and learning and memory deficits in Neuroinflammatory diseases

“…Currently, the amyloid hypothesis stating that Aβ aggregation is the leading cause of AD ( McGeer and McGeer, 2013 ) is subjected to severe scrutiny, mainly because the therapies directed to reduce the senile Aβ plaques or the peptide aggregation have failed or proven minimally effective ( Hilund-Carlsen et al, 2022 ). In fact, for long time, it has been recognized that brains with significant amyloid Aβ burden can still function well when neuroinflammation is under control ( Echeverria et al, 2009 ).…”

“…The drugs approved by the US Food and Drug Administration (FDA) to treat cognitive impairment include acetylcholinesterase inhibitors (AChEI), donepezil, galantamine, and rivastigmine, the NMDA receptor antagonist memantine and a new immunotherapeutic treatment; these drugs delay the progression of the disease but do not stop its progression ( Porsteinsson et al, 2008 ; Kavanagh et al, 2011 ; Tayeb et al, 2012 ). The treatment for immunotherapy against Aβ peptides aggregation with aducanumab has been controversial, being one of the arguments that quantification of amyloid deposition by PET was imprecise due to the lack of specificity of the PET imaging probe ( Hilund-Carlsen et al, 2022 ).…”