The amyloid cascade hypothesis:an updated critical review

Results from recent clinical trials of antibodies that target β-amyloid (Aβ) for Alzheimer's disease (AD) have created excitement and have been heralded as corroboration of the amyloid cascade hypothesis. However, while Aβ may contribute to disease, genetic, clinical, imaging, and biochemical data suggest a more complex etiology. Here we review the history and weaknesses of the amyloid cascade hypothesis in view of the new evidence obtained from clinical trials of anti-amyloid antibodies. These trials indicate that the treatments have either no or uncertain clinical effect on cognition. Despite the importance of amyloid in the definition of AD, we argue that the data point to Aβ and amyloid playing a minor etiological role. We also discuss data suggesting that the concerted activity of many pathogenic factors contribute to AD and propose that evolving multi-factor disease models will better underpin the search for more effective strategies to treat the disease

FDG-PET versus Amyloid-PET Imaging for Diagnosis and Response Evaluation in Alzheimer’s Disease:Benefits and Pitfalls

In June 2021, the US Federal Drug and Food Administration (FDA) granted accelerated approval for the antibody aducanumab and, in January 2023, also for the antibody lecanemab, based on a perceived drug-induced removal of cerebral amyloid-beta as assessed by amyloid-PET and, in the case of lecanemab, also a presumption of limited clinical efficacy. Approval of the antibody donanemab is awaiting further data. However, published trial data indicate few, small and uncertain clinical benefits, below what is considered “clinically meaningful” and similar to the effect of conventional medication. Furthermore, a therapy-related decrease in the amyloid-PET signal may also reflect increased cell damage rather than simply “amyloid removal”. This interpretation is more consistent with increased rates of amyloid-related imaging abnormalities and brain volume loss in treated patients, relative to placebo. We also challenge the current diagnostic criteria for AD based on amyloid-PET imaging biomarkers and recommend that future anti-AD therapy trials apply: (1) diagnosis of AD based on the co-occurrence of cognitive decline and decreased cerebral metabolism assessed by FDA-approved FDG-PET, (2) therapy efficacy determined by favorable effect on cognitive ability, cerebral metabolism by FDG-PET, and brain volumes by MRI, and (3) neuropathologic examination of all deaths occurring in these trials.</p

Reference values for fluorine-18-fluorodeoxyglucose and fluorine-18-sodium fluoride uptake in human arteries : a prospective evaluation of 89 healthy adults

OBJECTIVE: Reference values of fluorine-18-fluorodeoxyglucose (F-FDG) and fluorine-18-sodium fluoride (F-NaF) uptake in human arteries are unknown. The aim of this study was to determine age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake. PARTICIPANTS AND METHODS: Uptake of F-FDG and F-NaF was determined in the ascending aorta, aortic arch, and descending thoracic aorta. In addition, F-FDG uptake was determined in the carotid arteries and F-NaF uptake was determined in the coronary arteries. Arterial F-FDG and F-NaF uptake were quantified as the blood pool subtracted maximum activity concentration in kBq/ml (BSF-FDGmax and BSF-NaFmax, respectively). In addition to determining reference values, we evaluated the influence of age and sex on BSF-FDGmax and BSF-NaFmax. RESULTS: Arterial F-FDG and F-NaF uptake was assessed in 89 healthy adults aged 21-75 years (mean age: 44±14 years, 53% men). Both BSF-FDGmax and BSF-NaFmax increased with age. BSF-FDGmax increased with age in the descending aorta (β=0.28; P=0.003), whereas BSF-NaFmax increased with age in the ascending aorta (β=0.18; P<0.001), aortic arch (β=0.19; P=0.006), descending aorta (β=0.33; P<0.001), and coronary arteries (β=0.20; P=0.009), respectively. BSF-FDGmax and BSF-NaFmax were not influenced by sex, except for BSF-FDGmax in the ascending aorta. CONCLUSION: Prospective evaluation of 89 healthy adults generated age-specific and sex-specific reference values of arterial F-FDG and F-NaF uptake. Our findings indicate that arterial F-FDG and F-NaF uptake tend to increase with age