It seems reasonable to believe, based on the evidence, that amyloid-β aggregation is associated with the onset of Alzheimer's disease, but the question has always been whether it was a suitable target to reverse the condition. The failure of reductions in brain amyloid-β via immunotherapy to produce meaningful clinical success has brought other views of the condition to the forefront. For example, raised amyloid-β may be a side-effect of persistent infections that produce chronic inflammation, and it is the inflammation that is important. Or amyloid-β may provoke sufficient inflammation and cellular senescence in supporting cells of the brain for it to become self-sustaining as the core of the condition, even once the amyloid is removed.

A logical next step at the present time would be to test senolytic therapies that can pass the blood-brain barrier, as this should both clear senescent cells and reduce the chronic inflammation in the brain that results from senescent cell signaling. If this produces results in humans that are as promising as those in mice, that might be a good indication that the primary driving mechanism of Alzheimer's disease (and perhaps many other neurodegenerative conditions) is chronic inflammation.

The Anti-Amyloid Treatment in Asymptomatic Alzheimer disease (A4) Study is an ongoing prevention trial in clinically normal older individuals with evidence of elevated brain amyloid. The large number of participants screened with amyloid positron emission tomography (PET) and standardized assessments provides an unprecedented opportunity to evaluate factors associated with elevated brain amyloid. This cross-sectional study included screening data in the A4 Study collected from April 2014 to December 2017 and classified by amyloid status. Data were was analyzed from 2018 to 2019 across 67 sites in the US, Canada, Australia, and Japan and included 4486 older individuals (age 65-85 years) who were eligible for amyloid PET, clinically normal, and cognitively unimpaired. Amyloid PET results were acquired for 4486 participants (71.29 ± 4.67 years; 2647 women), with 1323 (29.5%) classified as amyloid-β (Aβ)+. Aβ+ participants were slightly older than Aβ-, with no observed differences in sex, education, marital or retirement status, or any self-reported lifestyle factors. Aβ+ participants were more likely to have a family history of dementia (3320 Aβ+ [74%] vs 3050 Aβ- [68%]) and at least 1 APOE ε4 allele (2602 Aβ+ [58%] vs 1122 Aβ- [25%]). Aβ+ participants demonstrated worse performance on screening Preclinical Alzheimer Cognitive Composite results and reported higher change scores on the Cognitive Function Index. In conclusion, elevated brain amyloid was associated with family history and APOE ε4 allele but not with multiple other previously reported risk factors for AD. Elevated amyloid was associated with lower test performance results and increased reports of subtle recent declines in daily cognitive function. These results support the hypothesis that elevated amyloid represents an early stage in the Alzheimer's continuum.

Link: https://doi.org/10.1001/jamaneurol.2020.0387