Biochemistry is complex, and particularly so in the brain. The amyloid cascade hypothesis of Alzheimer's disease essentially states that slow aggregation of amyloid-β over years causes the onset of later and much more severe stages of Alzheimer's disease, meaning the chronic inflammation in brain tissue and tau aggregation that kills neurons. The hypothesis has so far survived the failure of amyloid-β clearance via immunotherapy to produce patient benefits, as well as the evidence for a subset of older individuals to exhibit high levels of amyloid-β without progressing to Alzheimer's disease. Researchers continue to explore and modify their hypotheses regarding how exactly amyloid-β leads to later issues.
At present, the research community appears to be leaning towards the idea that once the later stages of inflammation and tau aggregation take hold, they form a self-sustaining feedback loop of increasing pathology, and amyloid-β becomes largely irrelevant after that point. In this case early use of immunotherapies should reduce disease risk, but trials focused on prevention will take a long time to run to completion. It is still possible that the most visible amyloid-β aggregation outside cells is only a side-effect of chronic infection or other processes that generate inflammation and pathology. In that case, targeting amyloid-β will not help. In either case, therapies that target the mechanisms of inflammation or tau aggregation will be the next focus. There is a good chance that senolytic treatments to remove senescent cells in the brain will help, for example.
In the Alzheimer's cascade hypothesis, plaques unleash tangles; alas, where neuroinflammation fits in has been hazy. Now, the first study to combine imaging of microglial activation with amyloid and tau PET in the human brain places neuroinflammation squarely in between the two. Researchers report PET findings from 108 adults who range from cognitively healthy to Alzheimer's disease (AD) dementia. Across this cohort, the regional distribution of microglial activation mirrored Braak staging, and correlated with tangle load. Moreover, the extent of microglial activation predicted the spread of tangles into later Braak regions, suggesting it drove this pathology. Notably, the relationship between neuroinflammation and tangles only occurred in the presence of amyloid plaques, and all three pathologies were required for cognitive decline.
"Amyloid potentiates microglial activation to drive tau propagation in the brain. The data suggest neuroinflammation should be included in biological definitions of AD. This is a very compelling study, and certainly advances our understanding of the crosstalk between microglial activation, amyloid, and tau burden in the clinical context."
PET imaging studies have consistently shown that as plaques spread into cortex, tangles break out of the medial temporal lobe to rampage across the brain, attacking cognition as they go. But the mechanistic connection between the pathologies remained mysterious. The medial temporal lobe contains little amyloid, making a direct interaction unlikely. Animal and in vitro studies hinted that microglia might be the missing link. In mice, activation of the NLRP3 inflammasome in microglia caused the cells to spew cytokines that triggered tau phosphorylation in neurons. Further, microglia isolated from AD brains contained tau seeds, which the cells released into the culture medium. The data implied that microglia phagocytose aggregated neuronal tau present in aging brain, then try but fail to digest it, and instead end up strewing it across the brain.