Evidence for Amyloid and Tau to Synergize to Make Neurodegeneration Worse

When looking at epidemiological evidence of the burden of amyloid-β and phosphorylated tau in the aging brain, and relating it to incidence and degree of neurodegenerative disease, it is worth bearing in mind that this doesn't demonstrate causation. It remains the case that amyloid-β aggregation could be peripheral to the progression of Alzheimer's disease, a side-effect of the primary mechanism, which could be something along the lines of chronic inflammation driven by cellular senescence or chronic inflammation driven by persistent infection by herpesviruses or the like.

That amyloid-β has been cleared in clinical trials without showing much benefit to patients could arise for many different reasons: that it is only important to pathology in early stages; that it is not important at all; that vascular issues and other problems present in many Alzheimer's patients would also need repair in order to see benefits; and so forth. This is one of the challenges inherent in dealing with complex end-stage age-related diseases. They have a number of potential contributing causes and the only viable way to understand which of those causes are actually important is to address them. Further, it is quite possible that given a set of equally important causes, addressing any one of them on its own may appear to fail.

Current Findings Give Backing to Anti-Amyloid Therapies

In the course of Alzheimer's disease, two proteins called amyloid and tau accumulate in the brain. A study with more than 200 participants now provides insights into the interaction of these pathological phenomena. The data suggest that tau load in the brain impairs memory functions only when amyloid burden is also high. These findings therefore support therapeutic approaches aimed at removing amyloid from the brain in the early stages of Alzheimer's disease.

"It has long been known that deposits of tau proteins in the hippocampus and in neighboring brain areas impair memory. In the case of amyloid, on the other hand, no clear relationship to memory performance has been found to date. For this reason, among others, it is debated whether it makes sense at all to target amyloid therapeutically. Our current results suggest that this could indeed be helpful for memory function in the early stages of the disease. The crucial aspect is that you don't look at tau in isolation, but together with amyloid pathology. This is where a link becomes apparent when you study a larger number of individuals and accordingly have solid statistics."

Amyloid pathology but not APOE ε4 status is permissive for tau-related hippocampal dysfunction

We investigated whether the impact of tau-pathology on memory performance and on hippocampal and medial temporal memory function in non-demented individuals depends on the presence of amyloid pathology, irrespective of diagnostic clinical stage. We conducted a cross-sectional analysis of the observational, multicentric DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE). Two hundred and thirty-five participants completed task functional MRI and provided CSF.

We found that total-tau and phospho-tau levels were negatively associated with memory performance in both tasks and with novelty responses in the hippocampus and amygdala, in interaction with Aβ42 levels. Our data show that the presence of amyloid pathology is associated with a linear relationship between tau pathology, hippocampal dysfunction, and memory impairment, although the actual severity of amyloid pathology is uncorrelated. Our data therefore indicate that the presence of amyloid pathology provides a permissive state for tau-related hippocampal dysfunction and hippocampus-dependent recognition and recall impairment.

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