. Functional brain architecture is associated with the rate of tau accumulation in Alzheimer's disease. Nat Commun. 2020 Jan 17;11(1):347. PubMed.


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  1. This work by Franzmeier and colleagues is an elegant study that further illuminates the relationship between tau deposition and the functional network architecture of the brain. A particularly interesting outcome of the work lies in the discovery of a longitudinal relationship between the increase in tau deposition and the functional connectivity of certain brain regions. More strongly connected brain regions showed a stronger covariance in the longitudinal tau deposition. In addition, the authors demonstrate the intriguing possibility to predict future tau deposition of a brain region based on its connectivity strength to other tau-seeding brain regions, their respective tau load, and the approximate length of the connections.

    The longitudinal aspect of this paper is of great relevance, because the possibility of predicting the course of the disease could play a major role, e.g., in the interpretation of follow-up data collected in therapy trials. The paper provides further convincing arguments for the relationship between functional connectivity and tau deposition, i.e., the network degeneration hypothesis. Of particular interest is the finding that regions with low-tau accumulation rates showed high connectivity to regions with similarly low-tau accumulation rates. This implies that connectivity strength per se is not the driver but rather the pathway of tau propagation.

    These results are in good agreement with the hypothesis of "neuronal spreading" of tau deposits depending on synaptic activity. It should not be forgotten, however, that a direct proof of this hypothesis cannot yet be deduced from these and other similar data. Other theories of the causal neuropathology of Alzheimer's disease are in principle also consistent with these results. Regions of strong functional connectivity may also be similar in their molecular/cell-biological nature, e.g., with regard to genetic background (as mentioned by the authors themselves), but also as far as other factors such as metabolic, vascular/perfusion-related conditions, etc., are concerned. The activity-induced tau release described by the authors themselves could lead to increased tau formation (or "missorting") at both ends of a functional connection in regions of high neuronal activity, without necessarily requiring a "spreading" of the tau pathology. Lifelong increased neuronal or metabolic activity within certain highly active networks could lead to a "wear and tear" effect, which could occur in the affected regions simultaneously, in correlation with their connectivity. It is also conceivable that a so-far-unidentified noxious factor agent that is causally upstream of the tau accumulation could spread along the affected networks, entailing tau aggregation. In this context, inflammatory effects are also to be considered. It would also be important to further investigate the connection with structural connectivity already discussed by the authors

    Further factors requiring additional research would be time-course and direction of tau distribution across the brain. Of note, the authors demonstrate a link between connectivity and tau accumulation in parallel, i.e., simultaneously at “both ends” of connected brain regions. However, in case of a neuronal spread, we would expect a certain delay between the starting point and destination of the spreading pathology. This is, of course, methodologically difficult to ascertain. Also, the analysis of functional connectivity does not allow a direct statement about the directionality of the connection. That is, in the models examined by the authors, it would have to be assumed that the tau pathology spreads in both directions, i.e. upstream from soma to dendrites or downstream from soma along the axon. Further molecular biological research would be important to address this question.

    As far as can be discerned, the authors seem to have used different fMRI connectivity data sets for the two populations studied, one (BioFINDER) from an independent healthy control collective (healthy connectivity) and one (ADNI3) from the patients themselves (possibly already affected connectivity). This may explain some of the differences between the results in the two groups and raises some questions: It is assumed that functional connectivity itself is impaired already early in the course of Alzheimer's disease (possibly by the protein pathology that is deposited). This means that the pattern of functional connectivity changes with disease progression, and thus, eventually also the spread of pathology. It seems to be legitimate to use connectivity data from healthy controls in order to obtain information on whether the pathology spreads along the "usual" connectivity pathways, i.e., those typical for healthy controls. This seems to be the case, but it does not allow direct conclusions on actual distribution pathways in patients. It is unclear whether the pattern of propagation in patients with affected network function is still determined by patterns of "previous (healthy)" or "current (diseased)" pathways of high connectivity.

    It seems paradoxical, at least at first glance, that high tau accumulation should still correlate positively with high connectivity in advanced disease stages. On the contrary, it is assumed that tau contributes to a breakdown of the functional connection (e.g., through reduced microtubular function or synaptic dysfunction). Thus, if high tau accumulation in a network contributes to network breakdown, then tau should eventually be high where network connectivity is low (i.e., correlation of high tau burden with low connectivity would be expected). This also has been demonstrated topographically, e.g., by the high tau deposition in the default-mode network and the known loss of connectivity of this network.

    In principle, it is also conceivable that the tau deposition could be a reaction to a disturbance of functional connectivity (e.g., as an attempt to improve or to reorient the connection of the affected neuron). In this case, tau would form in "previously" highly interconnected brain regions, as soon as connectivity between those regions declined. From this point of view, the attempt to block the spread of tau by targeted therapeutic reduction of neural activity or connectivity could be counterproductive and harmful.

    Finally, the question of the interplay between tau and amyloid remains open. The authors report, in line with previous work, that tau accumulation was accelerated in amyloid-positive individuals in their study. This seems plausible, but the pathophysiological interaction with tau is still unclear, especially with regard to network function. It is often discussed that amyloid, especially in soluble form, may exert a synaptotoxic effect. If this is the case, the result would be reduced functional connectivity, which would then contribute to a reduced rather than increased spread of the tau pathology. This illustrates that research will still have to focus on coherently merging different disease hypotheses.

    In summary, the current study provides compelling evidence for an interrelation between functional connectivity and longitudinal tau accumulation in the brain, supporting the network degeneration hypothesis. The study nicely adds to current disease hypotheses and also stimulates the need for additional research in this interesting field. Particularly the question about the relationship between tau deposition and functional connectivity before and after disease onset (with resulting changes in network function) requires further attention.

    View all comments by Alexander Drzezga
  2. This paper carries forward an emerging theme in the literature, which they reference, that Alzheimer’s disease is a network disease of the brain. By that I mean that the anatomy, or the space the disease occupies, conforms to what has been dubbed the brain’s cortical-hippocampus memory system. This can be viewed also as the brain’s default mode network, with which the hippocampus has an intimate relationship. Of interest here is that such networks have been identified largely by functional brain imaging, first with PET and now routinely with fMRI. They can be seen in resting-state fMRI data as very specific regional correlations in the fMRI signal (a very surprising and important discovery). Along with the default mode network, others go by names such as dorsal and ventral attention, salience, control, and the more commonly known ones such as motor and visual.

    The idea that AD would reside in one of these networks is certainly of interest and that it is a network concerned with memory makes sense. But what is emerging is that AD not only resides within a network but, as the disease progresses, it “moves” from one part of the network, in this case from the hippocampus, to the back end of the default mode network where AD pathology (i.e., plaques, then tangles) begins in the back of the brain and moves forward. What this paper addresses is how that might occur with regard to tau accumulation. The authors are suggesting that within a functional network tau is passed from one part of the network to another. To put it simply, relationships matter in the progression of the disease. This is an interesting but not an entirely new idea. It is nice to see it so well-articulated here but exactly how this is occurring remains to be fully understood.

    View all comments by Marcus Raichle
  3. This work elegantly addresses an important question: Does tau spread through synaptically connected brain regions as Alzheimer's disease progresses? By using detailed functional connectivity maps and, importantly, two independent cohorts of individuals, the authors provide compelling evidence that neuronal connections, rather than anatomical proximity, are key for propagation of tau pathology.

    View all comments by Amy Pooler

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  1. Connectivity, Not Proximity, Predicts Tau Spread