Derek Lowe's commentary on drug discovery and the pharma industry. An editorially independent blog from the publishers of Science Translational Medicine . All content is Derek’s own, and he does not in any way speak for his employer.

I’ve written a couple of times over the years about the idea that Alzheimer’s disease might have an infectious component to it. That’s been proposed many times, but it’s fair to say that it’s never caught on. For one thing, the amyloid hypothesis has always had a lot more going for it. I realize that I’ve poured scorn on that one in recent years, but that’s after a string of massive clinical failures based on it being right. It started out as by far the most plausible mechanism around, and even now, any further explanation of the disease is going to have to include an amyloid component, in much the same way that Einstein’s relativity also included an explanation of why Newtonian mechanics was so workable so much of the time.

A new paper in Neuron, though, looks to be the most unignorable one yet with evidence that there’s some sort of viral/bacteial/fungal component to the disease. A team led out of a Mt. Sinai research group has gone over a pretty large sample of Alzheimer’s brain tissue (622 patients who died with the disease, and over three hundred control brains as well), sequencing infectious organism DNA, looking for changes in the proteome, etc. They find that aging brains in normal patients display plenty of viral signatures (as indeed is probably the case in many other tissues). But the AD samples were particularly enriched in herpesviruses 6A and 7, a result that repeated across three independent cohorts from different geographical locations (the brain tissue collections were from more than one previous effort). According to Stat, there’s a paper coming out next month from another group entirely that also implicates HHV6.

But are these viruses a cause of the disease, or are they something that shows up later? That is, do HHV 6A/7 give you Alzheimer’s, or does having Alzheimer’s bring on those viral infections? This has been the problem with many previous proposals for an infectious agent, and it’s a very difficult objection to overcome. I think that this is the first study, though, that has made it over that hurdle. The paper shows that viral DNA is, in fact, incorporated into neurons from the affected regions of the brain. What’s more, analysis of both protein and mRNA levels suggest that such infection produces changes in several transcriptional regulators (specifically, a set of zinc-finger transcription factors and G-quadraplex-associated proteins) that in turn affect expression of a number of very suggestive proteins downstream:

We found that multiple viruses interact with AD risk genes. HHV-6A stood out as notable with significant overlap (FDR < 3e-3) between the set of host genes it collectively induces across all tissues and AD-associated genes (Figure 5D, Table S7). This includes several regulators of APP processing and AD risk-associated genes, including gamma-secretase subunit presenilin-1 (PSEN1), BACE1, amyloid beta precursor protein binding family B member 2 (APBB2), Clusterin (CLU), Bridging Integrator 1 (BIN1), and Phosphatidylinositol Binding Clathrin Assembly Protein (PICALM). We also found that several other viruses regulate, or are regulated by, AD risk genes, including: (1) HAdV-C-induced expression of Complement Receptor 1 (CR1), and inhibition of Solute Carrier Family 24 Member 4 (SLC24A4), (2) inhibition of KSHV by Fermitin Family Member 2 (FERMT2), and (3) inhibition of HSV-2 by Translocase of Outer Mitochondrial Membrane 40 (TOMM40). These findings indicate multiple points of overlap between virus-host interactions and AD risk genes.

There’s also an association with neuronal loss, and this and other pathways seem to converge on miR-155 as an important factor (HHV6A inhibits its expression). The team then crossed a mouse strain that’s knocked out for this microRNA with one of the APP/presenilin mutant mouse lines that is susceptible to amyloid problems. And indeed, the resulting mice show significantly more amyloid plague formation at four months, and significantly more amyloid 1-42 in the brain.

This gets right at what I mentioned above: any alternate theory of Alzheimer’s will have to explain why there are so many apparent connections to amyloid handling. So this might well be real, and if it is, it really does open up a whole new set of mechanistic (and even therapeutic) possibilities. Although I don’t keep up with the literature in this field as well as I would were I still working in it, I think that this is one of the most significant Alzheimer’s papers I’ve seen in years. A mechanism through viral disturbance of transcription factors, miRNAs, and other such gene-expression pathways would fit well with the variations seen in the incidence and severity of the disease, because that lands you right into the mess of environmental factors, immune system variations, and so on.

The integrated findings of this study suggest that AD biology is impacted by a complex constellation of viral and host factors acting across different timescales and physiological systems (Figure 8B). This includes host mucosal defense and modulation of innate immune response by virus and host. It also includes disturbance of core biological processes, including some that are well described in AD (e.g., APP processing, cytoskeletal organization, mitochondrial respiration, protein synthesis, and cell-cycle control) and some that are less well characterized (e.g., widespread shifts in G4 activity and C2H2-TF regulatory programs). We note potential mechanisms (and candidate molecular mediators) that we find perturbed by viral species and that have known impacts on these altered processes, for instance, virally driven changes in protein synthesis machinery, tRNA synthetase activity, and nucleotide pool maintenance, which collectively exert complex effects on G4 regulation and C2H2-TF activity.

This paper immediately suggests several lines of research. HHV6A needs to be studied in more detail (and distinguished from HHV6B, which current tests don’t always do). Viral mechanisms of transcriptional disruption have already been investigated in other contexts, but there’s a lot to be done in the Alzheimer’s territory. We need to see if miR-155 is a real node in the system, and so on. And it wouldn’t do any harm to look at the effects of existing antiviral drugs on these HHV strains, would it? After years of writing about amyloid-centric disappointments, I think it’s great to have some new hypotheses to test!