So, I've been swapping back and for forth several hours the past couple days - Axe2 in my amp's loop, Axe2 4CM, pedalboard, straight into amp - and I've come to a conclusion.
Using the AxeFX2 with my amp via the 4 cable method produces a tone with a significantly muddied harmonic structure. What does that nonsense mean? Let me explain.
So, I'm not talking about "brighter" or "darker" tone. As far as I can tell, the frequency content is mostly the same - or near enough to not make much difference to me. What I'm talking about is the fidelity of the gain coming from the amp. If you plug directly into a nice amp with nice tubes, guitar tuned, and you hammer out a thick open-string chord with open-sounding harmonies (think power chords or 2 chords), you're going to hear some beautiful harmonic resonance. Depending on how nice your amp is, you'll be able to practically hear each string and its overtones ring individually (rather than just a mess of noise), and the overdrive, while hairy, shouldn't blend all that harmonic information into unrecognizable sludge. In my experience, the more cable you run, the more times your signal is passed through a DSP, the cheaper your amp is, the more that harmonic information is smeared and the more the fidelity (clarity) of your tone is diminished. It's the kind of thing that makes you look at your amp, go "hmm...", and start reaching to turn your Bass knob down even though you don't feel like there's too much Bass in your sound.
In my opinion, using the Axe2 significantly decreases the fidelity of my overdrive sound - more so than my pedalboard. I was hoping to have the Axe's far superior effects supplant my pedalboard entirely (maybe I'd keep a drive or two), but, now that I've heard what it's doing to my clarity of my sound, I think I'll be sticking to my board. At least that stuff can be removed from the signal chain when I'm not using it.
Ahh well. It's still an awesome recording resource and digital rig!