One thing that came to mind is that computers are notoriously brittle compared to a brain. If you damage a single transistor in the processor you can bring down the whole thing. Not so sensitive with components in memory. We know the brain can take some damage and still function quite well, but are there single neurons or tiny groups of them that will basically bring down the system if damaged?

I also think the brain has important features more detailed in function than a 6502 so the applicability of the methods isn't necessarily invalid. For example, we don't know why neurons can transfer mitochondria between them, we don't know what is encoded in DNA, we don't even know how instinctive behaviors are encoded (or perhaps I just don't know).

As someone who once reverse engineered a processor from the gates up, I honestly don't know how one could do it top-down. The details at the bottom are critical, but also not critical. Decoding the microcode was critical, but determining precise timing and some other things was not needed to write a fairly functional emulator.