How will I notice when the spare fails, if it's only a spare and I don't regularly use it? Then I'm down to only one key, and as any grumpy backup admin will tell you, if you have only one copy of something, you have zero copies.

I would have a key plugged into the computer pretty much all the time when I'm working, so anyone who compromises the computer can impersonate me as long as I'm at work. This would be mildly inconvenient to the attacker, but wouldn't actually stop the attacker. And if the computer isn't compromised, how is anyone going to get into my GitHub account even without 2FA? They certainly aren't going to do it by guessing my 16-character generated password or Ed25519 SSH key.

Something-I-know is worthless for authentication in the age of GPU password cracking. Most humans, including myself, do not have photographic memories with which to memorize cryptographically secure passwords. We're all using password managers for a reason, and a password database is something you have, not something you know.