Driftless
Donor
Have one of the Portuguese explorers who tried to reach the americas before Columbus make it there, inevitably spread disease, but get lost at see trying to return to Europe. the earlier European diseases are introduced to the americas the sooner the mass die off happens and the more time people have to recover their numbers before interacting with actually European colonizers, not just their germs.
I think the disease cycle has to start by 1100-1200CE to allow time for both spread, adaptation, and population recovery. That is, if the next wave of Europeans arrive by 1500CE