I’m not sure about the current state of the science but there were a bunch of studies that showed that first contact with Europeans had transmitted smallpox as early as 1520 which over the next couple hundred years wiped out maybe 50% or more of the native population in advance of colonization such that later arriving Europeans had the mistaken impression that the continent had always been largely empty when some estimates put the native population pre-colonization at 120 million or more.