Ask Lemmygrad

In both cases, smallpox/disease reduced the native population by about 90%

It should be noted; it wasn't just disease, or rather, disease (as always throughout history and till today) only got far, far worse when natives were also subjected to constant war, violent encroachments, and man-made (American-enforced, rather) famines.

Subject any population- European populations included- to such pressures and their immune systems will be greatly compromised. It wasn't just disease- these went hand-in-hand with systemic policies, ideology, and rhetoric that encouraged disease and killed and terrorized the natives in many other ways, with the end goal of- as you said, assimilation or death (ie. genocide)- and even the question of how much "assimilation" was actually on the table is another matter- they wanted to erase their cultures, religion, livelihoods, rights, etc. yes- but even those who had adopted much of the western customs like the "5 civilized tribes" eventually were driven west in forced marches (the trail of tears- ie. another form of genocide, akin to what was inflicted on the Armenians) despite the US law itself being on their side.

Because no amount of "assimilation"- by natives, by blacks (as one can see with "black Wall Street"/Tulsa, Oklahoma), by other minorities- changed the guiding ethos of the US- if white settler society wanted what you had, or simply wanted you out of the way and saw you as an eyesore to be culled, or wanted you as a slave- one way or another it would take what it wanted through force. And white settler-colonial and imperialist society wants everything the world over and more (and even that would not quench it IMO- because it is a all-devouring, monstrous system that, without new lands to conquer or peoples to subjugate and enslave, would likely collapse in on itself as it is doing now)- still does to this day, as should be clear to anyone sensible as well.