The modern explanation is that disease played a major role, but it's disease that's closely related to the social and political disruptions from European contact.

Some examples: Spaniards enslave the Taino of Hispaniola, who are ravaged by diseases with lethality and infectiousness boosted by the malnutrition and stress of their enslavement. Spaniards take over Tenochtitlan, then destroy the sewer systems of the valley of Mexico. A series of E. Coli and salmonella epidemics known as Cocoliztli subsequently ravage the Mexican highlands. Spaniards get involved with a bitter civil war in Peru, and diseases decimate the displaced and destabilized populations. Spaniards institute corvee labor and create a famine in the southwest, which is followed by decades of recurrent epidemic diseases that heavily affect the people most directly under Spanish influence. Nomadic groups largely outside Spanish control, but still physically in the same regions like the Apache and the Comanche then became ascendant political forces in the resulting demographic collapse.

And the result of these losses was permanent because the populations ended up displaced or absorbed into colonialism.