I have been reading in recent years about the pre-Colombian status of the American population. Arciologists are constantly discovering large settlements , before contact with Europe there were a lot more people here than we realise.
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Over half the population of Tenotichtlan, as Mexico City was called in its Aztec days, died from various diseases, such as smallpox, cholera and European childhood diseases like measles and whooping cough within a year of the arrival of the Spanish. Indians had no immunity to these diseases.
Plymouth Colony was built on the remains of an older Indian village. The area had been previously visited by English, and an Indian named Squanto who had sailed away with them and then sailed back and spoke some English, told them that this village had mostly all died from disease.
Before the settlers and the pioneers came the trappers and explorers, and with them came diseases. It is safe to assume that half the native population or more had died of European and African diseases before the settlers arrived.
With the Europeans came horses, and with horses, the Indians became more nomadic, most tribes moving westward, away from diseases and settlers.