Worst case is that 99% of the rest of the city is still accessible by automobile. High density areas like city downtowns should cater to pedestrians more due to that being the more humane overall.
As other people mentioned, there'd be workarounds for people with mobility issues for sure.
Well, Calgary for example has a Land area of 825.56 km2 or an Urban area of 586.08 km2, and a downtown area of 1.8 km2. Which means it has less than 0.3% area for the downtown.
I suppose there are pockets of high density that aren't counted for. Also Calgary is probably unusually spread out for the given population compared to larger cities like New York or Los Angeles or San Francisco.
As other people mentioned, there'd be workarounds for people with mobility issues for sure.