About 1 year ago I completed the restoration of a 3 story row house in Philadelphia, which also included replacement of the ancient oil-fired FA furnace with one of the new 90% efficiency gas units (Rheem, bought on-line). I also added AC, using a Rheem 3.5 ton unit (which features a screw compressor!!; pretty quiet and smooth running).
To make the AC work, I built a three story return, which included a 10" vent fan, 2 speed, 2 and 3.5 amps, located at the top of the return. This pulls air from the two top floor BR's (about 300 sq ft, 8' ceiling) thru a soffit on a common wall. The near-to-ceiling grids mounted on each side of the soffit are 8" X 30", and there is a 8" X 8" in the stairwell/hallway, at the end of the soffit.
During the winter, the return vent fan is not used, and the original in-floor returns (a 15" X 40" in the centrally located DR, where the thermostat is, and a 8" X 12" in the entrance hall way, both on the first floor) are used as the original heating system was planned.
During the summer, the 15" X 40" is sealed off, and the return fan is run with the AC. This arrangement works quite well; guests sometimes complain that the top floor is too cold in the summer, despite a flat roof, and full western exposure of the front of the building. (We did blow insulation above the ceiling.) The middle floor's two vents we open in the summer, keep half to 2/3rds closed in the winter. 1st floor is ~ 700 sq ft, 2nd ~ 600, each of these have 10' ceilings.
Ceiling fans on the 3rd floor are directed upwards, and help the AC (less so when directed downwards), and are not run in the winter.
All of the supply (i.e., not return) vents are either in-floor, or low in-wall. Our feeling is that the partial vacuum created by the return vent fan and furnace blower (the cover on the large return is nicely sucked down and seals when the AC is on) pulls cold air up to the 3rd floor pretty well, while the partial closing the 1st and 2nd floor's supply vents in the winter provides plenty of warm air to be sent throughout the house.
My point is: Seasonal adjustment of the supply and return flows are required to heat / cool a multi-story using a single HVAC system.
BK