Does hypoxia affect pilots differently from people on the ground?
The analogy that if someone can become acclimated to working at high altitudes and therefore should not need supplemental O2 in an airplane is flawed. While flying - at least straight and level - does not require strenuous exertion, it is very cognitively taxing. It's a constant process if taking in a deluge of incoming data, be it instrument read outs, navigation information, external stimuli, radio chatter, the grunt work of flying the aircraft etc. 

Unfortunately, the conscious and cognitive centers of the brain as well as the eyes require an oxygen rich blood supply in order to operate fully; if this is denied or reduced, serious deterioration of these abilities will occur and can happen rapidly within seconds.

Night vision is also severely impaired by hypoxia as the rods in your eyes require a lot of oxygen as well. I did an experiment one night in C172 where I took off at sea level and climbed to 12,500 feet. Looking outside the aircraft at those altitudes I could see a few bright stars but after I had landed back at close to sea level, I looked up at the night sky while tying down the airplane and could see a sky filled with stars as well as the bright gaseous strip of the Milky Way. The effect was dramatic; you really are affected by hypoxia at night.