One thing that strikes you is how much used to happen in an episode. The episode might feature the person who got the flashbacks but there were usually sub-plots going on, some of them totally unrelated to the person with the flashbacks.
The flashbacks were a lot shorter, also. Several 3rd season episodes were little more than framing scenes for the flashback. In the first season the flashback never dominated the episode. I would guess that they took 1/4-1/3 of the screen time. In later seasons I would put it more like 2/3 of the screen time.
Knowing what is coming doesn't change the experience much. I know that half the first season cast will be dead by the end of the fourth season but the episodes are interesting enough to distract you from this.
There were a lot of dropped sub-plots. A few of them like the meaning of the numbers were resolved in other media. Others might yet be resolved but it is hard to see how. Danielle's entire backstory would appear to have been dropped when she was killed. Then there is the statue and the skeletons in the cave. Some plot points have been contradicted. It was important that Claire raise her child but Kate ended up with him.
Some characters lost their edge. In the first season Kate was secretive and manipulative. At one point she wanted on the raft so she arranged for Sun to drug Michael, drawing suspicion to Sawyer. She regularly lied and tricked both Jack and Sawyer. More recently she has simply become part of a love triangle (or possibly a love pentagram).
Of course the biggest difference is that in the first season we were still meeting the characters and they were still meeting each other. Plus the island was still new. Now we are familiar with them. Introducing new characters helps a little but the core cast is still there and getting a little tiresome. Especially Jack.