Quarterback Ryan Fitzpatrick will be counted on to lead the Bills to a win over the Patriots and Tom Brady, who is 18-2 against Buffalo in his career. (US Presswire)

Patriots at Bills -- Week 4

Where: Ralph Wilson Stadium, Orchard Park, N.Y. (turf, outdoors)

When: Sunday, 1 p.m., ET (CBS)

Spread: Patriots by 3.5

Forecast: Light rain, overcast, 51-60 degrees

Records: Bills (Overall: 2-1, AFC East: 0-1); Patriots (Overall: 1-2, AFC East: 0-0)

Past results: Two most recent meetings -- Jan. 1, 2012: Patriots 49, Bills 21; Sept. 25, 2011, Bills 34, Patriots 31. Series record: Patriots hold a 62-41-1 advantage.

What matters: Can the Bills grab a two-game lead over the defending AFC East champions? The Patriots have dominated the division for the past decade, but they’re off to a slow start to 2012. A loss to Buffalo would put the Bills in prime position for a legitimate push for the division crown, though you can never count out the Patriots. Last year’s Bills-Patriots game in Buffalo was one of the Bills’ most exciting games in franchise history -- a 34-31 thriller that ended Buffalo’s long losing streak to New England. In that game, Buffalo staged a remarkable comeback to defeat the Patriots for the first time in its last 16 attempts. But the Patriots trounced the Bills in the regular-season finale, 49-21. The Bills have one of their better teams in years, but it remains to be seen if the balance of power in the division has truly shifted.

Who matters: For the Bills, it starts with their defensive line. Can the revamped front get after Tom Brady in the pocket? The Bills gave out $120 million to Mario Williams and Mark Anderson to create havoc for opposing QBs -- and if you read between the lines, Brady in particular. The line is coming off a productive Week 3 win over Cleveland, when each starting lineman picked up at least one sack. It remains to be seen how the Bills’ backfield will look on offense -- both RBs C.J. Spiller and Fred Jackson are dealing with injuries. Jackson is making his way back from a sprained knee he suffered in Week 1; Spiller suffered a sprained shoulder in Week 3. As always, the QBs matter. Brady (79 of 118, 887 yards, 4 TDs, 1 INT) hasn’t been exactly Brady-like to start the year, but he always is dangerous. Most of his struggles have to do with subpar pass protection. Bills QB Ryan Fitzpatrick rebounded nicely from his Week 1 debacle (50 of 86, 581 yards, 8 TDs, 3 INTs thus far), but his accuracy leaves something to be desired. He’ll need to be at his best against New England.

Key matchups: DE Mario Williams vs. RT Sebastian Vollmer, LB Bryan Scott vs. TE Rob Gronkowski, CB Justin Rogers vs. WR Wes Welker. Williams picked up his first sack as a Bill in Week 3, and the Bills are hoping he can increase that total against New England. Vollmer and the Patriots offensive line have had some issues holding up in protection and have had to keep TEs in more frequently. That could limit the opportunities for Gronkowski, who has had some big days against the Bills in the past. Scott is the team’s top nickel linebacker and will likely see plenty of Gronkowski. Rogers has performed well since replacing Leodis McKelvin as Buffalo’s nickel CB, but he’ll go up against one of the best slot receivers ever in Welker. After a slow start to the year, Welker has picked it up as of late, as he made eight receptions for 142 yards in a Week 3 loss to the Ravens.

Injuries of note: Jackson (right knee sprain) is expected to make his return, which would be a major boost for the Bills. Spiller (left shoulder) is hoping to return, but another week is more likely. WR Ruvell Martin (ankle) is not expected to play.

Inside stuff: It’s not often that a holder is worth watching, but it’s worth noting for this game. After the surprise release of P Brian Moorman on Tuesday, the Bills will have a new holder for K Rian Lindell -- either Moorman’s replacement, Shawn Powell, or backup QB Tyler Thigpen. Powell practiced his holds during the open portions of practice during the week. If the game comes down to a big kick, it’s possible the new holder could directly affect the outcome.

Connections: Bills DE Mark Anderson rejuvenated his career with the Patriots last year, recording 10 sacks with New England in 2011. Gronkowski is from Amherst, N.Y., a northern suburb of Buffalo. Bills TE Lee Smith was New England’s fifth-round pick in 2010.

Stat you should know: Brady has an 18-2 record against the Bills in his career. He’s thrown more touchdowns (46) against Buffalo than against any other opponent in the NFL.

Record watch: With one touchdown, Spiller could become the first Bill since Cookie Gilchrist in 1962 to score a TD in seven consecutive games.

Looking ahead: The Bills have a difficult West Coast trip following the Patriots game. They go up against San Francisco in Week 5 and Arizona in Week 6. Given the Cardinals’ surprising start, that stretch looks more difficult than it did before the season. The Bills will also be staying in Arizona between Weeks 5 and 6 instead of returning to Buffalo, which will make for a long road trip. The Patriots, meanwhile, will head back home and get ready for an always entertaining battle between Brady and the Denver Broncos’ Peyton Manning.

Prediction: Patriots 28, Bills 21

For more updates on the Bills, follow correspondent Mark Ludwiczak on Twitter @CBSBills and @MarkLud12.