Considering the time between seasons, it would be perfect! Cancer!! Start the last season filming James Gandolfini as he is now: overweight. Then, stop production and allow Gandolfini to go on a diet to lose all the weight and beyond, to get outright skinny to give the impression that he is sick. The start of the series had Jackie, the Boss,dying from cancer, and you can have the end of the series with Tony, the Boss, dying from cancer.

Other options for the weight loss include a flashback scene (ala Godfather II) with Gandolfini a skinnier man and a hairpiece to indicate youth, with Carmella in a 1970's doo, showing them as they were when their kids were kids in happier times - perhaps in the aftermath of Meadow or Anthony, Jr getting wacked.