Leon is notably cold towards Luis for a long time, only really accepting his earnestness just before he dies. It seems strange, but considering the last person Leon trusted during a crisis situation was Ada Wong? It makes sense Leon would consider outside parties offering "help" untrustworthy. More so when this version of Luis used to work for Umbrella.
Luis being a former cop in the original RE4, it kind of makes sense that original RE4 Leon was not wary against Luis then. But considering that RE2 REmake's Leon met RE2 REmake Ada who introduced herself as an "FBI Agent", it still makes sense for RE4 REmake Leon to be wary of Luis even if Luis is still introduced as a former cop.
One possible reason why the Merchant isn't bothered by the more hostile Plagas, no matter where he goes? The blue-light lantern he keeps next to him may have either similar or identical properties to the blue-flamed lanterns that Ashley can throw to immobilize the Armadura Leon has to fight after he picks up the Lion Head, and the blue-flame lantern she has to use during her solo section. One of the notes Ashley can read on getting the Salazar family crest makes mention of the blue flames for protection against them. Las Plagas don't show up in daytime when the sun is out, so it stands that the blue-flames emit some spectrum of ultraviolet light that incapacitates them. On the theory of the Merchant being also infected by las Plagas, if the implications that his Plagas is much like his original personality, then his Plagas simply cedes control to him whenever the blue lantern is lit.
Luis is revealed to be a member of Umbrella Lab No. 6, A.K.A the exact same team that worked on the Nemesis project. It makes total sense that someone who has worked on advanced parasites like him before will have the know-how to make the Plaga the potent bioweapon it is.
Though no longer a former cop this time around, Luis' past as an Umbrella scientist still somewhat justifies his combat skills. After all, anyone who works in an environment where both their bosses and their creations could kill them at any moment would be dumb to not learn some self-defense skills.
The Plaga suppressant Luis gives Leon is now an injector pen rather than a pill bottle. This makes a lot more sense; injectable medicine is delivered much faster into the bloodstream whereas pills have to be metabolized in the stomach which takes more time and their potency can be diminished. When dealing with something like Las Plagas where time is of the essence, having the suppressant be injectable is a smart move.
Luis is a big fan of Don Quixote, and believes Leon to be the Sancho to his Quixote and Ashley's Dulcinea. One well known moment from Cervantes' work has the title character fighting a windmill, believing it to be a giant. Guess what kind of boss Luis helps Leon fight in the castle? An El Gigante. Also, Quixote dies, Just like Luis.
Méndez sparing Leon once his infection is confirmed makes a little more sense this time around, as Krauser is a trusted member of the Los Iluminados in this continuity. The aspect of having another servant just as capable as Krauser must be extremely appealing to Saddler, while Krauser himself definitely wants his former comrade to join him and further validate his decision to abandon his humanity (which is exactly what he tries to convince Leon to do during their boss fight).
In the Amber Storeroom when Saddler tries to force Ashley to shoot Leon with his own gun, Ashley resists, manages to divert two of the shots to two cultists, but is eventually forced to pull the trigger on Leon. Luckily, the gun conveniently jams. This makes perfect sense since a semi automatic pistol with a slide requires a steady wrist to cycle the next round after firing. Ashley is untrained, fires one handed at the cultists, and is probably still resisting. The gun is even correctly shown to have a jammed casing in the ejection port, which Leon has to clear.
Ashley not holding the gun steadily/firmly has an explicit term: limp wristing. And a jammed casing sticking out of the ejection port is referred to as a stovepipe. Limp wristing has a direct effect on increasing the risk of creating a stovepipe, as the ejection mechanism in a semi-automatic pistol is designed around the gun being held firmly in order to work properly.
The designs of the new female enemies in the castle make it clear that the Ganados fought there are generally much younger than the ones fought in the village, as the latter all appear to be middle-aged or older. This can be explained by Salazar drafting the young and most physically able villagers into his personal fighting force, while leaving the older inhabitants to watch over the village under the command of Méndez.
Why send only one agent for an operation to rescue the President's daughter? Or, why won't Leon contact Hunnigan for more reinforcements apart from a single combat helicopter when the situation becomes even more complicated? It's because of the circumstances of Ashley's kidnapping being an inside job forcing Leon and Hunnigan to make do on what they have because its hard to find another trustworthy agent apart from Mike to assist Leon at the moment.
Luis' last words- "People can change, right?"- applied to both himself and Krauser, the man who dealt the fatal wound to him. Luis started out as a villain since he was involved in bio-weapon research, but became disillusioned with his research being exploited for the wrong ends and sought to make things right, never stopping even beyond his dying breath. Krauser, on the other hand, started out as a hero, but was disillusioned with what happened to his men during Operation Javier, as well as the government successfully obstructing his attempt to get justice for said men. As a result, he developed a misguided lust for power that turned him into a villain, eventually leading to his own demise.
Leon even asked Ada this question on whether she has changed. Of course, being the wild card that she is, Ada never changed as she is ultimately on her own side but one thing is for sure when it comes to Ada: She will never kill the innocent, at least not without any good reasons.
The ED theme "The Bullet or The Blade" has several lyrics that foreshadow Leon's careers before and after he joined DSO and worked with the others to combat biohazard threats. They mention Leon's failures to save Raccoon City and/or civilians from being killed by bioterrorists and at one point, has to fight rogue soldiers and rogue agents who align with said bioterrorists.
In the remake Ashley is slower to trust Leon during their first meeting, running away from him even after he tells her that her father sent him to rescue her. This makes sense when you find the document in Krauser's camp outlining the kidnapping plan, as it reveals that Krauser and his accomplices had infiltrated her security detail. Ashley has already been betrayed by her father's people once, so of course she's going to be jumpy even around her supposed rescuer.
There has been some confusion amongst fans as to why Wesker is using a regular Beretta in his arsenal instead of his custom Samurai Edge. However, when one remembers his appearances in Resident Evil 5, when dealing with Sheva, he indeed only used a generic Beretta. However, when facing off against his former STARS comrades Chris and Jill, that's when he makes it a point to use his Samurai Edge.
Fridge Humor: It's shown that the black-robed Verdugo, Pesanta, is a mutation of Salazar's female housekeeper in lore documents in the main game. From that, it suddenly makes sense why she was absent for most of the remake and became The Heavy to Ada Wong - her gender makes her pursuit of Ada a Designated Girl Fight, fully aping the more schlocky B-moviesResident Evil invokes, made horrifying by Pesanta's completely inhuman appearance.
Leon congratulates Ashley at one point by believing she already has experience in running away from creeps. He meant well, but it was obviously a very awkward thing to say. Assuming he's right in his assessment, however, implies some uncomfortable details about Ashley's life prior to having been kidnapped...
The remake features a number of new files containing background lore:
The Old Man's Journal and Village Records No. 1 tells the story of the Navarro Family, a grandfather and grandson who lived at the lake. The grandfather took the boy out hunting and told him stories of Don Quixote. One day, the grandfather was bitten by a wolf and became sick from his wound as his "body moves on its own" and he "can hear voices" from inside his head. Accepting his fate, he tells Bitores, "If anything happens, you know what to do." The villagers regrettably burn the grandfather to death in his cabin as his grandson watches in silence before leaving the village completely.
Salazar's castle contains a number of notes that cover the history of the Salazar family and Ramon himself. For generations, the Salazars had managed to both seal away Las Plagas and expand their household, but all of their efforts eventually unraveled by the modern day. Ramon's mother, Catalina, had "invited the devil" into their home and Ramon himself descended into complete violent insanity as he pledged to release the Plagas on Saddler's orders.
"8th Gen. Count Ramon" "His illness should have taken him."
The island covers the research that went on behind the scenes of the game's events. Saddler had kidnapped scientists and forced them to create new, evolved stages of the Plagas. If they refused, they were injected with the initial strain of Plagas, becoming too simple-minded for any complex task. If they followed orders, they would be injected with the superior species as part of Saddler's end goal.
A lot of fans have taken shots at Regeneradors having flabby skin, noting that it looks silly in an otherwise horrifying redesign. The thing is that the flabby skin is a realistic sign of what the regeneration is doing to the monster's body. If high speed regeneration was real, it would significantly increase the chances of cancer because the influx of new cells doesn't necessarily mean each new cell was replicated properly. If the Regeneradors have been regenerating on a constant basis since they were created, then there is a high chance those flabs of skin are tumors... tumors that can't kill them because they constantly regenerate. The alternative idea, is that the flabby skin is caused by high blood pressure. To regenerate at such rabid speeds, the Regenerador would need hyper fast blood pressure that is able to carry the nutrients through the blood stream as fast as possible. In real life, a side effect of high blood pressure is flabby skin, meaning that the Regeneradors with a blood pressure that is dozens of times faster than a normal human would have immensely flabby skin. It's easy to mock them as "thicc" or "fat" but what you're seeing is the realistic consequences of high speed regeneraton.
Osmund Saddler might have already been dead by the time the game begins. His advanced mutation compared to the original, his lack of care about his henchmen (the original game made a note of how Salazar and Mendez's losses hurt him) and hideously mutated body imply the Plagas infection destroyed the man. What's walking around now is a parasite wearing his skin like a suit. Alternately, Osmund and the Plaga inside him might have been working in concert up until Leon forces the One-Winged Angel transformation in the climax. Saddler makes many of the same chants in the climax that the ordinary Ganados do. Perhaps his powerful parasite also required a sacrifice of his higher brain functions?
During Separate Ways, Ada puts a tracking device on Leon with a microphone on the island and then activates it later only to hear Ashley struggling to say "Stop! No!" while crying, then Saddler saying "Sweet child, do not resist!". Ada doesn't have much knowledge of Saddler's mind control of the plaga so it can lead to some unfortunate implications to what Ada is thinking of what Saddler is doing to Ashley at this moment in front of Leon.
And a jammed casing sticking out of the ejection port is referred to as a stovepipe.