There are MANY differences. The Uni-Q drivers are profoundly better than the LS50 Uni-Q. According to Johan Coorg, a spokesman and "Brand Ambassador" for KEF, the LS50 uses the same Uni-Q driver as the R500's. The one used in Reference and Blade/Blade 2 is hand built with higher-end components (voice coils, poles and shorting rings) and matched to within 0.5dB output of each other for a matched pair.
Moving onto the crossover network, the Reference series uses high-end capacitors and inductors, plus Nordost internal wiring. The LF and HF networks are built on separate boards and decoupled from the cabinets. The "Link"-equipped binding posts are carefully machined and operate silky smooth.
The hand-built cabinet includes a multi-layer front baffle with a thick brushed aluminum front plate and inner plate sandwiching a "constrained layer" damping material. Throughout the cabinet, similar constrained layer damping material is employed to reduce any cabinet resonance. On the outside of the cabinets, the wood finishes are given multiple coats of hand-rubbed lacquer, while the Piano Black and HIgh Gloss White finishes are done in the same way as a high-end piano for years of service and enough thickness to endure refinishing if required. The "Flexible Port" features interchangeable soft, specially shaped tubes of different lengths so the speaker port output is configurable for various placement, and are devoid of turbulent noise that could affect sound quality.
All are built to order, so each is given individual attention and documentation signed off by the people who worked on them. When they have a major upgrade available, they can be retrofitted (at a cost.) This has happened so far with only the $220,000 Muon. Being made to order, KEF will not be stuck with discounting "remaining stock" as they have with the previous Q series and now underway with the R series.
All this adds significant cost, but from what I've heard it's worth it if you have the money to invest.