Tufte’s two-page spreads are designed one by one, based on the content. He painstakingly arranges every figure and every word so that the books will be both clear and beautiful.

Using LaTeX is to some extent antithetical to this idea. Instead of arranging everything by hand, you’re letting the typesetting engine make most of the decisions. There’s nothing inherently wrong with ceding this control, but it’s pretty much the opposite of Tufte’s style.

An expert using this tool is never going to be able to make something as carefully as Tufte would make it, because seizing precise manual control of typesetting and layout in LaTeX is a pain in the ass compared to using a tool like InDesign (or for that matter compared to scissors, paper, and a xerox machine).

The types of documents where (La)TeX excels are heavily structured and usually full of mathematical formulas. The more important the relationship between diagrams/images and the text, the worse off LaTeX is relative to a visual tool. Tufte’s books are at the furthest end of this spectrum, where LaTeX performs absolutely worst.

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For example, this document (among the links from ajtulloch’s sibling comment) looks absolutely nothing like a Tufte book, and is filled with typographic problems that wouldn’t ever make it past a halfway competent publishing house: http://tullo.ch/static/cambridge/AdvancedProbability-Lecture... (I’m not trying to pick on anyone; this is always going to be a problem when you compare the output of an automated tool against hundreds of hours of work by a perfectionist expert.)

Moreover, many of the design choices IMO make no sense in the context of a mathematical paper.