Normally, however, the defining issue in Southern Politics post Civil War was race and populism, and free trade was actually the more "populist" belief at the time because it made farmer's lives much easier and made purchasing goods cheaper. There is not to my knowledge reason to think that racial attitudes in these regions were all that much more progressive than the rest of the South at the time as the Knoxville Riots and Lynchings proved, nor do I have much reason to think that the population in the area was much more rich and prosperous than the rest of the South. Nationalism and a lack of unionization are good Republican indicators, sure, but what exactly attracted East Tennesseans to the Gold standard, high protective tariffs, and support for civil rights for African Americans? Because from 1868-1932, that is what they would have been voting for.
Being a very fundamentalist area in terms of religion, as well as not having substantial amounts of industry, with many poor small farmers with perhaps crude racial beliefs, you would think this would be right in William Jennings Bryan's wheelhouse. Yet McKinley swept the area both times, and they were his strongest areas besides Vermont in 1896.
East Tennessee had the first Abolitionist news paper in the nation, and in 1814 had an emancipation society that was pretty strong until the 1830s. The Knoxville Riots were a rather one off event to the best of my knowledge, with the contemporary Black leaders of the city stating the riots were not indicative of the larger community while the local National Guard (Predominantly White) units rather forcefully ended the disturbances. Was discrimination an issue? Yes, but it certainly appears a lot less than in the nation at large and certainly so for the South.
As far industry and tariffs go, the region was rather stalwart proponents of Henry Clay and his tariff systems, with several Whigs elected prior to the Civil War. Chattanooga and Knoxville, due to railroads being established through the area, have rather consistently grown in size and industry since the 1850s. Kingsport has had the Eastman Kodak plant since the 1920s, and a munitions plant (Owned by BAE) since around WWII.
Maybe if East Tennessee got to be it's own state (almost certainly as a result of the Civil War, no doubt), the local Democrats could organise themselves better and you could have more competitive elections there, maybe something like West Virginia.
West Virginia got its strong Democratic trend due to large numbers of coal miners able to be unionized, which East Tennessee lacks.
Patronage certainly may have been a part of it, no doubt.
They voted for Whigs and Republicans rather strongly prior to the rise of the patronage systems, so that doesn't appear to be a cause. Even with the rise of the system, the local Republicans had to come to what was basically a power-sharing arrangement with the State Democrats over it.
It just seems strange that you have an area's political alignment survive several realignment periods. That level of continuity is unusual. Demographically speaking, it likely should have gone to the Democrats after the demise of the Bourbon Democrat faction, as the old Civil War loyalty component became less important with the rise of W.J. Bryan. If not then, however, FDR likely should have made the difference, due to his massive approval rating in the poor areas of the South. LBJ was probably the most successful in turning areas of mid Appalachia to the Democrats, to be fair, but the turmoil that followed only united the region with the rest of the South, still under the banner of the Republican Party.
Strong opposition to big government (Civil War issues relating to such, Moonshine culture, etc...) and the first signs of the emerging divide of social issues came with FDR. Plus, although I don't have the data for it, I have a strong inkling GDP per capita has been high in the area for a rather long time.