Your ancestor–perhaps more than one–may have perished in a 19th century epidemic. Cholera and other illnesses could sweep through an area, wrecking devastation in a very short matter of time. The difficulty now can be in learning about these past outbreaks.
Local newspapers and county histories are two places to start looking for this type of information. If the time period is right, one can look through old death certificates one after the other to see the cause of death.
Academic articles in a variety of journals (historical, sociological, medical, etc.) may also mention earlier epidemics. Readers without home access to materials of this type may wish to see if they can access academic journals though their local library. Some academic studies may be online and located through an internet search–that’s where one on Indiana was located. Annual reports of state boards of health (if they existed) may mention epidemics as well. These items may be on GoogleBooks as was this 1880-1881 report from Illinois was.
An article on the Library of Congress website, “Cartography of Contagion” may be of interest as well.
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If you look at disease records, it’s apparent that tuberculosis was a world wide epidemic for centuries. It was definitely one of the main killers prior to the 20th century. Not much was known as to contagion factors or control. In 19th century America tb accounted for one out of every 10 deaths according to the NIH! But it didn’t kill everyone who got it.
Something I didn’t realize until I read a book about Benjamin Franklin and his family and then did some research was that tuberculosis can affect the brain as well as or instead of the lungs.
That might be a reason you could find ancestors listed as an inmate in a mental institute in a 19th century or even early 1900s census.
Mortality Schedules are an interesting snapshot of localized, moment in time look at what communities were going through.