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followed from 2002 to 2012. Cox proportional hazards models and restricted cubic splines were used to estimate the HRs of tHcy levels on the risk of dementia.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer\u2019s disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (\u22646.4 \u00b5mol\/L), the multivariable-adjusted HRs (95%\u2009CI) of the highest quintile (\u226511.5 \u00b5mol\/L) were 2.28 (1.51\u20133.43) for all-cause dementia, 1.96 (1.19\u20133.24) for AD and 2.51 (1.14\u20135.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8\u201315 \u00b5mol\/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity \u22640.02). In stratified analyses by the most recognised genetic polymorphism affecting tHcy concentrations (methylenetetrahydrofolate reductase C677T), the positive association of tHcy with all-cause dementia persisted in both non-carriers and carriers of the risk allele, and even tended to be stronger in the former (p for heterogeneity=0.07).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>High serum tHcy levels are associated with an elevated risk of dementia, AD and VaD in a non-linear manner, such that an exposure-response association is present only within a relatively high range of tHcy levels. Non-genetic factors affecting serum tHcy concentrations may play important roles in tHcy-dementia associations irrespective of the genetic susceptibility for raised tHcy.<\/jats:p><\/jats:sec>","DOI":"10.1136\/jnnp-2019-322366","type":"journal-article","created":{"date-parts":[[2020,3,31]],"date-time":"2020-03-31T21:17:21Z","timestamp":1585689441000},"page":"540-546","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":27,"title":["Serum homocysteine and risk of dementia in 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