Serum homocysteine and risk of dementia in Japan

J Neurol Neurosurg Psychiatry. 2020 May;91(5):540-546. doi: 10.1136/jnnp-2019-322366. Epub 2020 Mar 31.


Objective: To examine the association between serum total homocysteine levels (tHcy) and dementia risk.

Methods: A total of 1588 Japanese adults aged ≥60 years without dementia were prospectively 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.

Results: During the follow-up, 372 subjects developed all-cause dementia; 247 had Alzheimer's disease (AD) and 98 had vascular dementia (VaD). Compared with the lowest tHcy quintile (≤6.4 µmol/L), the multivariable-adjusted HRs (95% CI) of the highest quintile (≥11.5 µmol/L) were 2.28 (1.51-3.43) for all-cause dementia, 1.96 (1.19-3.24) for AD and 2.51 (1.14-5.51) for VaD. In restricted cubic splines, the risk of all-cause dementia steadily increased between approximately 8-15 µmol/L and plateaued thereafter, with a similar non-linear shape observed for AD and VaD (all p for non-linearity ≤0.02). 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).

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / blood
  • Alzheimer Disease / etiology
  • Dementia / blood
  • Dementia / etiology*
  • Dementia / genetics
  • Dementia, Vascular / blood
  • Dementia, Vascular / etiology
  • Genetic Predisposition to Disease / genetics
  • Homocysteine / blood*
  • Humans
  • Hyperhomocysteinemia / blood
  • Hyperhomocysteinemia / complications
  • Japan / epidemiology
  • Methylenetetrahydrofolate Reductase (NADPH2) / genetics
  • Middle Aged
  • Proportional Hazards Models
  • Prospective Studies
  • Risk Factors


  • Homocysteine
  • MTHFR protein, human
  • Methylenetetrahydrofolate Reductase (NADPH2)

Supplementary concepts

  • Homocysteinemia