An Examination of Reverse Causation in the Association between Serum Folate Deficiency and Dementia
Anat Rotstein, Arad Kodesh, Yair Goldberg, Abraham Reichenberg, Stephen Z Levine- Psychiatry and Mental health
- Cellular and Molecular Neuroscience
- Geriatrics and Gerontology
- Neurology (clinical)
- Developmental Neuroscience
- Health Policy
- Epidemiology
Abstract
Background
Evidence suggests that serum folate deficiency increases the likelihood of deficits in cognitive performance and neurological functioning. This situates serum folate as a possible biomarker positioned to modify the risk of dementia. However, the few observational studies that have examined the association between serum folate deficiency and the risk of dementia have shown inconsistent results. Prior studies of the associations between serum concentrations of folate and the risks of incident dementia have been unable to directly exclude the possibility that such associations are a by‐product of reverse causation. Reverse causation has been demonstrated to be particularly relevant to studies of dementia, because the neuropathological processes of dementia may start decades before a formal diagnosis is given. Thus, plausibly, serum folate deficiency is a consequence of preclinical dementia rather than its cause.
Method
A prospective cohort aged 60‐75 years (n = 27 188) without pre‐existing dementia for at least 10 years, was tested for serum concentrations of folate and followed up for dementia. Serum folate deficiency was classified as present (<4.4 ng/mL), otherwise absent. HRs and 95% CIs from competing risks Cox models were fitted to quantify the associations between serum folate deficiency and the risks of dementia. To examine reverse causation, the analysis was stratified by duration of follow‐up. Based on the median follow‐up cut point, the associations between serum folate deficiency and dementia were scrutinized in the first then second half of follow‐up. Serum folate deficiency was assumed to be little affected by preclinical dementia when the assessment was long before dementia onset and considerably affected when the assessment was nearer the diagnosis.
Result
The presence compared with the absence of serum folate deficiency was associated with higher risks of dementia (HR = 1.68; 95% CI 1.32 to 2.13; p<0.001). Evidence for reverse causation were moderate for dementia.
Conclusion
Serum concentrations of folate may function as a biomarker used to identify those at risk of dementia and mortality; however, reverse causation is likely. Further research is needed to examine the role of serum folate deficiency in dementia etiology.