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Title: Association of serum vitamin D with the risk of incident dementia and subclinical indices of brain aging the framingham heart study

Author
item KARAKIS, IOANNIS - Emory University
item PASE, MATTHEW - Boston University
item BEISER, ALEXA - Boston University
item BOOTH, SARAH - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item JACQUES, PAUL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item ROGERS, GAIL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University
item DECARLI, CHARLES - University Of California
item VASAN, RAMACHANDRAN - Framingham Heart Study
item WANG, THOMAS - Vanderbilt University
item HIMALI, JAYANDRA - Boston University
item ANNWEILER, CEDRIC - University Of Western Ontario
item SESHADRI, SUDHA - Boston University

Submitted to: Journal of Alzheimer's Disease
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/11/2015
Publication Date: 3/15/2016
Citation: Karakis, I., Pase, M.P., Beiser, A., Booth, S.L., Jacques, P.F., Rogers, G., Decarli, C., Vasan, R.S., Wang, T.J., Himali, J., Annweiler, C., Seshadri, S. 2016. Association of serum vitamin D with the risk of incident dementia and subclinical indices of brain aging the framingham heart study. Journal of Alzheimer's Disease. doi: 10.3233/JAD-150991.

Interpretive Summary: Beyond its function in maintaining bone health, vitamin D is increasingly recognized as an important multipurpose steroidal hormone. Vitamin D deficiency has been associated with a number of neurological illnesses including multiple sclerosis, Parkinson's disease, cerebrovascular disease, and dementia. Studies comparing patients with and without dementia have indicated that those with Alzheimer's disease (AD) have lower levels of vitamin D. Similarly, cross-sectional studies have identified that low levels of vitamin D are associated with poorer global cognitive performance and executive function, which involves cognitive processes related to reasoning, planning, and problem solving. However, these earlier studies that involved comparing patients with pre-existing cognitive impairment to subjects without cognitive impairment are susceptible to weaknesses because individuals with existing cognitive impairment may alter behavior or diet in ways that might affect vitamin D status (e.g. reduced mobilization leading to limiting sun exposure or reduced vitamin D intake.) Therefore, the results from these cross-sectional studies can be untrustworthy and difficult to interpret. Community-based prospective cohort studies, in which vitamin D status of participants without cognitive impairment is determined and related to the future risk of developing cognitive impairment and dementia, are not subject to these weaknesses, and consequently their results are more easily interpreted. However, few such studies have been done. Our objective was to explore the prospective association of serum vitamin D concentrations with incident dementia and clinically characterized AD in the large, community-based Framingham Heart Study. We also examined the associations of serum vitamin D concentrations with tests of neuropsychological function and structural brain changes using MRI scans. Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations (a marker of vitamin D status) measured between 1986 and 2001. Vitamin D status was considered as a continuous variable and dichotomized as deficient or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia, multiple neuropsychological tests and MRI markers of brain volume, white matter hyperintensities (a marker of a diminished state of overall brain health,) and silent cerebral infarcts. We observed that participants with vitamin D deficiency (8% of the cognitive sample) displayed poorer performance on neuropsychological tests of executive function, processing speed, and visuo-perceptual skills. Vitamin D deficiency was also associated with lower hippocampal volumes but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. The current study adds support to a growing body of literature implicating vitamin D deficiency in the development of neuropsychological impairment and subclinical brain injury. Correcting vitamin D deficiency through diet, lifestyle change, or supplementation may potentially help prevent brain injury and cognitive decline.

Technical Abstract: Background: Identifying nutrition- and lifestyle-based risk factors for cognitive impairment and dementia may aid future primary prevention efforts. Objective: We aimed to examine the association of serum vitamin D levels with incident all-cause dementia, clinically characterized Alzheimer's disease (AD), MRI markers of brain aging, and neuropsychological function. Methods: Framingham Heart Study participants had baseline serum 25-hydroxyvitamin D (25(OH)D) concentrations measured between 1986 and 2001. Vitamin D status was considered both as a continuous variable and dichotomized as deficient (<10ng/mL), or at the cohort-specific 20th and 80th percentiles. Vitamin D was related to the 9-year risk of incident dementia (n=1663), multiple neuropsychological tests (n=1291) and MRI markers of brain volume, white matter hyperintensities and silent cerebral infarcts (n=1139). Results: In adjusted models, participants with vitamin D deficiency (n=104, 8% of the cognitive sample) displayed poorer performance on Trail Making B-A (beta=-0.03 to -0.05 +/- 0.02) and the Hooper Visual Organization Test (beta=-0.09 to -0.12 +/- 0.05), indicating poorer executive function, processing speed, and visuo-perceptual skills. These associations remained when vitamin D was examined as a continuous variable or dichotomized at the cohort specific 20th percentile. Vitamin D deficiency was also associated with lower hippocampal volumes (beta=-0.01 +/- 0.01) but not total brain volume, white matter hyperintensities, or silent brain infarcts. No association was found between vitamin D deficiency and incident all-cause dementia or clinically characterized AD. Conclusions: In this large community-based sample, low 25(OH)D concentrations were associated with smaller hippocampal volume and poorer neuropsychological function.