Association Between Serum 25(OH) Vitamin D and the Risk of Cognitive Decline in Older Women.
ABSTRACT Background: Results of prospective studies examining the association between 25 hydroxyvitamin D (25[OH]D) levels and cognitive decline have been inconsistent. We tested the hypothesis that lower 25(OH)D levels are associated with a greater likelihood of cognitive impairment and risk of cognitive decline. Methods: The study is a cross-sectional and longitudinal analysis of a prospective cohort of 6,257 community-dwelling elderly women followed for 4 years. Global cognitive function was measured by the Modified Mini-Mental State Examination and executive function was measured by Trail Making Test Part B (Trails B). Cognitive impairment at baseline was defined as a score >1.5 SD below the sample mean; cognitive decline was defined as decline from baseline to follow-up >1 SD from mean change in score. Results: Women with very low vitamin D levels had an increased odds of global cognitive impairment at baseline: odds ratio (95% confidence interval), 1.60 (1.05-2.42) for women with 25(OH)D <10 ng/mL (25 nmol/L) compared with those with 25(OH)D levels ≥30 ng/mL (75 nmol/L). Compared with women with baseline 25(OH)D level ≥30 ng/mL (75 nmol/L), women with lower levels had an increased risk of global cognitive decline: odds ratio (95% confidence interval), 1.58(1.12-2.22) for women with levels <10 ng/mL (25 nmol/L), and 1.31 (1.04-1.64) for those with levels 10-19.9 ng/mL (25-49 nmol/L). Levels of 25(OH)D were not associated with executive cognitive function. Conclusions: Low 25(OH)D levels among older women were associated with a higher odds of global cognitive impairment and a higher risk of global cognitive decline.
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ABSTRACT: Vitamin D is an important calcium-regulating hormone with diverse functions in numerous tissues, including the brain. Increasing evidence suggests that vitamin D may play a role in maintaining cognitive function and that vitamin D deficiency may accelerate age-related cognitive decline. Using aging rodents, we attempted to model the range of human serum vitamin D levels, from deficient to sufficient, to test whether vitamin D could preserve or improve cognitive function with aging. For 5-6 mo, middle-aged F344 rats were fed diets containing low, medium (typical amount), or high (100, 1,000, or 10,000 international units/kg diet, respectively) vitamin D3, and hippocampal-dependent learning and memory were then tested in the Morris water maze. Rats on high vitamin D achieved the highest blood levels (in the sufficient range) and significantly outperformed low and medium groups on maze reversal, a particularly challenging task that detects more subtle changes in memory. In addition to calcium-related processes, hippocampal gene expression microarrays identified pathways pertaining to synaptic transmission, cell communication, and G protein function as being up-regulated with high vitamin D. Basal synaptic transmission also was enhanced, corroborating observed effects on gene expression and learning and memory. Our studies demonstrate a causal relationship between vitamin D status and cognitive function, and they suggest that vitamin D-mediated changes in hippocampal gene expression may improve the likelihood of successful brain aging.Proceedings of the National Academy of Sciences of the United States of America. 09/2014;
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ABSTRACT: Background and purposeStudies investigating the association between 25-hydroxyvitamin D [25(OH)D] and cognition in the very old (85+) are lacking.Methods Cross-sectional (baseline) and prospective data (up to 3 years follow-up) from 775 participants in the Newcastle 85+ Study were analysed for global (measured by the Standardized Mini-Mental State Examination) and attention-specific (measured by the attention battery of the Cognitive Drug Research test) cognitive performance in relation to season-specific 25(OH)D quartiles.ResultsThose in the lowest and highest season-specific 25(OH)D quartiles had an increased risk of impaired prevalent (1.66, 95% confidence interval 1.06–2.60, P = 0.03; 1.62, 95% confidence interval 1.02–2.59, P = 0.04, respectively) but not incident global cognitive functioning or decline in functioning compared with those in the middle quartiles adjusted for sociodemographic, health and lifestyle confounders. Random effects models showed that participants belonging to the lowest and highest 25(OH)D quartiles, compared with those in the middle quartiles, had overall slower (log-transformed) attention reaction times for Choice Reaction Time (lowest, β = 0.023, P = 0.01; highest, β = 0.021, P = 0.02), Digit Vigilance Task (lowest, β = 0.009, P = 0.05; highest, β = 0.01, P = 0.02) and Power of Attention (lowest, β = 0.017, P = 0.02; highest, β = 0.022, P = 0.002) and greater Reaction Time Variability (lowest, β = 0.021, P = 0.02; highest, β = 0.02, P = 0.03). The increased risk of worse global cognition and attention amongst those in the highest quartile was not observed in non-users of vitamin D supplements/medication.Conclusion Low and high season-specific 25(OH)D quartiles were associated with prevalent cognitive impairment and poorer overall performance in attention-specific tasks over 3 years in the very old, but not with global cognitive decline or incident impairment.European Journal of Neurology 08/2014; · 4.16 Impact Factor
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ABSTRACT: To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.Neurology 08/2014; · 8.30 Impact Factor
Journal of Gerontology: MEDICAL SCIENCES
Cite journal as: J Gerontol A Biol Sci Med Sci. 2012 October;67(10):1092–1098
Published by Oxford University Press on behalf of the Gerontological Society of America 2012.
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Advance Access published on March 27, 2012
Journal of Gerontology: MEDICAL SCIENCES
Cite journal as: J Gerontol A Biol Sci Med Sci
A growing body of literature supports the role of vitamin D
in brain function ( 3 , 4 ); however , studies examining the
association between vitamin D and cognitive function
have reported confl icting results ( 5 ). Although some cross-
sectional studies report an association between lower levels
of 25(OH)D and worse performance on cognitive testing
( 6 – 13 , 16 ), other studies found no association between
vitamin D levels and cognitive performance ( 14 ) or reported
worse cognitive performance by the elderly participants in
the highest 25(OH)D quintile ( 15 ) . Results of prospective
studies examining the association between 25(OH)D levels
and cognitive decline have also been inconsistent. Our
group found an association between lower 25(OH) vitamin D
level and greater risk of incident cognitive decline in a cohort
HE prevalence of 25 hydroxyvitamin D ( 25[OH]D )
defi ciency is high among the elderly participants ( 1 , 2 ) .
of community-dwelling older men, but the association was
no longer statistically signifi cant after adjustment for con-
founders ( 14 ) . Llewellyn and coworkers ( 16 ) reported a
higher risk of cognitive decline in a cohort of Italian men
and women with 25(OH)D levels <10 ng/mL (25 nmol/L)
compared with those with 25(OH)D level > 30 ng/mL
(75 nmol/L ). We aimed to test the hypothesis that lower
25(OH)D levels are associated with a greater likelihood
of cognitive impairment and increased risk of cognitive
decline in older women. To achieve the aim, we measured
25(OH)D and assessed cognitive function using modifi ed
Mini-Mental State Examination (mMMSE) and Trail Making
Test Part B (Trails B) in a cohort of Caucasian community-
dwelling women aged ≥ 65 years who were enrolled in
the Study of Osteoporotic Fractures and followed them
prospectively for changes in cognitive function.
Association Between Serum 25(OH) Vitamin D and the
Risk of Cognitive Decline in Older Women
Yelena Slinin , 1 , 2 Misti Paudel , 3 Brent C. Taylor , 1 , 2 , 3 Areef Ishani , 1 , 2 Rebecca Rossom , 1 Kristine Yaffe , 4 , 5
Terri Blackwell , 6 Li-Yung Lui , 6 Marc Hochberg , 7 and Kristine E. Ensrud , 1 , 2 , 3 for the Study of Osteoporotic
Fractures Research Group
1 Center for Chronic Disease Outcomes Research, VA Medical Center, Minneapolis, Minnesota .
2 Department of Medicine and 3 Division of Epidemiology and Community Health, University of Minnesota, Minneapolis .
4 Departments of Psychiatry, Neurology, and Epidemiology, University of California, San Francisco .
5 Department of Psychiatry, VA Medical Center, San Francisco, California .
6 California Pacifi c Medical Center Research Institute, San Francisco .
7 Departments of Medicine and Epidemiology and Public Health, University of Maryland, Baltimore .
Address correspondence to Yelena Slinin, MD, MS, One Veterans Drive (111J), Minneapolis, MN 55417. Email: firstname.lastname@example.org
Background: Results of prospective studies examining the association between 25 hydroxyvitamin D (25[OH]D)
levels and cognitive decline have been inconsistent. We tested the hypothesis that lower 25(OH)D levels are associated
with a greater likelihood of cognitive impairment and risk of cognitive decline.
Methods: The study is a cross-sectional and longitudinal analysis of a prospective cohort of 6,257 community-
dwelling elderly women followed for 4 years. Global cognitive function was measured by the Modifi ed Mini-Mental
State Examination and executive function was measured by Trail Making Test Part B (Trails B). Cognitive impairment at
baseline was defi ned as a score >1.5 SD below the sample mean; cognitive decline was defi ned as decline from baseline
to follow-up >1 SD from mean change in score.
Results: Women with very low vitamin D levels had an increased odds of global cognitive impairment at baseline:
odds ratio (95% confi dence interval), 1.60 (1.05 – 2.42) for women with 25(OH)D <10 ng/mL (25 nmol/L) compared with
those with 25(OH)D levels ≥ 30 ng/mL (75 nmol/L). Compared with women with baseline 25(OH)D level ≥� 30 ng/mL
(75 nmol/L), women with lower levels had an increased risk of global cognitive decline: odds ratio (95% confi dence
interval), 1.58(1.12–2.22) for women with levels <10 ng/mL (25 nmol/L), and 1.31 (1.04–1.64) for those with levels
10–19.9 ng/mL (25–49 nmol/L). Levels of 25(OH)D were not associated with executive cognitive function.
Conclusions: Low 25(OH)D levels among older women were associated with a higher odds of global cognitive
impairment and a higher risk of global cognitive decline.
Key Words: Vitamin D — Cognitive decline — Executive function — Cohort studies — Risk factors in epidemiology .
Received September 26 , 2011 ; Accepted February 8 , 2012
Decision Editor: Luigi Ferrucci, MD, PhD
25(OH)D AND COGNITION IN ELDERLY WOMEN
Study of Osteoporotic Fractures is a prospective study
involving 9 , 704 ambulatory, community-dwelling, Caucasian
women aged 65 years and older who were originally
recruited between September of 1986 and October of 1988
from population-based listings in four areas of the United
States: Baltimore, Maryland; Minneapolis, Minnesota;
the Monongahela Valley, Pennsylvania; and Portland,
Oregon ( 17 ) .
Year 6 visit (1992 – 1994) served as the baseline visit for
this analysis; the participants were administered cognitive
testing at Year 6, Year 8, and Year 10 visits. Of 6 , 350 women
who had Year 6 25(OH) vitamin D measurement, 6 , 242 had
Year 6 mMMSE and 5 , 692 had Year 6 Trails B. The study
sample for this analysis consists of 6 , 257 women (74.7% of
8 , 381 women who completed the Year 6 examination) who
had determination of 25(OH) vitamin D level and completion
of the mMMSE and/or Trails B testing. On average, the Year
6 examination took place 5.8 years after the study enrollment.
All women provided written informed consent, and the
study was approved by the appropriate Institutional Review
Specimens and Assays
Serum 25(OH) vitamin D measurements were obtained
on specimen collected at Year 6 examination. Fasting morn-
ing blood was collected; serum was prepared immediately
after phlebotomy and then stored at − 70°C. Measures for
25(OH)D 2 (ergocalciferol) and 25(OH)D 3 (cholecalciferol)
were performed at the Mayo Clinic using mass spectrometry
as previously described ( 18 ) . The minimum detectable limit
for 25(OH)D 2 was 4 ng/mL (10 nmol/L) and for 25(OH)D 3
was 2 ng/mL (5 nmol/L). Using the pooled serum, the inter-
assay coeffi cient of variation (between assays) was 4.4%
and the intra-assay coeffi cient of variation (within assay)
was 4.9%. Total 25(OH)D was calculated by adding the
25(OH)D 2 and 25(OH)D 3 values. Ninety-four women with
undetectable 25(OH)D level were considered to have 25(OH)
D level in the lowest quartile or category. We used clinical
categories of the total vitamin D as the primary predictor:
<10 ng/mL (25 nmol/L) (severely defi cient), 10 – 19.9 ng/mL
(25 – 49 nmol/L) (defi cient), 20 – 29.9 ng/mL (50 – 74 nmol/L)
(insuffi cient), and ≥ 30 ng/mL (75 nmol/L) (suffi cient ) ( 1 ) .
All analyses were adjusted for season and clinic site.
Trained examiners administered the mMMSE at Year 6,
8, and 10 visits and the Trails B test at Years 6 and 10 visits.
The mMMSE is a brief, global cognitive function test with
orientation, concentration, language, praxis, and memory
components designed to screen for cognitive impairment
( 19 ) . Scores range from 0 to 26, with higher scores indicating
better cognition. Cognitive impairment at baseline was
defi ned as a score >1.5 SD below the sample mean ( 20 ) .
Cognitive decline was defi ned as decline from baseline
to follow-up >1 SD from mean change in score between
Year 6 and Year 10 exams (equivalent to 2.9 or more point
decline in the mMMSE score ) ( 21 ) .
The Trails B is a test of executive function. It assesses
attention, concentration, psychomotor speed, cognitive
shifting , and complex sequencing function by measuring
the time required to connect a series of sequential numbered
and lettered circles. Cognitive shifting and complex sequenc-
ing ability as measured by Trails B are signifi cantly associ-
ated with instrumental activities of daily living that predict
real-world functioning and outcomes in the elderly partici-
pants ( 22 ). Scores were measured in seconds to completion,
with shorter completion time indicating better perfor-
mance. When women were not able to complete the test in
180 seconds, the testing was stopped and their completion
time was extrapolated based on the completed portion of the
test. To avoid outliers, we assigned a time of 421 seconds to
all women whose extrapolated times exceeded 420 seconds.
Cognitive impairment at baseline was defi ned as time required
to complete Trails B >1.5 SD above the sample mean ( 20 ) .
Cognitive decline was defi ned as >1 SD above the sample
mean change in time required to complete Trails B between
Year 6 and Year 10.
Study of Osteoporotic Fractures participants completed
questionnaires and attended clinic visit at Years 6, 8, and 10.
At baseline, information on education, age, health behav-
iors such as alcohol use, smoking and physical activity, and
medical history, including self-reported history of physician
diagnosis of stroke, diabetes mellitus, congestive heart failure,
hypertension, cardiovascular disease, lung disease, kidney
disease, and Alzheimer’s disease was collected. The 15-item
Geriatric Depression Scale was administered, with scores
ranging from 0 to 15, with higher scores indicating more
symptoms of depression ( 23 ) . Depression was defi ned as a
score of 6 or higher on the Geriatric Depression Scale .
Functional status was determined by the modifi ed version
of the Stanford Health Assessment Questionnaire, which
assesses independence in six instrumental activities of daily
living ( 24 ). Functional impairment was defi ned as report of
diffi culty with one or more of these activities.
A comprehensive examination included measurements of
body weight and height. Body mass index was calculated as
weight in kilograms divided by the square of height in meters.
Differences in baseline (Year 6 examination) characteris-
tics according to the category of 25(OH)D level were
compared using chi-square tests for categorical variables,
analysis of variance for continuous variables with normal
1094 SLININ ET AL.
distributions, and Kruskal – Wallis tests for variables with
We used logistic regression models to examine the asso-
ciation between baseline 25(OH)D levels and odds of cog-
nitive impairment and risk of cognitive decline. In addition,
we performed a secondary analysis using linear mixed
model regression to examine the association between
25(OH)D level and mMMSE score as a continuous variable
at baseline (Year 6 exam) and at Years 8 and 10.
Women who reported having a physician diagnosis of
dementia or were cognitively impaired at Year 6 as defi ned
by mMMSE or Trails B testing were excluded from the lon-
gitudinal analyses of cognitive decline by respective tests.
Sensitivity analyses that maintained these impaired women
in the cohort were also performed with similar results ( data
not shown). Crude models were adjusted for clinic site and
for season when the serum sample for vitamin D was drawn.
Base models were adjusted for clinic site, season of blood
draw, age , and education. Fully adjusted models, adjusted
for variables that were associated with 25(OH)D levels with
p < .05 and variables that were known or suspected con-
founders of the association between 25(OH)D and cogni-
tion. To account for baseline cognitive function infl uencing
the rate of cognitive decline, all models of cognitive decline
were adjusted for respective baseline scores.
Analyses were performed using SAS 9.1 version (SAS
Inc., Gary, NC).
25OH(D) Levels and Baseline Cognitive Function
At Year 6, 6242 women with 25(OH)D measurements
completed mMMSE testing and 5 , 692 women completed
Trails B testing. Of these, 446 (7.2%) women were classi-
fi ed as impaired by mMMSE (score <21.6) and 409 (7.2%)
were classifi ed as impaired by Trails B performance (extrap-
olated time to completion of Trails B test >250 seconds). In
the cohort, 7.3% of women were severely defi cient, 32.7%
were defi cient, 38.6% were insuffi cient, and 21.4% were
suffi cient for 25(OH)D. Characteristics of the study partici-
pants by categories of serum 25(OH)D concentration are
listed in Table 1 .
There was an independent association between low
vitamin D status and greater odds of cognitive impairment
defi ned by mMMSE performance ( Table 2 ). In a crude model,
there was an association between 25(OH)D categories and
odds of cognitive impairment by Trails B defi nition at base-
line, but this relationship was no longer signifi cant after
adjustment for age and education ( Table 2 ).
Table 1 . Baseline Characteristics of the Study Participants by Quartile of 25(OH) Vitamin D
( n = 6257)
Vitamin D Categories
p Value †
( n = 452)
10 – 19.9 ng/ml
(25 – 49 nmol/L)
( n = 2,037)
20 – 29.9 ng/ml
(50 – 74 nmol/L)
( n = 2,408)
≥ 30 ng/ml
( n = 1360)
Age, years, mean ± SD
Education, years, mean ± SD
Geriatric Depression Scale score, mean ± SD
Self-reported good or excellent health status, n (%)
≥ 1 Instrumental activity of daily living impairment, n (%)
Current smoker, n (%)
Alcohol use within previous 30 d, n (%)
History of stroke, n (%)
Congestive heart failure, n (%)
Hypertension, n (%)
Diabetes, n (%)
Cardiovascular disease * , n (%)
Lung disease, n (%)
Dementia or Alzheimer’s disease, n (%)
Kidney disease, n (%)
Body mass index, kg/m 2 , mean ± SD
Winter blood draw, n (%)
Spring blood draw, n (%)
Summer blood draw, n (%)
Fall blood draw, n (%)
Baseline MMSE score, mean ± SD
Baseline Trails B time (s), mean ± SD
Takes walks for exercise (%)
Vitamin D supplementation (%)
76.6 ± 4.7
12.8 ± 2.8
1.8 ± 2.2
26.4 ± 4.6
24.4 ± 1.9
145.1 ± 70.0
77.4 ± 5.0
12.7 ± 2.8
2.0 ± 2.3
26.9 ± 5.1
24.2 ± 2.4
157.6 ± 75.6
77.0 ± 4.8
12.5 ± 2.8
1.7 ± 2.1
27.1 ± 4.9
24.3 ± 2.1
151.9 ± 73.0
76.3 ± 4.6
12.9 ± 2.8
1.7 ± 2.2
26.3 ± 4.4
24.6 ± 1.8
141.0 ± 67.9
76.3 ± 4.6
13.0 ± 2.7
1.8 ± 2.2
25.5 ± 4.2
24.5 ± 1.7
138.8 ± 66.0
Notes: All characteristics measured at the Year 6 examination . MMSE = Mini-Mental State Examination.
* Cardiovascular disease includes self- reported history of heart attack, coronary, MI, angina .
† P values obtained from the analysis of variance F -test .
25(OH)D AND COGNITION IN ELDERLY WOMEN
25OH(D) Levels and Cognitive Decline
A total of 5 , 336 participants completed at least one follow-
up cognitive testing at Years 8 or 10, were not impaired,
and were included into the prospective analyses for either
mMMSE or Trails B outcomes ( Figure 1 ) . Overall, 320 women
who were impaired at baseline by the mMMSE criteria
and 144 women who were impaired by the Trails B criteria
were excluded from analyses of decline as defi ned by the
Table 2 . Association Between 25(OH) Vitamin D and Odds of Cognitive Impairment at Baseline and Cognitive Decline
Odds Ratio (95% Confi dence Interval)
Crude Model * Base Model † MV Model ‡ Crude Model * Base Model † MV Model ‡
Cognitive impairment at baseline by mMMSE Cognitive impairment at baseline by trails B
10 – 19 ng/mL
20 – 29 ng/mL
≥ 30 ng/mL
1.85 (1.26 – 2.71)
1.29 (0.99 – 1.69)
0.81 (0.62 – 1.06)
1.62 (1.10 – 2.39)
1.13 (0.86 – 1.49)
0.80 (0.60 – 1.05)
Cognitive decline by mMMSE §
1.60 (1.05 – 2.42)
1.09 (0.82 – 1.44)
0.79 (0.60 – 1.06)
1.26 (0.80 – 1.99)
1.43 (1.07 – 1.92)
1.11 (0.83 – 1.48)
1.14 (0.72 – 1.82)
1.24 (0.91 – 1.67)
1.13 (0.84 – 1.52)
Cognitive decline by trails B ||
1.09 (0.68 – 1.76)
1.23 (0.90 – 1.68)
1.12 (0.82 – 1.52)
10 – 19 ng/mL
20 – 29 ng/mL
≥ 30 ng/mL
1.63 (1.18 – 2.26)
1.34 (1.08 – 1.66)
1.07 (0.87 – 1.32)
1.52 (1.09 – 2.11)
1.24 (1.00 – 1.54)
1.07 (0.87 – 1.33)
1.58 (1.12 – 2.22)
1.31 (1.04 – 1.64)
1.13 (0.91 – 1.41)
1.06 (0.69 – 1.63)
1.01 (0.77 – 1.32)
0.84 (0.65 – 1.09)
1.01 (0.65 – 1.56)
0.95 (0.72 – 1.24)
0.85 (0.66 – 1.11)
1.00 (0.64 – 1.56)
0.93 (0.70 – 1.23)
0.83 (0.64 – 1.09)
Notes: mMMSE = modifi ed Mini-Mental State Examination MV, Multivariate.
* Adjusted for clinic site and season of blood collection for vitamin D measurement.
† Adjusted for clinic site, season of blood collection, age at baseline, and years of education.
‡ A djusted for clinic site, season of blood collection, age at baseline, years of education, self-reported health status, instrumental activity of daily living impairments,
smoking status at baseline, body mass index, history of hypertension, history of diabetes and depression, baseline cognitive function (for models of cognitive decline
only), walking for exercise, and baseline vitamin D supplementation.
§ Cognitive decline at follow-up defi ned as >1 SD (2.9 points) below the mean difference between baseline and follow-up at Year 10 examination (or Year 8 if Year
10 examination was not performed).
|| Cognitive decline at follow-up defi ned as >1 SD (87.3 s) above the mean difference in time to completion of Trails B testing between baseline and follow-up.
6350 women with
baseline 25(OH)D at Year 6
5692 completed baseline
Trails B at Year 6
6242 completed baseline
mMMSE at Year 6
45 terminated study
6 with Alzheimer’s/Dementia
20 terminated study
22 with Alzheimer’s/Dementia
mMMSE at Year 8
5499 completed mMMSE
at Year 8 or 10
320 excluded for
impairment at baseline
Trails B at Year 10
144 excluded for
impairment at baseline
5179 included in
3973 included in
mMMSE at Year 10
Figure 1 . Study roadmap.
1096 SLININ ET AL.
respective tests ( Figure 1 ) . Compared with women who
were included in prospective analyses, the women who did
not return for cognitive testing at follow-up were older
(79 vs 76 years), had slightly lower baseline mean vitamin D
levels (22.1 vs 23.0 ng/mL), lower mean baseline mMMSE
(22.7 vs 24.7) , and took longer to complete Trails B (197.7
vs 137.9 seconds) (all p < .05).
Eight hundred thirteen (15.7%) women had cognitive
decline based on mMMSE score decline of >1 SD (2.9 points)
and 465 (11.7%) women developed cognitive decline as
defi ned by the change in time to completion of Trails B >1
SD (87.3 seconds).
In multivariate models, there was evidence of an association
between lower 25(OH)D levels and higher odds of incident
cognitive decline as defi ned by the mMMSE performance:
adjusted odds ratio (95% confi dence interval ), 1.58 (1.12 – 2.22),
1.31 (1.04 – 1.64), and 1.13 (0.91 – 1.41) for 25(OH)D
categories of <10 ng/mL (25 nmol/L), 10 – 19.9 ng/mL
(25 – 49 nmol/L), and 20 – 29.9 ng/mL (50 – 74 nmol/L),
respectively, compared with 25(OH)D ≥ 30 ng/mL (75 nmol/L)
( p trend < .003) ( Table 2 ).
There was no evidence of an association between 25(OH)
D level and cognitive decline by performance on Trails B
testing ( Table 2 ).
In base random effects models adjusted for clinic site,
season of blood draw, age at baseline and education, women
with 25(OH)D levels <10 ng/mL (25 nmol/L) declined by
an additional 0.14 mMMSE points between visits compared
with women with 25(OH)D levels ≥ 30 ng/mL (75 nmol)
( p = .049). This association persisted after adjustment for
other covariates ( p = .039) ( Figure 2 ).
Very low 25(OH)D levels (<10 ng/mL [ 25 nmol/L ])
among older women were associated with a higher odds of
global cognitive impairment at baseline and low 25(OH)D
levels (<20 ng/mL [50 nmol/L]) among nonimpaired
women were associated with a higher risk of incident global
cognitive decline, as defi ned by mMMSE performance.
Women with 25(OH)D levels between 20 and 30 ng/mL
(50 – 75 nmol/L) had global cognitive performance similar
to that of 25(OH)D suffi cient women. We found no inde-
pendent association between 25(OH)D level and odds of
executive cognitive impairment or risk of cognitive decline
as defi ned by performance on Trails B.
Our results are in general agreement with those of
Llewellyn and colleagues who found an association between
25(OH)D levels <10 ng/mL (25 nmol/L) and risk of cog-
nitive decline as measured by MMSE in a cohort of 858
community- dwelling Italian elderly participants ( 16 ) . Our
group found an association of similar magnitude, although
not statistically signifi cant, in a cohort of community-
dwelling elderly men ( 114) . Other studies reported the
association between vitamin D levels and cognitive impairment
in women ( 25 , 26 ), but not in men ( 26 ). There is experimen-
tal evidence to support neuroprotective qualities of vitamin
D ( 3 – 7 , 27 ). Vitamin D might have neuroprotective effect
through prevention of vascular dementia ( 7 ): a study by
Buell and coworkers found that 25(OH)D defi ciency was
associated with increased white matter hyperintensity volume
and prevalence of large vessel infarcts on brain imaging of
homebound elderly participants ( 6 , 7 , 27 ) . On the other hand,
it is possible that the observed association is a result of
residual confounding. Low vitamin D is a marker of poor
physical and cognitive functioning, poor nutritional state ,
and homebound status in the elderly participants , all of
whom might lead to a higher likelihood of cognitive impair-
ment and greater risk of cognitive decline.
In contrast to Llewellyn and colleagues ( 16 ), we did not
fi nd an association between 25(OH)D levels and either
baseline cognitive impairment or risk of decline of execu-
tive function as measured by Trails B. However, our current
fi nding is in agreement with our fi nding in a community
cohort of elderly men. Our fi ndings also agree with previ-
ously published reports that demonstrated an association
between vitamin D level and global cognitive function, but
not specifi c aspects of cognition, such as executive function
( 5 ). In addition, the difference in fi ndings across the studies
might be partially explained by the difference in the cohort
population, defi nition of impairment, and handling of base-
Several randomized controlled trials evaluated the effect
of vitamin D supplementation on cognitive function in the
elderly participants with mixed results ( 28 – 31 ) . Two trials
in select elderly populations did not fi nd improvement in
mental state in participants randomized to vitamin D sup-
plementation ( 30 , 31 ) . A trial randomized institutionalized
elderly participants to a nutrient dense drink that contained
520 Units of vitamin D a day, found better cognitive func-
tion (as assessed by Alzheimer’s Disease Assessment Scale
Figure 2 . Change in cognitive function by category of serum 25(OH)D
concentration. Results are based on a random-effects model with multivariate
adjustment for clinic site, season of blood collection, age at baseline, years of
education, self-reported health status, instrumental activity of daily living
impairments, smoking status at baseline, body mass index, history of hyperten-
sion, history of diabetes, depression , and baseline cognitive score. P values for
comparison with > 30ng/mL (reference): 20 – 29 ng/mL p = .1630; 10 – 19 ng/mL
p = .7969; <10 ng/mL p = .0385.
25(OH)D AND COGNITION IN ELDERLY WOMEN
and its language subscore) only in a subgroup of partici-
pants with lower weight at baseline ( 29 ) . Another trial that
randomized 139 elderly participants with a history of falls
and 25(OH)D defi ciency to a single intramuscular injection
of 600,000 units of ergocalciferol or placebo found a greater
improvement in choice reaction time and aggregate functional
performance time in participants randomized to vitamin D
compared with those randomized to placebo at 6 months
( 28 ). Large randomized controlled trials powered to evaluate
the effect of vitamin D supplementation on the risk of cog-
nitive decline and dementia are needed.
The strengths of the study include a prospective design, a
large sample size, comprehensive measures of the cohort
baseline characteristics, and a gold-standard analytical
method used to quantify 25(OH)D levels, but it also had
several limitations. Only one baseline measurement of
vitamin D was available for analysis. We extrapolated times
to completion of Trails B values for women who were not
able to complete the test in 3 minutes, and this might have
infl uenced our fi ndings. The absolute effect size of the
association between baseline vitamin D level and rate of
cognitive decline is small and of uncertain clinical signifi -
cance. The participants were mostly healthy, Caucasian,
elderly, community-dwelling women; therefore, the fi ndings
might not be generalizable to other populations. The par-
ticipants who did not have cognitive testing or did not par-
ticipate in the follow-up were older and frailer, leaving
healthy women in the cohort. Although widely accepted
measures of cognition in older people were used, no uniform
defi nition of cognitive impairment or decline exists for
mMMSE or Trails B testing.
In conclusion, we found an independent association
between low baseline vitamin D levels and higher odds
of global cognitive impairment and risk of global cognitive
decline in the cohort of community- dwelling elderly women.
Further research designed to test the hypothesis whether
vitamin D supplementation prevents cognitive decline are
needed before uniform recommendation of vitamin D
supplementation for neuroprotection can be made.
The Study of Osteoporotic Fractures is supported by National Institutes
of Health funding. The National Institute on Aging provides support under
the following grant numbers: AG05407 , AR35582 , AG05394 , AR35584 ,
AR35583 , AG005407 , AG027576 , AG005394 , and AG027574 .
Role of the sponsor: The funding agencies had no direct role in the
conduct of the study; the collection, management, analyses, and interpre-
tation of the data; or preparation or approval of the manuscript. Disclo-
sure: Ms. Paudel, Ms. Lui, Ms. Blackwell, Dr. Taylor, Dr. Rossom,
Dr. Slinin, Dr. Hochberg, and Dr. Ensrud report no disclosures. Dr. Ishani
receives grant support from the National Institutes of Health (NIH) and
VA RR&D. Dr. Yaffe has served on the Alzheimer ’ s Association Scien-
tifi c Plenary Committee, International Conference on Alzheimer ’ s Dis-
ease, Women ’ s Health Initiative OSMB committee, and Texas Alzheimer ’ s
Advisory committee. She received funding for travel from the NIH,
Alzheimer ’ s Association, American Academy of Neurology, Canadian
Colloquium on Dementia, and Alzheimer ’ s Disease Research Centers of
California. Dr. Yaffe has served as an Associate Editor for the American
Journal of Geriatric Psychiatry . She received honoraria and/or consulting
fees from Novartis, Posit Science, Inc., American Academy of Neurology,
Drexel University, and Sidley Austin. Her research support is received from
the U.S. Department of Defense, National Institutes of Health, National
Alliance for Research on Schizophrenia and Depression, and an anony-
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