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Abstract
Background: Vitamin D deficiency has been implicated as a risk factor for dementia in several
cross-sectional studies. We tested the hypothesis that reduced plasma 25-hydroxyvitamin D (25
[OH]D) is associated with increased risk of Alzheimers disease (AD) and vascular dementia in
the general population.
Methods: We measured baseline plasma 25(OH)D in 10,186 white individuals from the Danish general population.
Results: During 30 years of follow-up, 418 participants developed AD and 92 developed vascular dementia. Multivariable adjusted hazard ratios for AD were 1.25 (95% confidence interval [CI], 0.95
1.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.29 (95% CI,
1.011.66) for less than the 25th seasonally adjusted 25(OH)D percentile vs. more than the 50th seasonally adjusted 25(OH)D percentile. Multivariable adjusted hazard ratios for vascular dementia were
1.22 (95% CI, 0.771.91) for 25(OH)D less than 50 nmol/L vs. greater than or equal to 50 nmol/L, and
1.22 (95% CI, 0.791.87) for less than or equal to the 50th vs. more than the 50th seasonally adjusted
25(OH)D percentile. Last, multivariable adjusted hazard ratios for the combined end point were 1.28
(95% CI, 1.001.64) for 25(OH)D less than 25 nmol/L vs. greater than or equal to 50 nmol/L, and 1.27
(95% CI, 1.011.60) for less than the 25th vs. more than the 50th seasonally adjusted 25(OH)D.
Conclusions: We observed an association of reduced plasma 25(OH)D with increased risk of the
combined end point of AD and vascular dementia in this prospective cohort study of the general population.
2014 The Alzheimers Association. All rights reserved.
Keywords:
1. Introduction
The pathogenetic hallmarks of Alzheimers disease (AD)
are thought to be accumulation of dysfunctional proteins
(i.e. amyloid beta [Ab] and tau protein derivates) in the brain
followed by oxidative damage and inflammation, leading to
deranged energy metabolism, localized synaptic failure, and
neuronal loss [1]. The hormonally active form of vitamin
D1,25-dihydroxyvitamin D (1,25-(OH)2-vitD)has
been shown to induce Ab removal [2,3], to reduce
oxidative stress-induced cell damage present in AD [4,5],
1552-5260/$ - see front matter 2014 The Alzheimers Association. All rights reserved.
http://dx.doi.org/10.1016/j.jalz.2013.05.1765
297
2. Methods
2.1. Study design
The Copenhagen City Heart Study is a prospective cohort
study of the Danish general population initiated in 1976 to
1978 with follow-up examinations in 1981 to 1983, 1991
to 1993, and 2001 to 2003 [2224]. Individuals 20 to 100
years of age were drawn randomly from the national
Danish Central Person Register and invited to participate;
all inhabitants in Denmark are uniquely identified through
their central person registration number, which also holds
information on age and sex.
The current study included 10,186 participants from the
1981 to 1983 examination, who were free of any type of diagnosed dementia at baseline and had available plasma samples for 25(OH)D measurement. A Danish ethics committee
approved the study (KF100.2039/91 and KF01-144/01). Participants provided written informed consent.
2.2. Measurements of 25(OH)D and other biochemical
analytes
Plasma samples collected at baseline in 1981 to 1983
were stored at 20 C until 2009 to 2010, when 25(OH)D
was measured using the DiaSorin Liaison 25(OH)D TOTAL
assay (Diasorin, Stillwater, MN). Assay precision was
tested daily whereas assay accuracy was tested monthly using an external quality control program. The interassay coefficient of variance was 10% for low-level control subjects
(w16 nmol/L) and 8% for high-level control subjects
(w54 nmol/L).
Colorimetric assays (Boehringer Mannheim, Mannheim,
Germany or Konelab, Espoo, Finland) were used to measure
creatinine, total cholesterol, and high-density lipoprotein
(HDL) cholesterol in plasma. Total cholesterol and HDL cholesterol were measured the same day as the blood sample was
collected, and creatinine was measured during 2009 to 2010
using samples stored at 220 C without previous thawing.
2.3. Covariates
Information on smoking habits was obtained from selfreported questionnaires completed together with an examiner
on the day of attendance. Participants were asked about duration and intensity of leisure time and work-related physical
activities (hours per week), level of income (high, medium,
or low), and level of education (years). Information on baseline diabetes mellitus and hypertension was assessed by questions regarding current morbidities, current medications, and
298
Table 1
Baseline characteristics according to clinical cut points for 25-hydroxyvitamin D plasma levels unadjusted for seasonal variation
Plasma 25-hydroxyvitamin D, nmol/L
Characteristic
,25 (n 5 2384)
2549.9 (n 5 4087)
.50 (n 5 3715)
Trend, P value*
Men, %
Age, years
Ever smoker, %
Body mass index, kg/m2
High physical activity (leisure), %
High physical activity (work), %
High income, %
Education, years
Diabetes mellitus, %
Hypertension, %
Alcohol consumption, units/weeky
Cholesterol, mmol/L
HDL cholesterol, mmol/L
Creatinine, mmol/L
45
58 (5065)
84
25 (2329)
27
26
16
7 (79)
5
60
3 (012)
5.8 (5.16.5)
1.1 (0.91.3)
94 (85105)
44
58 (4965)
78
25 (2328)
34
25
21
8 (710)
4
56
4 (111)
5.9 (5.26.7)
1.1 (0.91.3)
94 (85104)
43
57 (4764)
77
24 (2227)
40
25
26
8 (710)
2
49
5 (211)
5.9 (5.16.7)
1.2 (1.01.4)
93 (85102)
.10
,.001
,.001
,.001
,.001
.46
,.001
,.001
,.001
,.001
,.001
.001
,.001
.001
clinical categories, and less than or equal to the 50th percentile vs. more than the 50th percentile for the seasonally adjusted percentiles. For trend tests, individuals in each group
were assigned the median value of their group, either as absolute values or as percentiles.
Cox proportional hazards regression was used to estimate
hazard ratios with a 95% confidence interval (CI) for incident
AD and vascular dementia. We used age as a timescale with
delayed entry (left truncation). Thus, age differences were adjusted automatically for and referred to in text, tables, and figures as age adjusted. However, for the test of interaction of age
with 25(OH)D levels on risk of dementia, we used years of
follow-up as the timescale. Multivariable adjusted Cox regression models included gender, age, smoking status
(never/ever), body mass index, duration and intensity of leisure time and work-related physical activities, income, education, diabetes mellitus, hypertension, alcohol consumption,
cholesterol, HDL cholesterol, creatinine, and calendar month
of blood draw because these are suspected risk factors for dementia and vitamin D deficiency. Interactions were tested using the Wald test with Cox regression models including
multiplicative two-factor interaction terms. For interaction
analyses and stratified analyses, we used a 20th percentile decrease in seasonally adjusted percentiles of plasma 25(OH)D
as the independent variable. The proportional hazards assumption was tested for with Cox regression models using
Schoenfeld residuals; no departures were detected for the different plasma 25(OH)D variables used. We analyzed the data
with STATA 12.1 (STATA, College Station, TX).
3. Results
Table 1 summarizes the baseline characteristics by
25(OH)D levels. Reduced levels of 25(OH)D were associ-
ated with increasing age, smoking, increasing body mass index, low duration and intensity of leisure time physical
activity, low income, low education, diabetes mellitus, hypertension, reduced alcohol consumption, reduced cholesterol, reduced HDL cholesterol, and increased creatinine
levels. A total of 418 events of AD and 92 events of vascular
dementia occurred during 30 years of follow-up. Both diagnoses were registered for 14 participants.
Median levels of 25(OH)D were 41 nmol/L among all
participants and 39 nmol/L among those who developed
AD or vascular dementia.
3.1. Alzheimers disease
Adjusted hazard ratios for AD increased with decreasing
levels of 25(OH)D by clinical categories and by seasonally
adjusted percentile categories (Tables 2 and 3), although
only with a significant trend when using seasonally adjusted
percentile categories. Multivariable adjusted hazard ratios
were 1.25 (95% CI, 0.951.64) for 25(OH)D less than 25
nmol/L vs. greater than or equal to 50 nmol/L, and 1.29
(1.011.66) for less than the 25th vs. more than the 50th seasonally adjusted percentile in the fully adjusted models.
Multivariable adjusted hazard ratios were 1.04 (1.001.09)
per 10-nmol/L decrease in 25(OH)D and 1.08 (1.011.16)
per 20th-percentile decrease in seasonally adjusted percentiles of 25(OH)D in the fully adjusted models.
3.2. Vascular dementia
Multivariable adjusted hazard ratios for vascular dementia were 1.22 (95% CI, 0.771.91) for 25(OH)D less than 50
nmol/L vs. greater than or equal to 50 nmol/L, and 1.22
(95% CI, 0.791.87 for less than or equal to the 50th vs.
299
Table 2
Risk of Alzheimers disease, vascular dementia, and the combined end point by plasma 25-hydroxyvitamin D (25[OH]D) in clinical categories unadjusted for
seasonal variation
End point
Alzheimers
disease
Vascular
dementia
Combined
25(OH)D,
nmol/L
Participants, n
Events, n
HR (95% CI)
P valuex
HR (95% CI)
P valuex
HR (95% CI)
P valuex
50
3715
151
.12
.12
.11
2549.9
,25
50
4087
2384
3715
174
93
31
1.11 (0.891.39)
1.23 (0.951.59)
1
.25
1.11 (0.891.39)
1.23 (0.941.61)
1
.44
1.12 (0.901.40)
1.25 (0.951.64)
1
.45
,50
50
2549.9
,25
6410
3715
4087
2384
61
175
210
111
1.29 (0.831.99)
1
1.16 (0.951.42)
1.26 (0.991.61)
.04
1.19 (0.761.86)
1
1.15 (0.931.41)
1.25 (0.981.60)
.06
1.22 (0.771.91)
1
1.16 (0.941.42)
1.28 (1.001.64)
.04
Table 3
Risk of Alzheimers disease, vascular dementia, and the combined end point by plasma 25-hydroxyvitamin D (25[OH]D) in seasonally adjusted percentile
categories
Model 1,* age and sex adjusted
End point
25(OH)D, %
Participants, n
Events, n
HR (95% CI)
P valuex
HR (95% CI)
P valuex
HR (95% CI)
P valuex
Alzheimers
disease
.50
5093
132
.07
.04
.03
2650
25
.50
2545
2548
5093
151
135
44
1.17 (0.931.48)
1.23 (0.971.56)
1
.26
1.20 (0.951.51)
1.25 (0.981.60)
1
.42
1.23 (0.971.55)
1.29 (1.011.66)
1
.42
50
.50
2650
25
5093
5093
2545
2548
48
156
177
163
1.26 (0.831.90)
1
1.20 (0.971.48)
1.23 (0.981.53)
Vascular
dementia
Combined
.04
1.19 (0.781.81)
1
1.21 (0.981.50)
1.23 (0.981.54)
.04
1.22 (0.791.87)
1
1.24 (1.001.54)
1.27 (1.011.60)
.02
300
Fig. 1. Risk of Alzheimers disease or vascular dementia (combined end point) by plasma 25-hydroxyvitamin D (25[OH]D) in strata. Each hazard ratio is per
20th percentile decrease in seasonally adjusted plasma 25(OH)D percentiles adjusted for gender, age, smoking status (never/ever), body mass index (BMI),
duration and intensity of leisure time and work-related physical activities, income, education, diabetes mellitus, hypertension, alcohol consumption, cholesterol,
high-density lipoprotein (HDL) cholesterol, and creatinine, excluding the variable used for stratification. Age, education, alcohol consumption, cholesterol, and
HDL cholesterol was categorized using the median. The size of each square corresponds to the size of the population compared with the total populationbased
on 10,186 individuals from the Danish general population in the Copenhagen City Heart Study monitored for up to 30 years after blood sampling for measurement of 25(OH)D. CI, confidence interval.
4. Discussion
In a prospective study on the risk of AD and vascular
dementia in the general population with reduced levels of
25(OH)D, we observed an increasing risk of AD with
decreasing levels of 25(OH)D.
Biologically, our results are plausible for AD because increased 1,25-(OH)2-vitD has been implicated in increased
clearance of Ab by macrophages [2,3]; inhibition of
mechanisms of free-radical production induced in, for example, AD [4,5]; upregulation of synaptic neurotrophic factors,
which are depleted in AD [6,9,10]; and, last, protection
of neurons from apoptosis induced by, for example, Ab
[1113]. For vascular dementia, clinical studies have
shown an association of reduced plasma 25(OH)D with
increased risk of stroke and white matter hyperintensities
[18,19], and in vivo studies have shown that higher plasma
25(OH)D levels may restrict the size of experimentally
induced infarctions [26]. Furthermore, plasma 25(OH)D or
vitamin D intake has been shown to be associated with cognitive function [2731] and cognitive decline [3234]
301
RESEARCH IN CONTEXT
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