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Alzheimers & Dementia 10 (2014) 296302

Reduced 25-hydroxyvitamin D and risk of Alzheimers disease


and vascular dementia
Shoaib Afzala, Stig E. Bojesena,b,c, Brge G. Nordestgaarda,b,c,*
a
The Department of Clinical Biochemistry, Herlev Hospital, Copenhagen University Hospital, Herlev, Denmark
The Copenhagen City Heart Study, Bispebjerg Hospital, Copenhagen University Hospital, Copenhagen, Denmark
c
Faculty of Health and Medical Sciences, University of Copenhagen, Herlev, Denmark

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:

Alzheimers disease; Vascular dementia; Vitamin D; General population; Cohort study

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],

*Corresponding author. Tel.: 145 38683297; Fax: 145 38683311.


E-mail address: Boerge.Nordestgaard@regionh.dk

to improve intracellular Ca21 homeostasis dysregulated in


AD [68], to upregulate neurotrophic factors [6,9,10], and
to induce neuroprotective processes [1113]. Furthermore,
several cross-sectional studies have shown reduced plasma
levels of 25-OH-vitamin D (25[OH]D) among AD patients
compared with control subjects [1416].
Vascular dementia develops as a result of infarcts [17],
and clinical studies have shown that vitamin D deficiency
is associated with white matter hyperintensities in patients
with dementia and risk of stroke [18,19]. Moreover,
vitamin D deficiency has been associated with common
risk factors for strokenamely, hypertension and diabetes
[20,21]further supporting a possible role for vitamin D
deficiency in the pathogenesis of vascular dementia.
However, this has never been tested previously.

1552-5260/$ - see front matter 2014 The Alzheimers Association. All rights reserved.
http://dx.doi.org/10.1016/j.jalz.2013.05.1765

S. Afzal et al. / Alzheimers & Dementia 10 (2014) 296302

Therefore, we tested the hypothesis that decreased


plasma 25(OH)D is associated with increased risk of AD
and vascular dementia in the general population. For this
purpose, we studied 10,186 white individuals from the Copenhagen City Heart Study monitored for up to 30 years
without losses to follow-up.

297

baseline measurements of nonfasting glucose (.11 mmol/L)


and blood pressure (.140/90 mmHg or .135/85 mmHg for
participants with diabetes mellitus). Participants were also
asked about type and amount of weekly alcohol consumption,
which was then calculated in units of 12 g/week. Body mass
index was calculated as measured weight (kilograms) divided
by measured height (meters) squared.

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

2.4. End points


Information on incident diagnoses of AD (International
Classification of Diseases [ICD], 8th edition, codes 290.0
290.1 and ICD, 10th edition, codes F00 and G30) and vascular
dementia (ICD, 8th edition, codes 293.09293.1 and ICD,
10th edition, codes F01) was collected from diagnoses entered in the national Danish Patient Registry and the national
Danish Causes of Death Registry [25]. Validation studies
have shown high validity of the dementia diagnosis and AD
diagnoses in Danish registries [25]. Follow-up time for each
subject began at the day of blood sampling in 1981 to 1983
and ended at diagnosis of AD (n 5 418) or vascular dementia
(n 5 92), death (n 5 6360), emigration (n 5 55), or May 2011
(n 5 3275), whichever occurred first. The median follow-up
time was 21 years (range, 0.0330 years). Follow-up was
100% completethat is, we did not lose track of even a single
individual. We also combined AD and vascular dementia for
three reasons: (i) to increase statistical power, (ii) AD and vascular dementia show clinical overlap, and (iii) vitamin D may
be involved in the pathogenesis of both diseases.
Participants with both diagnoses were included in both
end points separately for two reasons: (i) it is well known
that some patients have dementia with phenotypes intermediate between AD and vascular dementia and (ii) excluding
these patients or only including them in one of the groups did
not change the effect estimates from the regression analyses
(data not shown).
2.5. Statistical analyses
We divided baseline 25(OH)D into the following a priori
seasonally unadjusted clinical categories of more than50
nmol/L (sufficient levels), 25 to 49.9 nmol/L (insufficient
levels), and less than 25 nmol/L (deficient levels). In addition,
because concentrations of 25(OH)D vary according to the
time of year because of the high-latitude geographic position
of Denmark, we also used seasonally adjusted 25(OH)D
levels. Two strategies were applied to adjust for the seasonal
variation in vitamin D. First, we used unadjusted 25(OH)D
levels in regression analyses and adjusted for calendar month
of blood draw. Second, calendar month-specific cut points
were obtained by assigning subjects to more than the 50th
percentile, the 26th to the 50th percentile, and less than or
equal to the 25th percentile categories within the same month
of sample collection. For vascular dementia, because of the
relatively few cases, we changed classifications to less than
50 nmol/L vs. greater than or equal to 50 nmol/L for the

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S. Afzal et al. / Alzheimers & Dementia 10 (2014) 296302

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

Abbreviation: HDL, high-density lipoprotein.


NOTE. International System of Units conversion factors: To convert 25(OH)D to nanomoles per liter from nanograms per liter, multiply values by 2.5.
Continuous values are shown as median (interquartile range).
*P values were calculated using Cuzicks nonparametric trend test.
y
One unit w 12 g.

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.

S. Afzal et al. / Alzheimers & Dementia 10 (2014) 296302

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

Model 1,* age and sex adjusted

Model 2,y partially adjusted

Model 3,z fully adjusted

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

Abbreviations: HR, hazard ratio; CI, confidence interval.


NOTE. International System of Units conversion factors: To convert 25(OH)D to nanomoles per liter from nanograms per liter, multiply values by 2.5.
*Adjusted for age, sex, and month of blood sample only.
y
Model 2 adjustment: model 1 covariates 1 smoking status, body mass index, leisure time and work-related physical activity, and alcohol consumption.
z
Model 3 adjustment: model 2 covariates 1 income level, education, baseline diabetes mellitus, hypertension, cholesterol, high-density lipoprotein cholesterol, and creatinine.
x
P values are from trend tests.

more than the 50th seasonally adjusted percentile (Tables 2


and 3). Multivariable adjusted hazard ratios were 1.02 (95%
CI, 0.921.12) per 10-nmol/L decrease in 25(OH)D and 1.05
(95% CI, 0.901.23) per 20th-percentile decrease in seasonally adjusted percentiles of 25(OH)D in the fully adjusted
models.
3.3. Combined end point
Adjusted hazard ratios for AD or vascular dementia (i.e.,
the combined end point) increased with decreasing levels of
25(OH)D by clinical categories and by seasonally adjusted
percentile categories (Tables 2 and 3). Multivariable adjusted hazard ratios 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 percentile
in the fully adjusted models. Multivariable adjusted hazard
ratios were 1.04 (95% CI, 1.001.09) per 10-nmol/L decrease in 25(OH)D and 1.08 (95% CI, 1.011.15) per
20th-percentile decrease in seasonally adjusted percentiles
of 25(OH)D in the fully adjusted models.
In all stratified analyses, a 20th-percentile reduction in
seasonally adjusted percentile of plasma 25(OH)D was associated with hazard ratios nominally above 1.00 except for
participants with diabetes mellitus (Fig. 1). There were no
interactions of 25(OH)D with other variables on risk of the
combined end point.

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

Model 2,y partially adjusted

Model 3,z fully 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

Abbreviations: HR, hazard ratio; CI, confidence interval.


*Adjusted for age and sex only.
y
Model 2 adjustment: model 1 covariates 1 smoking status, body mass index, leisure time and work-related physical activity, and alcohol consumption.
z
Model 3 adjustment: model 2 covariates 1 income level, education, baseline diabetes mellitus, hypertension, cholesterol, high-density lipoprotein cholesterol, and creatinine.
x
P values are from trend tests.

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S. Afzal et al. / Alzheimers & Dementia 10 (2014) 296302

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]

among the elderly population, supporting indirectly a role


for plasma 25(OH)D in maintenance of cognitive function.
Our results are in accordance with most previous crosssectional studies showing reduced levels of 25(OH)D in
patients with AD or cognitive impairment [1416].
Furthermore, studies have shown an association of low
intake of vitamin D with increased risk of AD [31,35], and
prospective studies have shown an association of low
plasma 25(OH)D with cognitive decline [34,36]. Also, the
current prospective association of reduced levels of
vitamin D with vascular dementia did not reach statistical
significance, probably because of low power. Previous
studies showed an association of reduced levels of 25(OH)
D with stroke [37], which is a prerequisite for developing
vascular dementia [17].
A major limitation of this study was relying on clinician
diagnoses of dementia for our primary outcomes. This is particularly problematic when relying on clinicians to make an
adequate distinction between AD and vascular dementia
without any verification of imaging studies, and the low

S. Afzal et al. / Alzheimers & Dementia 10 (2014) 296302

number of vascular dementia cases seems to reflect this.


However, validation studies have shown high validity of
the dementia diagnosis and AD diagnoses in Danish registries [25]. Other potential limitations of our study include
healthy participant bias because participants are typically
healthier than background populations; however, this would
tend to weaken the associations rather than strengthen them,
and thus is unlikely to explain our findings. The delay in
measurement from 1981 to 1983 to 2009 to 2010 could raise
concern of decay in plasma 25(OH)D, but this seems unlikely for several reasons: we noticed the expected seasonal
variation of 25(OH)D levels [38,39]; median concentrations
of plasma 25(OH)D across plasma samples from three
different examinations on the same healthy participants
with storage times of 10, 20, and 30 years were similar
[38,39]; previous studies have shown high stability during
storage [40]; the median concentration observed in our study
of 16 nmol/L was similar to that in comparable populations
[41]; and a reduced quality of the 25(OH)D measurement
would tend to weaken rather than inflate an association. Another potential limitation was the use of only a single measurement of plasma 25(OH)D, although studies have
shown that a single measurement is a reasonable predictor
of long-term exposure to plasma 25(OH)D [42]. It is also
a potential limitation that we were not able to adjust for depression. Furthermore, all participants were white, limiting
the applicability of our results to other ethnic groups. The diagnoses were based on registry data and there is a high probability of underdiagnosis of dementia, which could affect
our results. However, admixture of cases and noncases
would tend to weaken the associations rather than strengthen
them and thus is unlikely to explain our findings.
The strengths of our study are that the study was conducted on the general population, we had up to 30 years of
follow-up with no losses to follow-up, we could account
for other major risk factors associated with risk of dementia,
and we had high statistical power to examine the prospective
associations of reduced plasma 25(OH)D levels with AD.
Furthermore, in northern Europe ultraviolet B radiation
from the sun is only adequate for sufficient endogenous vitamin D production in the skin during the summer months
(MaySeptember) and food has never been fortified with vitamin D in Denmark. Thus, this cohort from the Danish general population allows determination of the natural history of
the association of vitamin D deficiency with risk of AD and
vascular dementia.
In conclusion, we observed an association of reduced
plasma 25(OH)D with increased risk of AD and vascular dementia in this prospective cohort study of the general population. However, these preliminary results require
confirmation in other studies.
Acknowledgments
The Danish Heart Foundation and Herlev Hospital, Copenhagen University Hospital provided research support. Diasorin

301

Liaison provided kits for measurement of 25(OH)D. The


sponsors had no role in the study design, statistical analysis,
data interpretation, manuscript drafting, manuscript revision,
or the decision to submit the manuscript for publication.

RESEARCH IN CONTEXT

1. Systematic review: We searched PubMed up until


December 01, 2012, for articles published in any language with the search terms Vitamin D and Dementia
or Alzheimers disease or Vascular dementia. We
also reviewed the reference lists of the documents
identified by this search.
2. Interpretation: Our prospective study of reduced 25hydroxyvitamin D and risk of Alzheimers disease
(AD) and vascular dementia extends epidemiologic
knowledge of the association between vitamin D
status and specific types of dementia. Our findings
suggest that a low level of 25-hydroxyvitamin D may
be a risk factor for future risk of AD.
3. Future directions: In our study, we had 418 patients
with AD, which is more than most previous studies
on this topic. However, given the size of the risk estimates, larger studies are required, especially regarding the possible role of 25-hydroxyvitamin D
in the development of vascular dementia.

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