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Epidos 2
Epidos 2
Department of Internal Medicine and Clinical Gerontology, Acute Unit for Alzheimers Patients, Toulouse, France.
2
Institut National de la Sante et de la Recherche Medicale (INSERM) U558, Toulouse, France.
Background. Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo biloba
extracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated that
because of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies have
been published to date to test its efficacy in prevention of Alzheimers disease. The potential association between use of
C4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type was
investigated.
Methods. A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years.
Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive function
remained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffers test
and whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-up
period. In order to study the factors associated with the onset of dementia, the data concerning women with a score of >8
on Pfeiffers test at inclusion, indicating normal cognitive function, were analyzed.
Results. A multivariate analysis including potential confounding factors showed that fewer women who developed
Alzheimers dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio 5 0.31,
95% confidence interval 5 0.120.82, p 5 .018). Figures for EGb 761 alone were similar but did not reach statistical
significance (odds ratio 5 0.38, 95% confidence interval 5 0.081.76, p 5 .22).
Conclusion. These results suggest that C4A treatment may reduce the risk of developing Alzheimers dementia in
elderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. To
establish a causal relationship, these findings have to be confirmed with prospective studies.
372
373
Statistical Analysis
Analysis was performed with SAS software (SAS Version
8.0; SAS Institute, Inc., Cary, NC). Bivariate analyses were
based on conventional tests comparing means for quantitative variables (analysis of variance), and frequency distributions for qualitative variables (chi-square test or Fisher exact
test, according to sample size). Comparisons were made
between AD patients and a control group consisting of five
controls for one case. For all cases, medication history was
available from six follow-up consultations: baseline (T0),
each year of follow-up study (T1, T2, T3, and T4), and at the
final examination (T7). For the cases diagnosed as AD
during follow-up and for their five corresponding controls,
only data preceding the diagnosis were used. In order to
study the factors associated with the onset of dementia, only
data for women with a score >8 on Pfeiffers test at baseline
(17,18), who were thus considered as cognitively normal,
were used. The analysis included 69 women with AD of the
110 women who were diagnosed with AD, and 345 controls
with normal cognitive evaluation.
To account for potential confounding factors, the
variables statistically related to AD and those related to
exposure to C4A treatment, with a value of p , .25, were
included in the logistic regression model, with Alzheimers
dementia as a dependent variable. The model was fitted by
using the HosmerLemeshow test (19).
RESULTS
Those patients lost to follow-up were initially in worse
health than those included in the study. However, there were
ANDRIEU ET AL.
374
Non-ATD
No. (%)
ATD
No. (%)
OR
95% CI
247 (71.6)
79 (22.9)
19 (5.5)
40 (57.9)
20 (29.0)
9 (13.1)
.0292
.1401
.0145
1
1.56
2.93
0.862.83
1.246.92
29 (8.4)
316 (91.6)
11 (15.9)
58 (84.1)
1
0.48
0.231.02
173
80
9
83
17
26
4
22
1
2.70
4.52
3.31
1.365.35
1.2616.25
1.706.44
(50.1)
(23.2)
(2.6)
(24.1)
(24.6)
(37.7)
(5.8)
(31.9)
284 (85.5)
48 (14.5)
46 (66.7)
23 (33.3)
100
190
20
35
14
41
7
7
.0531
.0005
.0045
.0207
.0004
1
2.96
1.655.32
(20.3)
(59.4)
(10.1)
(10.1)
.0002
.3125
.1942
.0802
.4781
1
1.54
2.50
1.43
0.802.96
0.907.00
0.533.83
329 (95.4)
16 (4.6)
60 (87.0)
9 (13.0)
.0219
1
3.08
1.307.30
315 (91.3)
30 (8.7)
56 (81.2)
13 (18.8)
.0117
1
2.44
1.204.96
309 (89.8)
35 (10.2)
59 (85.5)
10 (14.5)
.2934
1
1.50
0.703.19
158 (45.8)
187 (54.2)
37 (53.6)
32 (46.4)
.2345
1
1.73
0.441.22
(29.0)
(55.1)
(5.8)
(10.1)
Notes: ATD 5 Alzheimers-type dementia; OR 5 odds ratio; CI 5 confidence interval; IADL 5 instrumental activities of daily living. Non-ATD = 345
(83.33%); ATD 5 69 (16.67%).
375
Non-ATD
No. (%)
ATD
No. (%)
342 (99.1)
3 (0.9)
68 (98.6)
1 (1.4)
249
77
12
7
(72.2)
(22.3)
(3.5)
(2.0)
50
14
4
1
(72.5)
(20.3)
(5.8)
(1.4)
242
23
31
49
(70.1)
(6.7)
(9.0)
(14.2)
49
8
6
6
(71.0)
(11.6)
(8.7)
(8.7)
232
62
25
26
(67.2)
(18.0)
(7.2)
(7.5)
44
15
5
5
(63.8)
(21.7)
(7.2)
(7.2)
270
43
14
18
(78.3)
(12.5)
(4.1)
(5.2)
51
11
6
1
(73.9)
(15.9)
(8.7)
(1.5)
169
57
39
80
(49.0)
(16.5)
(11.3)
(23.2)
35
16
12
6
(50.7)
(23.2)
(17.4)
(8.7)
264
37
20
24
(76.5)
(10.7)
(5.8)
(7.0)
57
8
2
2
(82.6)
(11.6)
(2.9)
(2.9)
OR
95% CI
.5192
.8006
.2181
.9240
.2743
.3634
.2181
.9240
.2743
.9078
.4625
.9181
.9785
.1811
.4134
.1091
.2387
.0289
.3689
.2959
.0280
.5254
.9973
.3086
.2046
1
1.68
0.1716.4
1
0.91
1.66
0.71
0.481.73
0.515.36
0.095.91
1
1.72
0.96
0.61
0.734.06
0.382.41
0.251.49
1
1.28
1.06
1.01
0.672.44
0.382.90
0.372.78
1
1.35
2.27
0.30
0.662.80
0.836.18
0.042.25
1
1.36
1.49
0.36
0.702.63
0.713.12
0.150.90
1
1.00
0.46
0.39
0.442.27
0.112.04
0.091.68
Notes: ATD5 Alzheimers-type dementia; OR 5 odds ratio; CI 5 confidence interval; NSAIDs 5 nonsteroidal anti-inflammatory drugs; C4A 5 cerebral and
peripheral vasotherapeutics; EGb 5 standardized Ginkgo biloba extracts.
DISCUSSION
Alzheimers dementia is a neurodegenerative disease with
long-term evolution before definitive lesions. With an
unprecedented demographic change in the Western population, prevention and effective treatment of age-dependent
disease is a public health priority. Many elderly people
worried about cognitive impairment are requesting therapy,
and millions of people in Europe and the United States are
regularly taking Ginkgo biloba extracts. The value of this
treatment deserves study.
Our objective was to investigate the potential association
between use of C4A treatments, in particular EGb 761
(standardized Ginkgo biloba extracts), and Alzheimers
dementia onset in elderly women. We found that women
regularly taking C4A treatment were three times more
numerous in the group without dementia than in the group
with dementia. The odds ratio for EGb 761 was similar but
did not reach statistical significance.
Women participating in the EPIDOS study were volunteers and therefore not representative of the general population. Cognitive status was evaluated in only 50% of the
initial population, so we could not study the relative risk of
AD associated with C4A prescription. However, our study
was prospective and could precisely determine the cognitive
status of the women (normal or AD). Therefore, a casecontrol study nested in the cohort was possible. One of the
strong points of the study is the fact that the population had
cognitive assessments at the outset by the Pfeiffer test and
only those with scores of 8 or more were included. Because
C4A treatments are physician prescribed, we could be sure
that all patients received the standardized extract of Ginkgo
biloba. The medication history was recorded each year, so
we assumed patients who had three consecutive recordings
of C4A medication received the treatment long term. It was
this group of patients who showed significant results.
However, in the early stages of dementia, women could
have forgotten whether they had taken specific medication.
We postulate that they were not more likely to have forgotten
their C4A treatment than their other treatments, and yet there
was no difference in the two groups for any other type of
medication (aspirin, calcium channel blockers, mineral
supplements, nonsteroidal anti-inflammatory drugs).
Epidemiological studies should help to identify risk factors
for AD. Our study has once again identified age attained as an
independent risk factor. It has not, however, shown any
relationship between aspirin or nonsteroidal anti-inflammatory treatment and risk for AD. This may be due to the relatively infrequent use of these drugs in the study population.
ANDRIEU ET AL.
376
Table 4. Bivariate Analysis: Characteristics of Women According to Exposure to C4A Treatment at the Time of Diagnosis
C4A Treatments
Baseline Parameters
Age
<80 y
8185
.85 y
End of primary school certificate
No
Yes
Income euros/mo)
.915
457915
,457
Unknown
Perceived health
Good
Poor
Marital status
Married
Widowed
Divorced
Single
Washing, dressing, & walking
Independent
Dependent
Binary IADL
0 incapacity
>1 incapacity
Hearing problem
No
Yes
Depression
No
Yes
Not Exposed
No. (%)
1 Exposure
No. (%)
>3 Exposures
No. (%)
2 Exposures
No. (%)
p
.01
154 (75.5)
44 (21.6)
6 (2.9)
43 (58.9)
21 (28.8)
9 (12.3)
37 (72.6)
10 (19.6)
4 (7.8)
53 (61.6)
24 (27.9)
9 (10.5)
16 (7.8)
188 (92.2)
12 (16.4)
61 (83.6)
5 (9.8)
46 (90.2)
7 (8.1)
79 (91.9)
29
23
3
18
23
12
0
16
47
17
4
18
.20
.50
91
54
6
53
(44.6)
(26.5)
(2.9)
(26.0)
(39.7)
(31.5)
(4.1)
(24.7)
(45.1)
(23.5)
(0.0)
(31.4)
(54.7)
(19.8)
(4.7)
(20.9)
.25
163 (82.7)
34 (17.3)
54 (76.1)
17 (23.9)
39 (79.6)
10 (20.4)
74 (88.1)
10 (11.9)
63
110
13
18
17
43
5
8
15
32
1
3
19
46
8
13
.42
(30.9)
(53.9)
(6.4)
(8.8)
(23.3)
(58.9)
(6.8)
(11.0)
(29.4)
(62.7)
(2.0)
(5.9)
(22.1)
(53.5)
(9.3)
(15.1)
.17
194 (95.1)
10 (4.9)
67 (91.8)
6 (8.2)
45 (88.2)
6 (11.8)
83 (96.5)
3 (3.5)
183 (89.7)
21 (10.3)
65 (89.0)
8 (11.0)
45 (88.2)
6 (11.8)
78 (90.7)
8 (9.3)
108 (52.9)
96 (47.1)
33 (45.2)
40 (54.8)
23 (45.1)
28 (54.9)
31 (36.1)
55 (63.9)
177 (86.8)
27 (13.2)
69 (94.5)
4 (5.5)
47 (94.0)
3 (6.0)
75 (87.2)
11 (12.8)
.97
.07
.18
Notes: C4A 5 cerebral and peripheral vasotherapeutics; not exposed, n 5 204 (49.3%); 1 exposure, n 5 73 (17.6%); 2 exposures, n 5 51 (12.3%); >3 exposures, n 5 86 (20.8%). IADL 5 instrumental activities of daily living.
Conclusion
In conclusion, our study including 414 patients over 75
years old showed that women with diagnosed dementia had
been less frequently exposed to chronic use of C4A
treatment. This effect remained significant after adjustment
for potential confounding effects. Although these results
should be interpreted with caution because of the study
design, the evidence for the protective effects of other
treatments was not stronger than that shown for C4A
treatment. Primary prevention trials should be undertaken to
confirm these findings. In fact, large interventional studies
are ongoing with EGb 761 in North America and Europe to
determine the preventive effect of these treatments, but
results will not be available for 6 to 7 years. A recent study
with Ginkgo extract treatment has shown no effects on
memory (20); however, this study was done in younger
people (68.5 years) with no cognitive complaints and with
only 6 weeks of treatment. The effect of Ginkgo on
oxidative stress and on vascular function will require much
longer time review to be effective. Following our long-term
observational study, some long-term placebo-controlled
studies are on the way over a 1-year period to prevent
dementia in older elderly persons (more than 75 years) with
cognitive complaints.
OR
95% CI
.0082
.0004
.0063
.0033
.0168
.0106
.0333
.0765
.0698
.7261
.4915
.0180
.7175
0.60
1.16
0.410.87
1.071.26
2.91
5.56
2.62
2.02
0.58
1.435.94
1.3622.70
1.255.47
1.063.86
0.321.06
0.87
1.34
0.31
0.411.86
0.593.04
0.120.82
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