TABLE 1: Characteristics of studies included in the meta-analysis
| Germany |
German |
AD† according to NINCDS-ADRDA† criteria. Medical and family history, general medical and neurologic examination, psychiatric interview, neuropsychological testing, blood and CSF† studies, and
CT† scans were performed to exclude other forms of dementia. 66.7% female (age range: 51-101 (74.4) years). |
A. Randomly selected healthy subjects (age: >50 years) from general population (n = 191). No psychiatric disorders and dementia on psychiatric interview and neuropsychological testing. 51.8% female (age range: 50–100 (70.6) years). |
102 |
351 |
Papassotiropoulos, 1999 (9) |
|
|
|
B. Nondemented, depressed hospitalized patients (n = 160). Same clinical evaluation as the AD group. 65.6% female (age range: 50–88 (68.0) years). |
|
|
|
| Germany |
German |
AD according to NINCDS-ADRDA criteria. Medical and family history, general medical and neurologic examination, psychiatric interview, neuropsychological testing, blood studies, and CT scans were performed to exclude other forms of dementia. 60.6% developed AD after the age of 65 years, and 62.2% had no family history for dementia. 61% female (mean age: 72.0 years). |
Nondemented subjects. Same clinical evaluation as the AD group. 61% female (mean age: 69.0 years). |
127 |
184 |
Papassotiropoulos, 2000 (7) |
| Germany |
Caucasian‡ |
AD according to NINCDS-ADRDA criteria. 71.6% female (mean age: 74.2 years). |
Patients or healthy volunteers with no signs of dementia and MMSE† score of >=27, interviewed by professional examiners. 59.9% female (mean age: 67.8 years). |
324 |
302 |
Menzer, 2001 (8) |
| Italy |
Italian |
AD diagnosis based on DSM† criteria. |
Subjects assessed to exclude diagnosis of any neurologic disorder. 66.6% female (age range: 26–108 (72.9) years). |
197 |
126 |
Bagnoli, 2002 (16) |
|
|
A. Sporadic AD cases (n = 131). 63.4% female (age range: 45–88 (71.1) years). |
|
|
|
|
|
|
B. AD cases belonging to autopsy-proven AD families (n = 66): 33 early onset AD (mean age: 66.4 years) and 33 late-onset AD (mean age: 76.2 years) cases. |
|
|
|
|
| Italy |
Italian |
AD according to NINCDS-ADRDA criteria. Clinical examination, including neuropsychological testing, laboratory studies, and neurologic examination. 76.8% female (mean age: 76.3 years). |
Community-dwelling elderly people with MMSE score of >= 28. Clinical examination performed as in cases. 75% female (mean age: 71.7 years). |
142 |
120 |
Ingegni, 2003 (12) |
| Japan |
Japanese |
AD according to NINCDS-ADRDA criteria. 71.6% female (mean age: 74.4 years). |
Community-dwelling elderly people judged cognitively normal by MMSE. 46.3% female (mean age: 74.9 years). |
275 |
479 |
Matsui, 2001 (15) |
|
American |
Autopsy-confirmed AD cases (mean age: 77.8 years). |
Not clarified (mean age: 61.1 years). |
69 |
50 |
|
| Poland |
Polish |
Late-onset AD according to NINCDS-ADRDA criteria. CT scan was obtained for each patient. 66% female (mean age: 76.4 years). |
Not clarified. 58% female (mean age: 74.2 years). |
100 |
100 |
Styczynska, 2003 (19) |
| Spain |
Spanish |
AD according to NINCDS-ADRDA criteria. 67% female (age range: 50–98 (75.3) years). |
Subjects randomly selected from a nursing home. Free from significant illness on complete neurologic and medical examinations, MMSE score of >= 28, verified on annual follow-up assessment. 70% female (age range: 63–100 (80.4) years). |
311 |
346 |
Mateo, 2002 (11) |
| Sweden |
Swedish |
AD according to NINCDS-ADRDA criteria. Clinical diagnosis based on medical history; physical, neurologic, and psychiatric examination; screening laboratory tests; ECG†; chest radiograph; EEG†; and brain CT (n = 111). Neuropathologic diagnosis based on CERAD† criteria (n = 93). No family history of dementia. 61.3% female. |
Healthy volunteers without history, symptoms, or signs of psychiatric or neurologic disease, malignant disease, or systemic disorders; MMSE score of >= 28 (n = 76). Autopsy group of patients who had died from cardiac or malignant disease; no history of dementia or psychiatric or neurologic diseases; negative autopsy for dementia (n = 108). 58.1% female. |
204 |
186 |
Prince, 2001 (14) |
| Sweden |
Scottish |
Early onset AD according to DSM III-R criteria. No family history of dementia (age range: 30–65 years). |
Not clarified. |
121 |
152 |
Emahazion, 2001 (18) |
| United Kingdom |
British |
AD according to DSM IV and NINCDS-ADRDA criteria. Where possible, a CT scan was performed to aid diagnosis. 66% female (mean age: 77.7 years). |
Healthy spouses or volunteers with unrevealing medical history and physical examination. 69% female (mean age: 77.1 years). |
183 |
187 |
McIlroy, 1999 (10) |
| United States |
American |
Late-onset AD (mean age of onset: 71.8 years) according to NINCDS-ADRDA criteria. 35% autopsy-confirmed cases. 65% female (mean age: 76.1 years). |
Controls recruited from dementia research center (n = 89) (mean age: 72.7 years) and survey study (n = 248) (mean age: 75.2 years). All survey subjects had an MMSE score of
>= 28. |
531 |
337 |
Bhojak, 2000 (13) |
| United States |
American |
AD according to NINCDS-ADRDA criteria. AD clinic cases participating in a multicenter clinical drug trial and patients evaluated at university clinics. Community-based AD cases participating in dementia screening with extensive subsequent diagnostic evaluation. 58.6% female (mean age: 75.8 years) for Caucasians, 69.6% female (mean age: 73.7 years) for Hispanics. |
Subjects evaluated in the community-screening program and found to be free from cognitive problems (MMSE score of >27). 50.8% female (mean age: 75.7 years) for Caucasians, 58.9% female (mean age: 72.6 years) for Hispanics. |
210 |
120 |
Crawford, 2000 (6) |
|
Hispanic |
|
|
79 |
112 |
|
| United States |
American |
AD cases from dementia research center. 18.5% had neuropathologically confirmed AD (mean age: 70.8 years). |
Cognitively normal subjects from the same dementia research center (mean age: 66.5 years). |
200 |
182 |
Bertram, 2001 (17) |
* All eligible subjects were genotyped with the exception of 21 controls in the study by Bhojak et al. (13), 12 controls in the study by Prince et al. (14), and one Alzheimer’s disease case and three controls in the study by Emahazion et al. (18).
† AD, Alzheimer’s disease; NINCDS-ADRDA, National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer’s Disease and Related Disorders Association; CSF, cerebrospinal fluid; CT, computed tomography; MMSE, Mini-Mental State Examination; DSM, Diagnostic and Statistical Manual of Mental Disorders; ECG, electrocardiogram; EEG, electroencephalogram; CERAD, Consortium to Establish a Registry for Alzheimer’s Disease.
‡ Germany: 173 cases, 217 controls; Switzerland: 44 cases, 55 controls; Italy: 107 cases, 30 controls.
TABLE 2: Distribution of CTSD alleles among Alzheimer’s disease cases and controls in the included studies
First author, year (reference) |
Ethnic group |
T/T |
C/T |
C/C |
| |
|
Alzheimer’s disease cases (no.) |
Controls (no.) |
Alzheimer’s disease cases (no.) |
Controls (no.) |
Alzheimer’s disease cases (no.) |
Controls (no.) |
| Papassotiropoulos, 1999 (9) |
German |
1 |
0 |
27 |
47 |
74 |
304 |
| McIlroy, 1999 (10) |
British |
0 |
1 |
29 |
16 |
154 |
170 |
| Bhojak, 2000 (13) |
American |
2 |
0 |
98 |
56 |
431 |
260 |
| Crawford, 2000 (6) |
American |
0 |
0 |
43 |
20 |
167 |
100 |
|
Hispanic |
0 |
2 |
13 |
28 |
66 |
82 |
| Papassotiropoulos, 2000 (7) |
German |
0 |
0 |
30 |
18 |
97 |
166 |
| Bertram, 2001 (17) |
American |
2 |
1 |
31 |
29 |
167 |
152 |
| Matsui, 2001 (15) |
Japanese |
0 |
1 |
4 |
7 |
271 |
471 |
|
American |
1 |
1 |
8 |
6 |
60 |
43 |
| Menzer, 2001 (8) |
Caucasian* |
3 |
1 |
43 |
33 |
278 |
268 |
| Emahazion, 2001 (18) |
Scottish |
0 |
3 |
13 |
27 |
107 |
119 |
| Prince, 2001 (14) |
Swedish |
0 |
0 |
27 |
22 |
177 |
152 |
| Mateo, 2002 (11) |
Spanish |
2 |
8 |
54 |
54 |
255 |
284 |
| Bagnoli, 2002 (16) |
Italian |
4 |
1 |
41 |
26 |
152 |
99 |
| Ingegni, 2003 (12) |
Italian |
4 |
1 |
29 |
21 |
109 |
98 |
| Styczynska, 2003 (19) |
Polish |
1 |
0 |
11 |
9 |
88 |
91 |
* German, Swiss, and Italian.
TABLE 3: Summary odds ratios for various contrasts
Contrast |
No. of study comparisons |
Random effects |
Fixed effects |
|
|
OR* |
95% CI* |
OR |
95% CI |
T vs. C |
16 (12,944)† |
1.17 |
0.95, 1.44‡ |
1.16 |
1.01, 1.32 |
T/T vs. C/C |
16 (5,552) |
1.07 |
0.55, 2.10 |
0.98 |
0.52, 1.85 |
T/T vs. (C/T + C/C) |
16 (6,472) |
1.05 |
0.54, 2.06 |
0.97 |
0.51, 1.84 |
(C/T + T/T) vs. C/C |
16 (6,472) |
1.19 |
0.97, 1.47§ |
1.18 |
1.03, 1.36 |
* OR, odds ratio; CI, confidence interval.
† Numbers in parentheses, number of cases and controls combined.
‡ Significant between-study heterogeneity (p < 0.01).
§ Significant between-study heterogeneity (p < 0.05).
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