From the Departments of Neurology, 1
Taiwan Miners General Hospital; 2
Taipei Medical University. Received March 9, 2006.
Revised and Accepted March 20, 2006.
Reprint requests and correspondence to: Chaur-Jong Hu, MD. Department of Neurology, Taipei Medical University, No. 250, Wu-Hsing Street, Taipei, Taiwan.
E-mail: chaurjongh@tmu.edu.tw
INTRODUCTION
Dementia is a group of diseases characterized by a decline of cognitive function. Patients with dementia gradually become disabled and dependent in daily activ-ities of life. Dementia is associated with a heavy finan-cial burden for families, society and the economy. In Taiwan and in other countries, the problems caused by dementia are becoming more and more urgent as the life span of the population increases. Reducing the impact of dementia requires a multi-disciplinary approach. From a
clinical perspective, correct diagnosis based on an understanding the underlying pathophysiological mech-anisms, and the selection of optimal intervention and prevention methods are essential.
The etiology of dementia is various. In most regions of the world including Taiwan, Alzheimer disease (AD) and vascular dementia (VaD) are the two leading causes of cognitive impairment in late life. In Taiwan, AD fol-lowed by VaD is the most common cause of dementia(1)
. There is now compelling evidence that genetic factors are involved in the pathogenesis of dementia. Genetic
Genetic Characteristics of Dementia in Taiwan
Hsin-Hung Chen
1,2and Chaur-Jong Hu
2Abstract- The most common causes of dementia in Taiwan are Alzheimer’s disease (AD) followed by
vas-cular dementia (VaD). Several genetic studies have documented an increased risk of AD among apolipopro-tein E gene allele 4 (ApoE4) carriers in Taiwanese (ethnic Chinese). Although ApoE4 is considered the most important risk factor for AD, the ApoE4 allele frequency is lower in Taiwanese (around 7%), than that in most Caucasian populations (over 10%). This phenomenon raises the hypothesis that low ApoE4 allele fre-quency contributes to the low prevalence of AD in Taiwanese. Other studies of the genetic impacts on mod-ulation or regmod-ulation of manifestations, progression, and treatment response of AD in Taiwan have been inconclusive. Familial AD, which is conferred by PS1 gene mutation has been identified. There were very few studies of fronto-temporal dementia (FTD) or dementia with Lewy body (DLB) in Taiwan. Genetic studies of VaD remain limited and only NOTCH3 gene mutation has been detected in a Taiwanese cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL) family. Limited data indicated that non- ApoE4-associated AD may represent a larger proportion of AD in Taiwanese, suggesting the existence of novel genetic factors which remain to be identified.
Key Words: Genetic study, Dementia, Alzheimer’s disease, Vascular dementia, Taiwan
variations among individuals may also be responsible for wide differences in the response to treatment and clinical course of dementia. Thus molecular genetic studies are becoming increasingly important in the clinical diagno-sis and prediction of treatment responses. Genetic stud-ies also are providing valuable information which is helping to unravel the pathophysiology of dementia. This article reviews the literature on molecular genetic research in dementia from Taiwan.
Alzheimer disease
The characteristic pathological changes of AD include extracellular senile plaques, intraneuronal rofibrillary tangles, neuronal and synaptic loss, and neu-rotransmitter deficits in the brain. The senile plaques and neurofibrillary tangles are pathologic markers for the diagnosis of AD. The pathogenesis of AD is complex and might involve both environmental and genetic fac-tors. Genes linked to early onset, familial AD include beta-amyloid precursor protein gene (APP), presenilin-1
(PS-1) and presenilin-2 (PS-2). Inheritance of the ε4 allele of apolipoprotein E (ApoE4) confers a genetic risk for developing late-onset, sporadic AD. Besides, some genes also were found for modulating and regulating the manifestations, progression, and treatment responses of AD.
Apolipoprotein E polymorphisms in Alzheimer disease
Apolipoprotein E (ApoE) is one of the proteins con-stituents of plasma lipoproteins. It transports cholesterol and other lipids to the liver by interaction with the low-density lipoprotein (LDL) receptor on the cell surface of hepatocytes(2). There are three isoforms of ApoE, desig-nated E2, E3, and E4, which are encoded for by three different alleles, Apoε 2, ε 3, and ε 4 respectively. Among the three polymorphisms of Apoε 2, 3, and 4, the allele frequency of the Apoε 4 allele is increased in AD patients in many ethnic populations in comparison with non-AD controls, whereas Apoε 2 allele was considered to have potential protection against AD(3)
. ApoE may contribute a final common pathway of neuronal repair and remodeling. It was speculated that ApoE3 and
ApoE2 but not ApoE4 function efficiently and effective-ly in supporting the repair and remodeling of damaged neuronal connections(4).
In 1996, Hong et al.(5)
reported the first results on allele frequencies of ApoE in Taiwanese with late-onset sporadic AD. Their data supported the association between Apoε 4 and AD(5). Later, several other studies from Taiwan also confirmed this important finding(3,6-10)
. Most studies have found a lower prevalence of AD among ethnic Chinese in comparison with Caucasian populations(1,11-13). HC Liu and CJ Hong at Taipei Veterans General Hospital first raised the possibility that this phenomenon may be partly attributable to the low
Apoε 4 allele frequency in Taiwanese population(5) . The reported Apoε 4 allele frequency in Taiwanese ranged from 4.9 to 11.0%, but was usually higher than approxi-mately 10.0% reported in studies of Caucasian popula-tions(5,6,13-15)
. However, the small sample sizes in these studies from Taiwanese might limit their ability to accu-rately assess this allele frequency. The most importantly, Liu et al.(16)
studied the distribution of ApoE alleles in a large community and found that the ApoE4 allele fre-quency was 8.1%, which is lower than the frequencies reported in most studies of Caucasian populations. Their data support the hypothesis that low ApoE4 allele fre-quency contributes to low prevalence of AD in Taiwanese(16)
. In addition, their data might also further support an important role of ApoE in AD in Taiwanese population because ApoE4 allele frequency affects the prevalence of AD(16). Results from Japanese studies regarding ApoE allele frequency are similar to those from Taiwan(17,18)
(Table 1). Lung et al.(3)
studied the impact of ApoE2 on AD and the interaction between
ApoE2 and ApoE4 and found that inheritance of an ε 2
allele significantly lowered the risk of ε 4-containers for AD.
Many studies have investigated the association between ApoE4 allele and psychiatric symptoms of dementia (BPSD) in patients with AD. Chang et al.(19) found that AD patients with ApoE4 allele had an increased incidence of psychotic symptoms, such as delusions and hallucinations. However, Liu et al.(20) found no association between depression and ApoE4 or
ApoE2 allele in AD. A study of the phenotype of
accel-erated reduction of cholinergic activity among ApoE4 allele carriers has suggested that ApoE4 allele is associ-ated with the treatment response of cholinesterase inhibitors(21)
. (Table 2)
A study from Japan found that ApoE4 allele was associated with both early-onset AD and late-onset AD and that ApoE4 allele may play a more important role in the early-onset AD than in late-onset AD(22)
. The role of
ApoE4 allele has also been demonstrated in familial AD
(FAD)(23). There is still inadequate data from Taiwan to
clarify the association between the polymorphisms of
ApoE, and FAD and early-onset AD.
Genetic risk factors other than ApoE in Alzheimer
disease
Many genes other than ApoE have been associated with AD. Some of these genes are associated with metabolism of amyloid β (Aβ), some with neuro-trans-mitters and some with inflammation or other mecha-nisms (Table 3-5).
Amyloid-beta (Aβ) is the most important component of senile plaques and is considered to play a crucial role in neural death in AD. Many enzymes are involved in the metabolism of Aβ, including amyloid precursor pro-tein (APP), presenilin-1 (PS-1), beta-site APP cleaving enzyme (BACE), neprilysin (NEP)(24), and alpha-2 macroglobulin (A2M) (Table 3). BACE and PS-1 digest APP, which consists about 700 amino acids, to produce Aβ, which consists of about 40 amino acids. Extra-cellu-lar Aβ enters the cells through as yet unknown receptors and is degraded by NEP. A2M might compete for the
Table 2. Genetic studies of ApoE in dementia
Alleles Authors Year Cohort Association Ref
Positive (Y) / Negative (N)
ApoE4 Hong et al. 1996 56 late-onset sporadic AD AD (Y) 5
57 controls
ApoE4 Hu et al. 1998 55 late-onset sporadic AD AD (Y) 7
93 controls
ApoE4 Lai et al. 2003 30 VaD patients VaD (N) 10
112 normal controls
ApoE4 Lin et al. 2004 49 VaD patients VaD (N) 48
112 normal controls
ApoE2 Lung et al. 2005 428 AD AD (N/Y) 3
807 control Part of the protective effect of ApoE2 against AD
ApoE2 Lin et al. 2004 49 VaD patients VaD (Y) Protective effect 48 112 normal controls
VaD: vascular dementia; AD: Alzheimer’s disease.
Table 1. ApoE4 allele frequencies in different populations
Authors Year ApoE4 allele frequencies Populations Reference
Hong et al. 1996 7.9 % Taiwanese 5
Hu et al. 1998 7 % Taiwanese 7
Nakayama et al. 1999 9 % Japanese 18
Ordovas et al. 1987 13.5 % Caucasian 14
Davignon et al. 1988 16 % Caucasian 15
receptors with Aβ. BACE is the rate-limiting enzyme in A-beta formation. Liu et al’s(25)study of all of the exons
of BACE gene by single strand conformation polymor-phism (SSCP) revealed a novel polymorpolymor-phism in this gene, but it showed no significant association with the occurrence of AD. The PS-1 gene is one of the genetic loci linked to early onset familial AD. Two previous studies showed no association between the intronic poly-morphism of the PS-1 gene and late-onset sporadic AD
in the Taiwanese population(7,8)
. A2M is a serum panpro-tease inhibitor which binds tightly to Aβ peptide and attenuates fibrillogenesis and neurotoxicity of Aβ by interfering with degradation of Aβ. Previous studies showed no association between A2M-2 (a polymorphism of A2M gene) and AD, and that A2M-2 was not a signifi-cant risk factor for AD among Taiwanese(8,26). Studies of
neurotransmitters in AD patients have led to the devel-opment of the current standard treatment for AD (Table
Table 3. Genetic studies of the association of dementia with amyloid metabolism in Taiwan
Gene Authors Year Cohort Association Ref
Positive / Negative
PS-1 Hu et al. 1998 55 late-onset AD patients AD (N) 7
93 controls
A2M Hu et al. 1999 65 AD AD (N) 26
84 controls
BACE Liu et al. 2003 25 AD patients AD (N) 25
100 controls
MMEL2 Liu et al. 2004 107 AD AD (N) 24
118 controls
PS-1: presenilin-1; A2M: Alpha-2 macroglobulin; BACE: Beta-site APP cleaving enzyme; MMEL2: Neprilysin-like 2.
Table 4. Genetic studies of the association of neurotransmitters with dementia in Taiwan
Gene Authors Year Cohort Association Ref
Positive / Negative
5-HT6 Tsai et al. 1999 92 AD AD (Y) 30
104 controls
BuChE Lee et al. 2000 89 AD AD (N) 27
101 controls
nAChR Liou et al. 2001 120 AD AD (N) 29
98 controls 5-HTTLPR Tsai et al. 2001 136 AD AD (N) 33 83 older controls 92 younger controls NR2b Tsai et al. 2002 132 AD AD (N) 34 114 controls
Alpha2a-adrenoceptor Hong et al. 2001 142 AD AD (N) 36
98 controls
A2aAR Liu et al. 2005 174 AD AD (N) 35
141 controls
CHRM1 Liu et al. 2005 232 AD AD (N) 28
169 controls
BuChE: butyrylcholinesterase; nAChR: nicotinic acetylcholine receptor; 5-HTTLPR: 5-HTT gene-linked promoter region; NR2b: NMDA recep-tor 2b subunit; A2aAR: adenosine A2a receprecep-tor; CHRM1: cholinergic receprecep-tor muscarinic 1.
4). Changes in the brain cholinergic system are critical for the development of AD as has been shown by studies of the pathophysiology of cognitive dysfunction, post-mortem pathological findings, animal studies and results of clinical studies using current standard treatments. Cholinesterase inhibitors are now widely used for the treatment of mild to moderate AD. Acetylcholine is degraded by two enzymes, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Increased BuChE activity has been reported to be associated with the for-mation of amyloid plaques and neurofibrillary tangles and may consequently be involved in the pathogenesis of AD. The genes encoding AchE, BuChE and cholinergic receptors are all candidates for genetic study of AD. Lee et al.(27) found no association between BuCHE-K and
either early or late onset (age > 65 years) AD in Taiwanese. They also found no synergistic effect between the BuCHE-K variant and ApoE4. Liu et al.(28)
tested the allelic variant (C267A) of the cholinergic receptor muscarinic 1 (CHRM1) and found that the
CHRM1 C267A polymorphism did not confer
suscepti-bility to AD. Changes in the nicotinic acetylcholine receptors (nAChRs) have been demonstrated in patients with AD. Liou et al.(29)
tested the association between the allelic variant, 2bp deletion, of the partially duplicated alpha7 nAChR gene and AD. They found that this genet-ic polymorphism of partially duplgenet-icated alpha7 nAChR contributed no major effect on AD. A role of serotoner-gic dysfunction in the pathogenesis of AD has been sup-ported by studies of serotonin and its metabolite in post-mortem specimens and CSF. Tsai et al.(30)
found that the 267C allele of one of the serotonin receptor genes,
5-HT6 gene, is a risk factor for AD. Two recent studies
have demonstrated an association between deletion/ insertion polymorphism on the promoter region of the serotonin transporter gene (5-HTTLPR) and AD(31,32)
.
Table 5. Genetic studies of the association of inflammation with dementia in Taiwan
Gene Authors Year Cohort Association Ref
Positive / Negative
Alpha1-antichymotrypsin Wang et al. 1999 157 AD AD (N) 45
114 controls
TPH Wang et al. 2001 150 AD AD (N) 43
100 controls
nNOS Liou et al. 2002 134 AD AD (N) 39
101 controls
ACE Cheng et al. 2002 173 AD AD (Y) 40
286 controls
IL-1A Tsai et al. 2003 234 AD AD (N) 37
170 controls
IL-1A Kuo et al. 2003 125 AD AD (N) 38
93 controls
IL-1A Kuo et al. 2003 70 VaD VaD (N) 38
93 controls
BDNF Tsai et al. 2004 163 AD AD (N) 46
89 controls
COMT Wang et al. 2005 66 AD AD (N/Y) 44
86 controls A synergistic effect of the COMT
HH genotype and APOE 4 allele
TPH: tryptophan hydroxylase, nNOS: neuronal NO synthase, ACE: angiotensin-converting enzyme, IL-1A: Interleukin 1A, BDNF: brain-derived neurotrophic factor, COMT: catechol-O-methyltransferase.
However, this finding was not confirmed in Tsai et al’s study(30)
. The study just showed no significant differences of genotype distribution or allele frequencies between AD patients and normal controls. Their results suggested that 5-HTTLPR polymorphism is unlikely to play a sub-stantial role in conferring susceptibility to AD in Taiwanese(33). N-methyl-D-aspartate (NMDA) receptor
dysfunction has been implicated in the pathogenesis of AD. The NMDA receptor is composed of several sub-units, of which the receptor 2b subunit (NR2b) is of par-ticular significance for AD. Tsai et al.(34), however,
demonstrated no significant association between the
NR2b C2664T polymorphism and AD.
Adenosine functions as a neuromodulator in the brain and it is widely distributed throughout the central nervous system. There is compelling evidence support-ing the involvement of adenosine A2a receptor (A2aAR) in the pathogenesis of AD. Liu et al.(35)
found no signifi-cant difference in A2aAR T1976C genotype distribution or allelic frequency between AD patients and controls, indicating that the A2aAR T1976C polymorphism is unlikely to play an important role in the occurrence of AD. There exists considerable evidence implicating abnormalities of the alpha-adrenergic system in the development of AD. Hong et al.(36)
studied the relation-ship between alpha1a/alpha2a-adrenoceptor gene poly-morphism and AD. Their results indicate that none of the alpha1a/2a-adrenoceptor polymorphisms is associated with increased risk to AD.
Inflammation is a characteristic change in the brain of AD patients. Interleukin 1A (IL-1A), a potent proin-flammatory cytokine, has been implicated in the patho-genesis of AD. Several recent studies have shown that a polymorphism in the IL-1A locus -889 was associated with occurrence and early onset AD, however, other studies did not support these findings. Studies of the
IL-1A C (-889)T polymorphism in the Taiwanese
popula-tion by at least two groups revealed no associapopula-tion with AD(37,38)
. Neuronal nitric oxide synthase (nNOS) has been implicated in the pathogenesis of AD. Liou et al.(39)
examined the role of the polymorphisms of neuronal NOS (nNOS) gene in AD and found no association between AD and nNOS polymorphism. Genetic
back-ground might affect the metabolism of neuro-transmit-ters and drugs. Mutations or defects of genes result in decrease of efficiency of enzymes which participate in the metabolism of drugs. The pharmacogenetics of this machinery could be directly involved in the response of treatment or even occurrence of AD.
Angiotensin-converting enzyme (ACE) has been shown to be involved in cognition and memory. Several studies of the association of polymorphisms of ACE gene with susceptibility to AD have yielded inconsistent results. Cheng et al.(40)demonstrated the association of
ACE gene polymorphism with AD in Taiwanese
patients. Two recent meta-analysis reports revealed ACE gene could be another important gene for AD other than
ApoE4(41,42). ACE might be a potential target for genetic
study of AD in the near future. Wang et al.(43)
found that tryptophen hydrolase gene (TPH) polymorphism was not a major genetic factor for AD.
A few studies showed an interaction between estro-gen and ApoE in AD. Estradiol promoted synaptic sprouting via an ApoE-dependent pathway. The neuro-protective effect of estradiol was seen only in ApoE-bearing mice. Wang et al.(44)
identified a synergistic effect of the estrogen-metabolizing gene, COMT, and ApoE4 on occurrence of AD. It is possible that a high metabo-lism rate of estrogen by COMT enzyme reduces the pro-tective effect of estrogen against AD in carriers of
COMT HH genotype.
Recent studies have shown that a common polymor-phism in alpha-1-antichymotrypsin (ACT) confers a sig-nificant risk for AD. Furthermore, the ApoE4 allele effect associated with AD risk is modified by ACT poly-morphisms. Association studies of ACT polymorphisms in Taiwanese AD patients by Wang et al.(45)
and Hu et al.(8)
, however, indicated that the ACT polymorphisms had no effect on the development of AD either alone or in combination with the ApoE4 allele. An association study showed no association between brain-derived neu-rotrophic factor gene (BDNF) Val66Met polymorphism and AD(46)
. (Table 5)
In summary, the ApoE4 allele is currently the only widely accepted genetic risk for AD. The genetic studies
of AD other than ApoE4 in Taiwan remain inconclusive.
ACE appears to be the candidate gene with the most
potential involvement but confirmation of its role requires further investigation.
Vascular dementia
VaD is the second leading cause of dementia in Taiwan(1)
. Genetic factors have been found for cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), a rare inherited autosomal dominant disease characterized by migraine, recurrent strokes, dementia, and psychiatric disorders. Mutations of the NOTCH3 gene have been identified in many CADASIL families. Tang et al.(47)
first reported the
NOTCH3, Arg332Cys mutation at exon 6 in Asian
patients. They emphasized the importance of genetic analysis of NOTCH3 for Asians with a phenotype con-sistent with CADASIL. This condition may be over-looked in Asia because of the higher prevalence for vas-cular dementia.
A few studies have documented changes in levels of plasma lipoproteins as risk factors for cerebral arte-riosclerosis. The association between the allele frequen-cy of ApoE4 and VaD is controversial. In Taiwan, sever-al studies have attempted to clarify whether the ApoE4 is associated with VaD(9,10,48). But, all of them concluded
that ApoE4 played no significant role in the development of VaD. On the other hand, ApoE4 was demonstrated to be an important risk factor for ischemic cerebrovascular disease in a Taiwanese cohort of uremic patients(49). By
contrast, ApoE2 was shown to have a protective effect against the development of intracranial vascular diseases (ICVD) and VaD in Taiwanese aged below 65 years(48)
. Kao et al.(38) examined polymorphism of IL-1a in
Taiwanese patients with VaD and found no difference in allele frequencies of C-889T polymorphism on IL-1a between VaD and non-VaD controls(38)
. In summary, there has been limited studies of the genetics of VaD in Taiwan. NOTCH3 gene mutation, which has been identi-fied in CADASIL families, is the only gene mutation which has been well established as a risk factor for VaD in this population.
ACKNOWLEDGEMENTS
We thank Mr. Michael Evans for the assistance of English editing.
REFERENCES
1. Liu HC, Lin KN, Teng EL, et al. Prevalence and subtypes of dementia in Taiwan: a community survey of 5,297 indi-viduals. J Am Geriatr Soc 1995;43:144-9.
2. Mahley RW. Apolipoprotein E: cholesterol transport pro-tein with expanding role in cell biology. Science 1998;240: 622-30.
3. Lung FW, Yen YC, Chou LJ, et al. The allele interaction between apolipoprotein epsilon 2 and epsilon 4 in Taiwanese Alzheimer’s disease patients. Acta Psychiatr Scand 2005;111:38-43.
4. Weisgraber KH, Mahley RW. Human apolipoprotein E: the Alzheimer’s disease connection. FASEB J 1996;10:1485-94.
5. Hong CJ, Liu TY, Liu HC, et al. Epsilon 4 allele of apolipoprotein E increases risk of Alzheimer’s disease in a Chinese population. Neurology 1996;46:1749-51.
6. Wang PN, Wang SJ, Hong CJ, et al. Risk factors for Alzheimer’s disease: a case-control study. Neuroepide-miology 1997;16:234-40.
7. Hu CJ, Sung SM, Liu HC, et al. Association of apolipopro-tein E genotype and intronic polymorphism of the prese-nilin-1 gene with Alzheimer’s disease in elderly Taiwan Chinese. J Neurol Sci 1998;157:158-61.
8. Hu CJ, Sung SM, Liu HC, et al. Genetic risk factors of spo-radic Alzheimer’s disease among Chinese in Taiwan. J Neurol Sci 2000;181:127-31.
9. Huang HM, Kuo YM, Ou HC, et al. Apolipoprotein E poly-morphism in various dementias in Taiwan Chinese popula-tion. J Neural Transm 2002;109:1415-21.
10. Lai CL, Tai CT, Lin SR, et al. Apolipoprotein E in Taiwan Chinese patients with dementia. Dement Geriatr Cogn Disord 2003;16:208-11.
11. Liu HC, Fuh JL, Wang SJ, et al. Prevalence and subtypes of dementia in a rural Chinese population. Alzheimer Dis Assoc Disord 1998;12:127-34.
an urban area in Taiwan. J Formos Med Assoc 1996;95: 762-8.
13. Yen YC, Liu CK, Lung FW, et al. Apolipoprotein E poly-morphism and Alzheimer’s disease. Kaohsiung J Med Sci 2001;17:190-7.
14. Ordovas JM, Litwack-Klein L, Wilson PW, et al. Apolipoprotein E isoform phenotyping methodology and population frequency with identification of Apoe1 and Apoe5 isoforms. J Lipid Res 1987;28:371-80.
15. Davignon J, Gregg RE, Sing CF. Apolipoprotein E poly-morphism and atherosclerosis. Arteriosclerosis 1988;8:1-21.
16. Liu HC, Hong CJ, Wang SJ,et al. ApoE genotype in rela-tion to AD and cholesterol: a study of 2,326 Chinese adults. Neurology 1999;53:962-6.
17. Nunomura A, Chiba S, Eto M, et al. Apolipoprotein E poly-morphism and susceptibility to early- and late-onset spo-radic Alzheimer’s disease in Hokkaido, the northern part of Japan. Neurosci Lett 1996;206:17-20.
18. Nakayama S, Kuzuhara S. Apolipoprotein E phenotypes in healthy normal controls and demented subjects with Alzheimer’s disease and vascular dementia in Mie prefec-ture of Japan. Psychiatry Clin Neurosci 1999;53:643-8. 19. Chang JB, Wang PN, Chen WT, et al. ApoE epsilon 4 allele
is associated with incidental hallucinations and delusions in patients with AD. Neurology 2004;63:1105-7.
20. Liu CY, Hong CJ, Liu TY, et al. Lack of association between the apolipoprotein E genotype and depression in Alzheimer’s disease. J Geriatr Psychiatry Neurol 2002;15: 20-3.
21. Soininen H, Kosunen O, Helisalmi S, et al. A severe loss of choline acetyltransferase in the frontal cortex of Alzheimer patients carrying apolipoprotein epsilon 4 allele. Neurosci Lett 1995;187:79-82.
22. Dai XY, Nanko S, Hattori M, et al. Association of apolipoprotein E4 with sporadic Alzheimer’s disease is more pronounced early onset type. Neurosci Lett 1994; 175:74-6.
23. Kamimura K, Tanahashi H, Yamanaka H, et al. Familial Alzheimer’s disease genes in Japanese. J Neurol Sci 1998; 160:76-81.
24. Liu HC, Leu SJ, Chang JG, et al. Association of Neprilysin-like 2 (MMEL 2) Polymorphisms with
Alzheimer’s Disease. Taipei City Med J 2004;1:418-25. 25. Liu HC, Leu SJ, Chang JG, et al. The association of
beta-site APP cleaving enzyme (BACE) C786G polymorphism with Alzheimer’s disease. Brain Res 2001;961:88-91. 26. Hu CJ, Sung SM, Liu HC, et al. No association of alpha-2
macroglobulin gene five-nucleotide deletion with AD in Taiwan Chinese. Neurology 1999;53:642-3.
27. Lee DW, Liu HC, Liu TY, et al. No association between butyrylcholinesterase K-variant and Alzheimer disease in Chinese. Am J Med Genet 2000;96:167-9.
28. Liu HC, Hong CJ, Liu TY, et al. Association analysis for the muscarinic M1 receptor genetic polymorphisms and Alzheimer’s disease. Dement Geriatr Cogn Disord 2005; 19:42-5.
29. Liou YJ, Lai IC, Hong CJ, et al. Association analysis of the partially duplicated alpha7 nicotinic acetylcholine receptor genetic variant and Alzheimer’s disease. Dement Geriatr Cogn Disord 2001;12:301-4.
30. Tsai SJ, Liu HC, Liu TY, et al. Association analysis of the 5-HT6 receptor polymorphism C267T in Alzheimer’s dis-ease. Neurosci Lett 1999;276:138-9.
31. Li T, Holmes C, Sham PC, et al. Allelic functional variation of serotonin transporter expression is a susceptibility factor for late onset Alzheimer’s disease. Neuroreport 1997;8: 683-6.
32. Oliveira JR, Gallindo RM, Maia LG, et al. The short vari-ant of the polymorphism within the promoter region of the serotonin transporter gene is a risk factor for late onset Alzheimer’s disease. Mol Psychiatry 1998;3:438-41. 33. Tsai SJ, Hong CJ, Liu TY, et al. Association study for a
functional serotonin transporter gene polymorphism and late-onset Alzheimer’s disease for Chinese patients. Neuropsychobiology 2001;44:27-30.
34. Tsai SJ, Liu HC, Liu TY, et al. Association analysis for the genetic variants of the NMDA receptor subunit 2b and Alzheimer’s disease. Dement Geriatr Cogn Disord 2002; 13:91-4.
35. Liu HC, Hong CJ, Liu TY, et al. Association analysis of adenosine A2a receptor 1976T>C polymorphisms and Alzheimer’s disease. Eur Neurol 2005;53:99-100.
36. Hong CJ, Wang YC, Liu TY, et al. A study of alpha-adreno-ceptor gene polymorphisms and Alzheimer disease. J Neural Transm 2001;108:445-50.
37. Tsai SJ, Liu HC, Liu TY, et al. Lack of association between the interleukin-1alpha gene C(-889)T polymorphism and Alzheimer’s disease in a Chinese population. Neurosci Lett 2003;343:93-6.
38. Kuo YM, Liao PC, Lin C, et al. Lack of association between interleukin-1alpha polymorphism and Alzheimer disease or vascular dementia. Alzheimer Dis Assoc Disord 2003;17:94-7.
39. Liou YJ, Hong CJ, Liu HC, et al. No association between the neuronal nitric oxide synthase gene polymorphism and Alzheimer Disease. Am J Med Genet 2002;114:687-8. 40. Cheng CY, Hong CJ, Liu HC, et al. Study of the association
between Alzheimer’s disease and angiotensin-converting enzyme gene polymorphism using DNA from lymphocytes. Eur Neurol 2002;47:26-9.
41. Elkins JS, Douglas VC, Johnston SC. Alzheimer disease risk and genetic variation in ACE: a meta-analysis. Neurology 2004;62:363-8.
42. Kehoe PG, Katzov H, Feuk L, et al. Haplotypes extending across ACE are associated with Alzheimer’s disease. Hum Mol Genet 2003;12:859-67.
43. Wang YC, Tsai SJ, Liu TY, et al. No association between tryptophan hydroxylase gene polymorphism and Alzheimer’s disease. Neuropsychobiology 2001;43:1-4.
44. Wang PN, Liu HC, Liu TY, et al. Estrogen-metabolizing gene COMT polymorphism synergistic APOE epsilon4 allele increases the risk of Alzheimer disease. Dement Geriatr Cogn Disord 2005;19:120-5.
45. Wang YC, Liu TY, Liu HC, et al. No association between alpha-1-antichymotrypsin polymorphism and Alzheimer’s disease in Chinese. Neuropsychobiology 1999;40:67-70. 46. Tsai SJ, Hong CJ, Liu HC, et al. Association analysis of
brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer’s disease and age of onset. Neuropsy-chobiology 2004;49:10-2.
47. Tang SC, Lee MJ, Jeng JS, et al. Arg332Cys mutation of NOTCH3 gene in the first known Taiwanese family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. J Neurol Sci 2005;228: 125-8.
48. Lin HF, Lai CL, Tai CT, et al. Apolipoprotein E polymor-phism in ischemic cerebrovascular diseases and vascular dementia patients in Taiwan. Neuroepidemiology 2004;23: 129-34.
49. Lim PS, Liu CS, Hong CJ, et al. Prevalence of apolipopro-tein E genotypes in ischaemic cerebrovascular disease in end-stage renal disease patients. Nephrol Dial Transplant 1997;12:1916-20.
