Alpha-1 antichymotrypsin and alpha-2 macroglobulin gene polymorphisms are not associated with Korean late-onset Alzheimer's disease

Alzheimer's disease (AD) is a multifactorial disorder with possible involvement of several genetic and environmental factors. For late-onset AD (LOAD), the epsilon4 allele of apolipoprotein E (APOE) has been identified as a major susceptible gene. However, the observation that APOE epsilon4 accounted for approximately one half of the genetic variance of LOAD prompted many researchers to undertake genome surveys to identify other susceptible genes. Recently, several candidate genes such as alpha-1 antichymotrypsin (ACT) and alpha-2 macroglobulin (A2M) were reported to be associated with LOAD. To evaluate the possible association between these genes and LOAD in Korean population, we genotyped ACT A/T and A2M 5-bp deletion (exon 18) polymorphisms in 89 LOAD cases and 50 age-matched healthy controls. The frequencies of ACT A and A2M 5-bp deletion alleles in LOAD and controls were 0.39 vs. 0.37, and 0.05 vs. 0.05, respectively. Although APOE epsilon4 clearly showed higher frequency in LOAD (0.34) than that in controls (0.09), giving an odds ratio of 5.14 (95% confidence interval, 2.31-11.76), neither ACT nor A2M showed statistically significant difference between LOAD and controls regardless of APOE carrier status. Our results do not support previously reported association of ACT and A2M with LOAD, at least in Korean population.     

Alpha-2 macroglobulin I1000 V polymorphism in Chinese sporadic Alzheimer's disease and Parkinson's disease

Several lines of evidence have revealed some overlapping pathologies in Alzheimer's disease (AD) and Parkinson's disease (PD). Although the alpha-2 macroglobulin gene (A2M) might be a risk factor of these two neurodegenerative diseases, conclusions from different studies have remained conflicting. Here we studied the role of A2M I1000 V polymorphism in both AD and PD in a Chinese Han population. We found that the A2M I/V genotype is associated with both AD (odds ratio (OR)=2.55, 95% confidential interval (95% CI): 1.20-5.43, attributable fraction (AF)=13.65%) and PD (OR=3.03, 95% CI: 1.30-7.02, AF=16.51%). After classifying according to the age of onset, this association is only detected in early-onset AD patients (OR=3.96, 95% CI: 1.28-12.26) and late-onset PD patients (OR=2.61, 95% CI: 0.97-7.09). Therefore, we conclude that in our samples, the A2M I/V genotype might be a susceptibility variant, even with minor effect, for both sporadic AD and PD.     

Changes in subcortical structures in early- versus late-onset Alzheimer's disease

Patients with early-onset Alzheimer's disease (EOAD) are reported to be different from those with late-onset Alzheimer's disease (LOAD) in terms of neuropsychological and neuroimaging findings. In this study, we aimed to compare the longitudinal volume changes of 6 subcortical structures (the amygdala, hippocampus, thalamus, putamen, globus pallidus, and caudate nucleus) between patients with EOAD and LOAD for 3 years. We prospectively recruited 36 patients with probable Alzheimer's disease (14 EOAD, 22 LOAD) and 14 normal control subjects. We analyzed the volume of subcortical structures using an automatic surface-based method. At baseline, there were no differences in the volumes of subcortical structures between patients with EOAD and LOAD. However, over 3 years of longitudinal follow-up, patients with EOAD showed more rapid volumetric decline in the caudate, putamen, and thalamus than patients with LOAD, which is consistent with neuropsychological results. Our findings suggested that the cognitive reserve theory might be applicable to explain different decline rates of the volumes of the basal ganglia and thalamus according to onset age.     

Alpha-2-macroglobulin intronic polymorphism is not associated with autopsy-confirmed late-onset Alzheimer's disease.

Alpha-2-macroglobulin (A2M) intronic polymorphism has recently been reported to be associated with late-onset Alzheimer's disease (LOAD). To corroborate this association, we analysed the A2M and apolipoprotein E (APOE) polymorphisms in autopsy cases of the MRC Alzheimer's Disease Brain Bank, Institute of Psychiatry, London. The frequencies of the insertion and deletion alleles in AD were 0.81 and 0.19, respectively, and these were not significantly different from control frequencies. After pooling the AD cases in epsilon4 positive and negative subgroups, there was again no significant difference between the A2M allele frequency in the two subgroups. In our present study, we were unable to corroborate the association between A2M intronic polymorphism and LOAD in autopsy cases.     

Monozygotic twins concordant for late-onset probable Alzheimer disease with suspected Alzheimer disease in four sibs.

Probable Alzheimer disease (AD) is described in 79-year-old male twins with monozygosity confirmed by DNA examination. The first twin to be affected began to show signs of intellectual deterioration at age 70. In the other, onset was at age 72. Four of their living sibs (current age range = 75-92) are also suspected to have AD. The possible roles of genetic and environmental factors in the development of AD in this sibship are discussed.     

Longitudinal changes of cortical thickness in early- versus late-onset Alzheimer's disease

Early-onset Alzheimer's disease (EOAD) has been shown to progress more rapidly than late-onset Alzheimer's disease (LOAD). However, no studies have compared the topography of brain volume reduction over time. The purpose of this 3-year longitudinal study was to compare EOAD and LOAD in terms of their rates of decline in cognitive testing and topography of cortical thinning. We prospectively recruited 36 patients with AD (14 EOAD and 22 LOAD) and 14 normal controls. All subjects were assessed with neuropsychological tests and with magnetic resonance imaging at baseline, Year 1, and Year 3. The EOAD group showed more rapid decline than the LOAD group in attention, language, and frontal-executive tests. The EOAD group also showed more rapid cortical thinning in widespread association cortices. In contrast, the LOAD group presented more rapid cortical thinning than the EOAD group only in the left parahippocampal gyrus. Our study suggests that patients with EOAD show more rapid cortical atrophy than patients with LOAD, which accounts for faster cognitive decline on neuropsychological tests.     

Lack of association of the two polymorphisms in alpha-2 macroglobulin with Alzheimer disease

Alzheimer disease is a complex neurodegenerative disorder that is characterized by cognitive decline and distinct neuropathology. The gene for alpha-2 macroglobulin (A2M) on chromosome 12 has two polymorphisms that, in some cases, are associated with Alzheimer disease. We examined these two polymorphisms in our families in the DNA Bank (a collection of DNA samples from families with Alzheimer disease in Texas). Using both association studies and sib transmission/disequilibrium tests, we found no association of the two polymorphisms with the disease in our collection. In addition, we did not find an association of the disease with the two polymorphisms in A2M in a small subset of National Institute of Mental Health (NIMH) families. Thus, our studies do not support the A2M polymorphisms as a risk factor for Alzheimer disease.     

Variation in the LRP-associated protein gene (LRPAP1) is associated with late-onset Alzheimer disease.

The LRP-associated protein is involved in the amount of mature LRP expressed on liver and brain. LRP is the main ApoE receptor and also binds alpha2-macroglobulin (alpha2M), a protein that associates with the beta-amyloid protein (betaA). By binding to alpha2M, LRP is responsible for the clearance of secreted betaA, thus preventing fibril formation. Genetic variation at the APOE, A2M, and LRP genes has been associated with the risk of developing late-onset Alzheimer disease (LOAD). We genotyped 373 patients, 300 controls, and 100 healthy elderly controls for a common DNA-polymorphism at the LRPAP1 gene (Insertion/Deletion, intron 5). Homozygotes for the rare Insertion (I) allele were at a significantly lower frequency in patients compared with controls (P = 0.002; OR = 0.29; 95% CI = 0.13, 0.68), and in patients compared with healthy elderly controls (P = 0.0002; OR = 0.18; 95% CI = 0.07, 0.46). No patient with an age at the onset below 75 years was II (0 of 214) compared with 8 in the group above 75 years (8 of 159) (P = 0.0044), suggesting that this genotype delays the onset of the disease. According to our data, the variation at the LRPAP1 gene is associated with the risk of developing LOAD. This is in agreement with the role of the LRPAP1 protein in the amyloidogenic pathway.     

Genome-wide association and linkage study in the amish detects a novel candidate late-onset Alzheimer disease gene

To identify novel late-onset Alzheimer disease (LOAD) risk genes, we have analysed Amish populations of Ohio and Indiana. We performed genome-wide SNP linkage and association studies on 798 individuals (109 with LOAD). We tested association using the Modified Quasi-Likelihood Score test and also performed two-point and multipoint linkage analyses. We found that LOAD was significantly associated with APOE (P= 9.0 × 10-6) in all our ascertainment regions except for the Adams County, Indiana, community (P= 0.55). Genome-wide, the most strongly associated SNP was rs12361953 (P= 7.92 × 10-7). A very strong, genome-wide significant multipoint peak [recessive heterogeneity multipoint LOD (HLOD) = 6.14, dominant HLOD = 6.05] was detected on 2p12. Three additional loci with multipoint HLOD scores >3 were detected on 3q26, 9q31 and 18p11. Converging linkage and association results, the most significantly associated SNP under the 2p12 peak was at rs2974151 (P= 1.29 × 10-4). This SNP is located in CTNNA2, which encodes catenin alpha 2, a neuronal-specific catenin known to have function in the developing brain. These results identify CTNNA2 as a novel candidate LOAD gene, and implicate three other regions of the genome as novel LOAD loci. These results underscore the utility of using family-based linkage and association analyses in isolated populations to identify novel loci for traits with complex genetic architecture.     

Different patterns of gray matter atrophy in early- and late-onset Alzheimer’s disease

We assessed patterns of gray matter atrophy according to-age-at-onset in a large sample of 215 Alzheimer’s disease (AD) patients and 129 control subjects with voxel-based morphometry using 3-Tesla 3D T1-weighted magnetic resonance imaging. Local gray matter amounts were compared between late- and early-onset AD patients and older and younger control subjects, taking into account the effect of apolipoprotein E. Additionally, combined effects of age and diagnosis on volumes of hippocampus and precuneus were assessed. Compared with age-matched control subjects, late-onset AD patients exhibited atrophy of the hippocampus, right temporal lobe, and cerebellum, whereas early-onset AD patients showed gray matter atrophy in hippocampus, temporal lobes, precuneus, cingulate gyrus, and inferior frontal cortex. Direct comparisons between late- and early-onset AD patients revealed more pronounced atrophy of precuneus in early-onset AD patients and more severe atrophy in medial temporal lobe in late-onset AD patients. Age and diagnosis independently affected the hippocampus; moreover, the interaction between age and diagnosis showed that precuneus atrophy was most prominent in early-onset AD patients. Our results suggest that patterns of atrophy might vary in the spectrum of AD.     

Evidence for parent of origin effect in late-onset Alzheimer disease

Evidence for a parent of origin effect in Alzheimer disease was obtained from a sample of 148 sibships on which affection status of the parents was sought using family history interviews. The parent study recruited families with two or more affected sibs for late onset AD utilizing rigorous diagnostic criteria. In 74 families, there was evidence of an affected parent, 49 maternal and 25 paternal. Genome scan data were analyzed for the sample as a whole and for the maternal and paternal families separately, using Genehunter-ASM. Seven regions with Z(lr) scores >or=2 were identified, four in maternal families (chr. 10,12,19,20) and three in paternal families (chr. 1,7,13). With the exception of the chromosome 10 finding, analysis by parent of origin greatly increased evidence of linkage in areas showing no linkage in the overall analyses. For example, a chr. 12 region reached a LOD = 2.29 among maternal families whereas the same region showed a LOD = 0.3 when all families were analyzed together. The strongest findings among maternal families (chr. 10 and 12) were followed up with fine mapping that resulted in an increase in maximum LOD scores from 2.7-3.2 on chr. 10, and 2.29-2.42 on chr. 12. These analyses highlight the importance of parent of origin effects in late-onset AD families and identify several genomic regions that may include genes linked to late-onset AD specific to disease transmission from the mother and require further investigation.     

No association between DCP1 genotype and late-onset Alzheimer disease

In a study of 261 patients with Alzheimer disease (AD) and 306 cognitively normal control subjects from Germany, Switzerland, and Italy, we found no association between genotype counts or allelic frequencies of DCP1, the gene encoding angiotensin-converting enzyme. In accordance with several other studies, our data could not confirm previous association findings. Critical review about all studies available on DCP1 genotyping and AD, age-associated cognitive decline, longevity, and other conditions revealed remarkable inconsistencies. Several studies showed significant deviations of genotype counts from Hardy Weinberg equilibrium (HWE). Deviations from HWE may limit the comparability of study results and require clarification before drawing conclusions with respect to disease risk, health conditions, or longevity in association with DCP1 genotype.     

Object relations and reality testing in early- and late-onset schizophrenia

One hundred fifty-seven U.S. military veterans with schizophrenia were divided into early-onset (i.e., onset at age 20 or before, n = 36) and late-onset (i.e., onset after age 30, n = 28) groups and completed the Bell Object Relations and Reality Testing Inventory (BORRTI), the Positive and Negative Syndrome Scale, and several representative neuropsychological instruments. Participants were compared on background characteristics and test measures. The early-onset group demonstrated significantly more object-relations and reality-testing deficits than the late-onset group. In contrast, no significant group differences were found on symptom or neuropsychological variables. An a posteriori three-group analysis that included the middle age of onset group (i.e., ages 21 to 30) found that the middle group had mean values that fell between early- and late-onset groups on most variables. No distinct patterns of BORRTI subscale scores distinguished the middle group. The finding that object-relations and reality-testing deficits are more pronounced in early-onset schizophrenia has implications for the treatment and rehabilitation of schizophrenia.     

Diagnosis and management of early- and late-onset cerebellar ataxia

Cerebellar ataxias represent a heterogeneous group of neurodegenerative disorders. Two main categories are distinguished: hereditary and sporadic ataxias. Sporadic ataxias may be symptomatic or idiopathic. The clinical classification of hereditary ataxias is nowadays being replaced by an expanding genotype-based classification. A large spectrum of degenerative and metabolic disorders may also present with ataxia early or late in the course of disease. We present a diagnostic algorithm for the adult patient presenting with subacute cerebellar ataxia, based on family history and straightforward clinical characteristics of the patient. Along with the algorithm, an overview of the autosomal dominant, autosomal recessive, X-linked, mitochondrial, symptomatic and idiopathic subtypes of cerebellar ataxia is presented. An appropriate diagnosis is of utmost importance to such considerations as prognosis, genetic counselling and possible therapeutic implications.     

A2M基因多态性与帕金森病和特发性震颤的关联

目的探讨α2-巨球蛋白基因（α2-macmglobulin gene，A2M）第24外显子1000G／A及第18外显子5’端剪接点5个碱基插入／缺失（insertion／deletion，IZD）多态与中国北方帕金森病（Parkinson’sdisease，PD）和特发性震颤（essential tremor，ET）的关联。方法应用聚合酶链反应-限制性片段长度多态性方法，对87例PD、73例ET和100名健康对照者A2MG／A和I／D两个位点的基因型和等位基因分布频率进行检测。结果（1）A2M基因G／A位点基因型和等位基因分布，在PD与ET、对照组间差异有统计学意义（P〈0．05），PD组的G等位基因和GA基因型明显高于ET、对照组（P〈0．05）；而ET与对照组间相比，差异无统计学意义（P〉0．05）。（2）A2M基因IZD位点基因型和等位基因分布，在PD、ET、对照组间差异无统计学意义（P〉0．05）。结论（1）G／A位点多态与PD的发病有关联，G／A位点多态与ET无关。（2）I/D位点多态与中国北方PD、ET无关。     

Positive association between risk for late-onset Alzheimer disease and genetic variation in IDE

Insulin degrading enzyme (IDE) is one of the principal proteases involved in the degradation of the beta-amyloid peptide, which is the major constituent of senile plaques in Alzheimer's disease (AD) brains. Previous association studies between AD and IDE have produced inconsistent results which may be indicative of a need for larger case-control series to identify what may be a relatively small effect size. Thus, we performed a large association study using four SNPs in the 276-kb haplotype block in and around IDE (IDE_7, IDE_9, IDE_14 and HHEX_23) in a previously unpublished Swedish and a UK case-control series, and combined our data with a previously reported Swedish case-control sample set from Prince et al., 2003. The combined genotype data from 1269 late-onset AD cases and 980 controls yielded a significant association to IDE_9 located in the 3'-end of the IDE gene after conservative multiple testing Bonferroni correction (p=0.005). The effect seemed to predominate in male cases. However, we did not observe a globally significant association to haplotypes generated from three "tag" SNPs. These findings indicate a role for IDE in AD, and provide models that may improve chances of further independent replication.     

Effect of heterogeneity on the chromosome 10 risk in late-onset Alzheimer disease

With the exception of ApoE (APOE), no universally accepted genetic association has been identified with late-onset Alzheimer disease (AD). A broad region of chromosome 10 has engendered continued interest generated from both preliminary genetic linkage and candidate gene studies. To better examine this region, we combined unbiased genetic linkage with candidate gene association studies. We genotyped 36 SNPs evenly spaced across 80.2 Mb in a family-based data set containing 1,337 discordant sibling pairs in 567 multiplex families to narrow the peak region of linkage using both covariate and subset analyses. Simultaneously, we examined five functional candidate genes (VR22, LRRTM3, PLAU, TNFRSF6, and IDE) that also fell within the broad area of linkage. A total of 50 SNPs were genotyped across the genes in the family-based data set and an independent case-control data set containing 483 cases and 879 controls. Of the 50 SNPs in the five candidate genes, 22 gave nominally significant association results in at least one data set, with at least one positive SNP in each gene. SNPs rs2441718 and rs2456737 in VR22 (67.8 Mb) showed association in both family-based and case-control data sets (both P=0.03). A two-point logarithmic odds (LOD) score of 2.69 was obtained at SNP rs1890739 (45.1 Mb, P=0.03 in 21% of the families) when the families were ordered from low to high by ApoE LOD score using ordered subset analysis (OSA). These data continue to support a role for chromosome 10 loci in AD. However, the candidate gene and linkage analysis results did not converge, suggesting that there is more extensive heterogeneity on chromosome 10 than previously appreciated.     

Evaluation of late-onset Alzheimer disease genetic susceptibility risks in a Canadian population

We performed case-control studies using 2 Canadian cohorts to examine the role of 10 promising Alzheimer's disease (AD) loci identified in recent genomewide association studies. Patients age 65 years and older diagnosed with AD at baseline (prevalent cases) or who developed AD during follow-up assessments (incident cases) were compared with control subjects with no cognitive impairment. Our prevalent case study comparing prevalent AD cases (n = 428) with participants with no cognitive impairment (n = 524) revealed a significant association of rs6656401 and rs3818361 (CR1), rs2075650 (TOMM40), rs7561528 (BIN1), and rs3865444 (CD33) with late-onset AD that were robust to adjustment with age and apolipoprotein E ε4 genotype. The incident case study comparing patients who developed AD during longitudinal observation (n = 152) with participants with no cognitive impairment found that rs2075650 (TOMM40) and rs3865444 (CD33) influence the risk of developing AD in this population. In addition, pooled analysis of our AD patients confirmed that CR1, TOMM40, BIN1, and CD33 contribute to late-onset AD susceptibility, in addition to apolipoprotein E.     

Electrophysiological evidence for cross-modal plasticity in humans with early- and late-onset blindness

It is commonly believed that sensory deprivation can lead to cross-modal reorganization in an immature hut not in a mature brain. The results of the present study suggest, however, that plasticity between sensory modalities is possible even in adults: activity indicating involvement of parietal or occipital brain areas in pitch-change discrimination was found in individuals blinded after childhood. Event-related brain potentials of early blinded (before the age of 2 years). late-blinded (12–28 years of age), and sighted adults were recorded to stimulus sequences consisting of standard tones occasionally replaced by deviant tones. Even when participants were not attending to auditory stimuli, the deviant tones elicited the mismatch negativity (MMN) in each group. There were no significant MMN front-back scalp distribution differences among the groups. However, when participants were detecting deviant stimuli, these stimuli elicited N2 and P3 waves that were posterior in distribution in both groups of blind participants relative to those of the sighted participants. These results suggest that cross-modal reorganization may occur even in the mature human brain.     

Genetic association between alpha-2 macroglobulin and Japanese sporadic Alzheimer's disease.

Alpha-2 macroglobulin (encoded by the gene A2M) is a serum pan-protease inhibitor that may be related with the pathogenesis of Alzheimer's disease (AD) because of its ability to mediate amyloid beta degradation. Recently, several groups have reported that the five-nucleotides deletion in A2M gene at the 5' splice site of exon 18 might increase risk for AD. In the present study, therefore, this mutation was studied in 69 healthy controls and 55 sporadic AD cases by polymerase chain reaction- restriction fragment length polymorphism method. The allelic frequencies with the deletion (A2M-2) are 9.4 and 6.4% in the control and AD groups, respectively. There is no significant difference in the A2M-2 frequencies between the controls and sporadic AD cases. This is the first report to study the frequencies of A2M-2 in Japanese AD cases, suggesting its no genetic association with sporadic AD.