***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Alzheimer 's disease ( AD ) is a complex genetic disorder . Linkage analysis has helped unravel a portion of the genetic component of AD by identifying four loci that play a role in the genetics of AD ( amyloid precursor protein , presenilin 1 , presenilin 2 , and apolipoprotein E ) . These loci account for approximately 50 % of the genetic etiology of AD . A total genomic screen is an efficient way to identify additional genetic effects in AD . A series of multiplex late-onset ( > 60 years ) AD families were ascertained ( NINDS-ADRDA diagnostic criteria ) and sample d. A subset ( n = 16 ) of the largest families ( 52 affecteds with DNA , 83 unaffecteds with DNA ) were used to rapidly screen the genome ( n = 280 markers ) for additional major genetic effects . Critical values for regional follow-up were p < or = 0.05 for SimIBD or sibpair analysis and /or a LOD score > or = 1.00 . Fifteen regions warranted initial follow-up based on these criteria . An additional screening set was used ( n = 38 families , 89 affecteds with DNA , 216 unaffecteds with DNA ) for the follow-up analysis . These analyses revealed four regions of continued interest on chromosomes 4 , 6 , 12 , and 20 . Chromosome 12 presented the strongest results . Peak two point " affecteds only " LOD scores were 1.3 , 1.6 , 2.7 , and 2.2 and ( affected relative pair SimIBD ) p values were 0.04 , 0.03 , 0.14 , and 0.04 for D12S373 , D12S1057 , D12S1042 , and D12S390 , respectively . These markers span approximately 30 cm near the centromeric region of chromosome 12 . Sibpair analysis result ed in two point Maximum Lod Score ( MLS ) results of 0.4 , 1.2 , 3.2 , and 1.0 for the above markers . Multipoint MLS analysis supported these findings . Saturation mapping of all available markers in the chromosome 12 region as well as further investigation of the regions on 4 , 6 , and 20 is ongoing with c and i date gene analysis to follow Alpha2-macroglobulin ( alpha2 M ) as well as its receptor , the low-density lipoprotein receptor-related ( LRP ) and the receptor-associated protein ( RAP ) are involved in the clearance of cerebral A beta . Current evidence suggests that polymorphisms in the genes of alpha2 M , LRP and RAP may have functional effects on the proteins . Two independent association sample s of 271 AD patients and 280 representative controls were investigated whether the risk for developing AD is altered in carriers of polymorphisms in the  alpha2M-gene ( Va1000Ile )  , in the  LRP-gene ( Ala216Val ) and in the RAP-gene ( Val311Met ) . Genotypes were determined by st and ard PCR and restriction fragment length polymorphism . The results were adjusted for age , gender and apolipoprotein E-epsilon4 ( APOE ) polymorphism . Inheritance of alpha2 M conferred a small increased risk for sporadic AD with an estimated Mantel-Haenszel odds ratio of 1.47 . There was no age- or gender-dependent increase in alpha2 M Val1000Ile allele frequencies in AD patients compared to controls . There was no significant difference in the allele frequencies among control and AD subjects for the LRP and RAP polymorphisms . We found no evidence of an interaction between the alpha2 M and RAP or LRP with regard to conferred risk . Our data suggest that the alpha2 M Val1000Ile polymorphism is weakly associated with AD . Although LRP as well as RAP seem to play an essential role in the metabolism of alpha2 M and APOE , there is no increase in the genetic risk for AD in patients carrying the investigated polymorphisms Recent advances in clinical , pathological and neuroscience studies have identified disease-modifying therapeutic approaches for Alzheimer 's disease that are now in clinical trials . This has highlighted the need for reliable and convenient biomarkers for both early disease diagnosis and a rapid signal of drug efficacy . We describe the identification and assessment of a number of c and i date biomarkers in patients with Alzheimer 's disease and the correlation of those biomarkers with rosiglitazone therapeutic efficacy , as represented by a change in the Alzheimer 's Disease Assessment Scale-Cognitive ( ADAS-Cog ) .  Plasma from 41 patients with Alzheimer 's disease were analysed by open platform proteomics at baseline and after receiving 8 mg rosiglitazone for 24 weeks . From a comparison of protein expression following treatment with rosiglitazone , 97 proteins were observed to be differentially expressed with a p-value<0.01 . From this analysis and comparison to recently published data from our laboratory , a prioritized list of 10 proteins were analysed by immunoassay and /or functional assay in a wider set of sample s from the same clinical study , representing a rosiglitazone dose response , in order to verify the changes observed . A number of these proteins appeared to show a correlation with change in ADAS-Cog at the higher treatment doses compared with the placebo . Alpha-2-macroglobulin , complement C1 inhibitor , complement factor H and apolipoprotein E expression showed a correlation with ADAS-Cog score at the higher doses ( 4 mg and 8 mg ) . These results are discussed in light of the pathology and other recently published data Recent reports have suggested that genetic polymorphisms in the alpha-2 macroglobulin ( A2 M ) gene are associated with an increased risk for Alzheimer 's disease . In the present study we tested two polymorphisms in the alpha-2 macroglobulin gene , a 5 bp deletion at the 5 ' splice site of exon 18 and a G/A point mutation ( V1000I ) in exon 24 , in a sample of 118 healthy , non demented controls and 238 consecutively recruited gerontopsychiatric patients , diagnosed as : Alzheimer 's disease ( N=88 ) , mild cognitive impairment ( N=32 ) , subjective cognitive complaints ( N=54 ) and depression/other psychiatric disorders ( N=64 ) . The aim of this study was to test whether the investigated polymorphisms has a high enough selectivity and specificity to distinguish between the different gerontopsychiatric disorders or to differentiate genetically AD from other forms of dementia , respectively . Also a possible relation to the APOE varepsilon4 polymorphism was examined . Our study failed to show an association between the two investigated polymorphisms in the alpha-2 macroglobulin gene and any of the four different  psychogeriatric patient subgroups , either alone or in combination with the APOE varepsilon4 genotype Recently , two studies have reported an association between the α2‐macroglobulin gene on chromosome 12 and late‐onset Alzheimer 's disease , whereas others have not been able to replicate these findings . By using a prospect i ve population ‐based study , we have investigated the relation between two polymorphisms in this gene with the presence of the disease and also with the extent of pathological changes in the cerebral cortex . The Vantaa 85 + Study includes all 601 persons , at least 85 years of age , who were living in Vantaa , Finl and , on April 1 , 1991 . The neocortical β‐amyloid protein load and the number of neurofibrillary tangles were determined on tissue sections by using methenamine silver staining and a modified Bielschowsky staining , respectively . The A/A genotype in exon 24 of the α2‐macroglobulin gene was associated with neuropathologically defined diagnosis of Alzheimer 's disease according to the CERAD ( Consortium to Establish a Registry for Alzheimer 's Disease ) criteria and with an increase in the neocortical β‐amyloid protein load . The effect of this association was stronger in the apolipoprotein E ε4–negative group . Therefore , genetic variability in the α2‐macroglobulin gene is a risk factor associated with neuropathologically defined Alzheimer 's disease in our population , as well as with the extent of neocortical β‐amyloid protein deposition Two genetic markers of the plasma protein alpha2-macroglobulin , a 5 bp deletion/insertion at the 5 ' splice site of exon 18 ( A2MI ) and the GTC/ATC ( VaIIO00IIe ) in exon 24 ( A2M2 ) , may have roles in the development of Alzheimer 's disease ( AD ) . Genotyping and linkage analysis of these markers in 426 Japanese sporadic AD patients , 85 autopsy-confirmed Caucasian AD cases , and , as controls , 382 Japanese and 65 Caucasians who were cognitively normal and 140 Japanese Parkinson 's disease patients showed racial diversity in the frequencies and relationship of the two markers . Comparison of genotype and allele frequencies , stratification of the sample s by the presence of the apolipoprotein E epsilon4 allele , and logistic regression analysis revealed no association of these markers with AD in either racial group 
    Output:
    
The meta- analysis suggests that there is no enough evidence for associations of A2 M gene polymorphisms ( 5 bp I/D , Ile1000Val ) with AD risk at present , even after stratification by ethnicity and APOE ε4 with genotypes of polymorphism sites .