***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: One of the major histopathological hallmarks of Alzheimer 's disease ( AD ) is redundant senile plaques mainly composed of beta-amyloid ( Abeta ) aggregates . Alternative cleavage of the amyloid precursor protein ( APP ) , occurring in both normal and AD subjects , results in the generation and secretion of soluble APP ( sAPP ) and Abeta . We examined the cerebrospinal fluid ( CSF ) for alpha- and beta-secretase cleaved sAPP ( alpha-sAPP and beta-sAPP ) in 81 sporadic AD patients , 19 patients with mild cognitive impairment , and 42 healthy controls by using newly developed s and wich enzyme-linked immunosorbent assay methods .  We found that neither the level of CSF-alpha-sAPP nor CSF-beta-sAPP differed between sporadic AD patients and healthy controls . These findings further support the conclusion that there is no change in APP expression in sporadic AD . However , the level of CSF-beta-sAPP was significantly increased in patients with mild cognitive impairment compared to controls . We also investigated the relationship between the CSF level of alpha/beta-sAPP and Abeta(42 ) and the apoE epsilon 4 ( apoE4 ) allele . Significantly lower levels of CSF-alpha-sAPP were found in AD patients possessing one or two apoE4 alleles than in those not possessing the apoE4 allele . Neither the levels of CSF-beta-sAPP nor CSF-Abeta(42 ) differed when comparing ApoE4 allele-positive with allele-negative individuals OBJECTIVE To investigate the effect of cerebrospinal fluid ( CSF ) abnormalities on the rate of decline in everyday function in normal aging , mild cognitive impairment ( MCI ) , and mild Alzheimer disease ( AD ) . DESIGN Immunoassays of total tau ( t-tau ) , tau phosphorylated at threonine 181 ( p-tau(181 ) ) , and beta-amyloid 1 - 42 ( Abeta(42 ) ) concentrations were performed in CSF obtained from participants in the Alzheimer 's Disease Neuroimaging Initiative . R and om effects regressions were used to examine the relationship among CSF abnormalities , cognitive impairment ( assessed with the Alzheimer Disease Assessment Scale-cognitive subscale [ ADAS-Cog ] ) , and functional decline ( assessed with the Pfeffer Functional Activities Question naire ) and to determine whether the impact of CSF abnormalities on functional decline is mediated by cognitive impairment . SETTING Fifty-eight sites in the United States and Canada . PARTICIPANTS One hundred fourteen cognitively intact adults , 195 patients with MCI , and 100 patients with mild AD . Main Outcome Measure Decline in the Pfeffer Functional Activities Question naire score . RESULTS Abnormalities in all CSF analytes were associated with functional decline in MCI , and all but the t-tau : Abeta(42 ) ratio were associated with functional decline in controls . No abnormal CSF analyte was associated with functional decline in AD . Among controls , p-tau(181 ) concentration was the most sensitive to functional decline , whereas in MCI it was Abeta(42 ) concentration . Cerebrospinal fluid biomarkers were uniformly more sensitive to functional decline than the ADAS-Cog score among controls and variably so in MCI , whereas the ADAS-Cog score was unequivocally more sensitive than CSF biomarkers in AD . The impact of CSF abnormalities on functional decline in MCI was partially mediated by their effect on cognitive status . Across all diagnostic groups , persons with both tau and Abeta(42 ) abnormalities exhibited the steepest rate of functional decline . CONCLUSIONS Abnormalities in CSF are associated with functional decline and thus with future development of AD in controls and patients with MCI . However , they do not predict further functional degradation in patients with AD . Persons with comorbid tau and Abeta(42 ) abnormalities are at greatest risk of functional loss In order to assess peripheral levels and activities of a broad spectrum of non-enzymatic and enzymatic antioxidants in elderly subjects with mild cognitive impairment ( MCI ) and Alzheimer 's disease ( AD ) , plasma levels of water-soluble ( Vitamin C and uric acid ) and of lipophilic ( Vitamin A , Vitamin E and carotenoids including lutein , zeaxanthin , beta-cryptoxanthin , lycopene , alpha- and beta-carotene ) antioxidant micronutrients as well as activities of plasma and red blood cell ( RBC ) superoxide dismutase ( SOD ) and of plasma glutathione peroxidase ( GPx ) were measured in 25 patients with MCI , 63 AD patients and 53 controls .  Peripheral levels and activities of antioxidants  were similarly lower in MCI and AD patients as compared to controls . As MCI may represent a prodromal stage of AD , and oxidative damage appears to occur as one of the earliest pathophysiological events in AD , an increased intake of antioxidants in patients with MCI could be helpful in lowering the risk of conversion to dementia CONTEXT Small single-center studies have shown that cerebrospinal fluid ( CSF ) biomarkers may be useful to identify incipient Alzheimer disease ( AD ) in patients with mild cognitive impairment ( MCI ) , but large-scale multicenter studies have not been conducted . OBJECTIVE To determine the diagnostic accuracy of CSF beta-amyloid(1 - 42 ) ( Abeta42 ) , total tau protein ( T-tau ) , and tau phosphorylated at position threonine 181 ( P-tau ) for predicting incipient AD in patients with MCI . DESIGN , SETTING , AND PARTICIPANTS The study had 2 parts : a cross-sectional study involving patients with AD and controls to identify cut points , followed by a prospect i ve cohort study involving patients with MCI  , conducted 1990 - 2007 . A total of 750 individuals with MCI , 529 with AD , and 304 controls were recruited by 12 centers in Europe and the United States . Individuals with MCI  were followed up for at least 2 years or until symptoms had progressed to clinical dementia . MAIN OUTCOME MEASURES Sensitivity , specificity , positive and negative likelihood ratios ( LRs ) of CSF Abeta42 , T-tau , and P-tau for identifying incipient AD . RESULTS During follow-up , 271 participants with MCI were diagnosed with AD and 59 with other dementias . The Abeta42 assay in particular had considerable intersite variability . Patients who developed AD had lower median Abeta42 ( 356 ; range , 96 - 1075 ng/L ) and higher P-tau ( 81 ; range , 15 - 183 ng/L ) and T-tau ( 582 ; range , 83 - 2174 ng/L ) levels than MCI patients who did not develop AD during follow-up ( 579 ; range , 121 - 1420 ng/L for Abeta42 ; 53 ; range , 15 - 163 ng/L for P-tau ; and 294 ; range , 31 - 2483 ng/L for T-tau , P < .001 ) . The area under the receiver operating characteristic curve was 0.78 ( 95 % confidence interval [ CI ] , 0.75 - 0.82 ) for Abeta42 , 0.76 ( 95 % CI , 0.72 - 0.80 ) for P-tau , and 0.79 ( 95 % CI , 0.76 - 0.83 ) for T-tau . Cut-offs with sensitivity set to 85 % were defined in the AD and control groups and tested in the MCI group , where the combination of Abeta42/P-tau ratio and T-tau identified incipient AD with a sensitivity of 83 % ( 95 % CI , 78%-88 % ) , specificity 72 % ( 95 % CI , 68%-76 % ) , positive LR , 3.0 ( 95 % CI , 2.5 - 3.4 ) , and negative LR , 0.24 ( 95 % CI , 0.21 - 0.28 ) . The positive predictive value was 62 % and the negative predictive value was 88 % . CONCLUSIONS This multicenter study found that CSF Abeta42 , T-tau , and P-tau identify incipient AD with good accuracy , but less accurately than reported from single-center studies . Intersite assay variability highlights a need for st and ardization of analytical techniques and clinical procedures Objective To evaluate the synergistic effects of the apolipoprotein E ( APOE ) ϵ4 and butyrylcholinesterase K-variant ( BCHE-K ) alleles on progression to Alzheimer 's disease ( AD ) in individuals with mild cognitive impairment ( MCI ) . Methods This was a post-hoc exploratory analysis from a 3–4-year , r and omized , placebo-controlled study of rivastigmine in participants with MCI ( InDDEx study ) . Participants who consented to genetic testing were included in the current analyses . The incidence of progression to AD , cognitive decline and changes in MRI brain volumes were investigated in participants from the placebo arm of the InDDEx study . Results Of the 1018 participants in the overall study , 464 were successfully genotyped for both APOE and butyrylcholinesterase . Of these , 68 ( 14.7 % ) carried ≥1 APOE ϵ4 and ≥1 BCHE-K allele . The presence of APOE ϵ4 was associated with a significantly higher incidence of progression to AD whereas the presence of BCHE-K had no independent effect on progression . A synergistic effect of the combined presence of APOE ϵ4 and BCHE-K on the time to clinical diagnosis of AD and on MRI brain volumes was seen . Progression to AD and hippocampal volumetric loss was greatest in participants who carried both APOE ϵ4 and BCHE-K alleles and lowest in BCHE-K carriers without the APOE ϵ4 allele . Conclusion In MCI , the risk of cognitive decline , hippocampal volumetric loss and progression to AD seems to be the greatest in individuals who carry at least one copy of both the BCHE-K and APOE ϵ4 alleles BACKGROUND The aim of this study was to evaluate the accuracy of combined structural magnetic resonance imaging ( MRI ) measures and plasma levels of vitamin E forms , including all eight natural vitamin E congeners ( four tocopherols and four tocotrienols ) and markers of vitamin E oxidative/nitrosative damage , in differentiating individuals with Alzheimer 's disease ( AD ) and mild cognitive impairment ( MCI ) from cognitively intact control ( CTL ) subjects . METHODS Overall , 81 patients with AD , 86 with MCI and 86 CTL individuals were enrolled from the longitudinal multicentre AddNeuroMed study .  MRI and plasma vitamin E data were acquired at baseline . MRI scans were analysed using Freesurfer , an automated segmentation scheme which generates regional volume and cortical thickness measures . Orthogonal partial least squares to latent structures ( OPLS ) , a multivariate data analysis technique , was used to analyse  MRI  and vitamin E measures in relation to AD and MCI diagnosis . RESULTS The joint evaluation of MRI and plasma vitamin E measures enhanced the accuracy of differentiating individuals with AD and MCI from CTL subjects : 98.2 % ( sensitivity 98.8 % , specificity 97.7 % ) for AD versus CTL , and 90.7 % ( sensitivity 91.8 % , specificity 89.5 % ) for MCI versus CTL . This combination of measures also identified 85 % of individuals with MCI who converted to clinical AD at follow-up after 1 year . CONCLUSIONS Plasma levels of tocopherols and tocotrienols together with automated MRI measures can help to differentiate AD and MCI patients from CTL subjects , and to prospect ively predict MCI conversion into AD . Our results suggest the potential role of nutritional biomarkers detected in plasma-tocopherols and tocotrienols-as indirect indicators of AD pathology , and the utility of a multimodality approach Alzheimer 's disease ( AD ) is the most common cause of dementia in Western countries and in Japan . Early diagnosis and treatment is needed to slow down the degenerative process and dementia in AD . The main histopathological characteristics of AD are senile plaques and neurofibrillary tangles . Based on the disease pathology , numerous blood and cerebrospinal fluid ( CSF ) tests have been proposed for early detection of AD . However , there is no definite clinical method to determine in which patients with mild cognitive impairment will progress to AD with dementia . Since pigment epithelium-derived factor ( PEDF ) has been recently shown to protect various types of cells including neuronal cells against oxidative stress- or glutamate-induced injury through its anti-oxidative properties , we examined here the expression levels of PEDF in AD 's brain . PEDF was found to have the strong immunoreactivity in cortical neurons and astrocytes in the brains of AD . Further , the distribution of PEDF proteins was good concordance with RAGE proteins , one of the receptors for amyloid beta peptides , which are involved in neuronal cell death and microglial activation in AD . These results suggest that PEDF overexpression may indicate a compensation mechanism to fight against neuronal cell injury in AD . Our present observations suggest that PEDF in CSF might reflect cerebral PEDF turnover and provide a means for monitoring neuronal perturbation induced by oxidative stress in the 
    Output:
    
The proposed panels of fluid biomarkers may be useful in the early diagnosis of AD , prediction of the progression of AD from pre clinical stages to the dementia stage , and the differentiation of AD from non‑AD dementia .
In combination with physical frailty , the present study surmised that these biomarkers may also be used as biomarkers for CF , thus contribute to discovering causes and informing interventions for cognitive impairment in individuals with CF