Increased 8,12-iso-iPF2alpha-VI in Alzheimer's disease: correlation of a noninvasive index of lipid peroxidation with disease severity

The isoprostane 8,12-iso-iPF2alpha-VI is a sensitive and specific marker of in vivo lipid peroxidation. We found elevated levels in the urine, blood, and cerebrospinal fluid of patients with Alzheimer's disease (AD) that correlated with measures of cognitive and functional impairment, established biomarkers of AD pathology (cerebrospinal fluid tau and amyloid) and the number of apolipoprotein E epsilon4 alleles. These results suggest that 8,12-iso-iPF2alpha-VI is a useful biomarker of oxidative damage in AD.     

Reduction of brain lipid peroxidation by CSF drainage in Alzheimer's disease patients

Alzheimer's disease (AD) is associated with an increase in cerebrospinal fluid (CSF) levels of the isoprostane 8,12-iso-iPF2alpha-VI, a specific marker of in vivo lipid peroxidation. Poor cerebral clearance of end products of oxidative reactions via CSF circulation may contribute to and sustain ongoing stress. CSF drainage via a low-flow ventriculoperitoneal (VP) shunt may improve removal of these products, reducing oxidative stress. We quantified this biomarker in patients with AD undergoing to VP shunt placement at baseline and after one-year period. CSF sampling occurred at baseline and quarterly visits for one year. Levels of this isoprostane were determined simultaneously at the end of the study by gas chromatography negative ion chemical ionization mass spectrometry. Over one-year, CSF 8,12-iso-iPF2alpha-VI levels consistently decreased versus baseline (51% of initial level), while CSF protein, glucose, cell count and IgG concentrations remained within normal limits. This finding supports the hypothesis that improving CSF drainage enhances extra-cellular clearance of end products of oxidative reactions and lowers brain lipid peroxidation.     

Down's syndrome is associated with increased 8,12-iso-iPF2alpha-VI levels: evidence for enhanced lipid peroxidation in vivo

Postmortem and in vitro studies have shown that oxidative stress plays a role in the pathogenesis of many of the clinical features of Down's syndrome. The isoprostane 8,12-iso-iPF2alpha-VI is a specific marker of lipid peroxidation. We found elevated levels of this isoprostane in urine samples of subjects with Down's syndrome compared with those of matched controls, which correlated with the duration of the disease. These results suggest that increased in vivo lipid peroxidation is a prominent component early in the course of Down's syndrome.     

Altered vascular phenotype in autism: correlation with oxidative stress

BACKGROUND: Autism is a neurologic disorder characterized by impaired communication and social interaction. Results of previous studies showed biochemical evidence for abnormal platelet reactivity and altered blood flow in children with autism. OBJECTIVE: To evaluate the vascular phenotype in children with autism. DESIGN AND MAIN OUTCOME MEASURES: Urinary levels of isoprostane F(2alpha)-VI, a marker of lipid peroxidation; 2,3-dinor-thromboxane B(2), which reflects platelet activation; and 6-keto-prostaglandin F(1alpha), a marker of endothelium activation, were measured by means of gas chromatography-mass spectrometry in subjects with autism and healthy control subjects. SETTING AND SUBJECTS: Children with a clinical diagnosis of autism attending the Pfeiffer Treatment Center. RESULTS: Compared with controls, children with autism had significantly higher urinary levels of isoprostane F(2alpha)-VI, 2,3-dinor-thromboxane B(2), and 6-keto-prostaglandin F(1alpha). Lipid peroxidation levels directly correlated with both vascular biomarker ratios. CONCLUSION: Besides enhanced oxidative stress, platelet and vascular endothelium activation also could contribute to the development and clinical manifestations of autism.     

Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment

The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls. Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD. Compared with controls, there was a significant increase of both metabolites in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD.     

Cerebrospinal fluid profile in frontotemporal dementia and Alzheimer's disease

We assessed cerebrospinal fluid (CSF) levels of tau and other biomarkers of neurodegenerative disease. CSF tau levels vary widely in reports of frontotemporal dementia (FTD). CSF samples were assayed for tau, amyloid beta1-42 (A1-42), and the isoprostane 8,12-iso-iPF2a-VI (iP) prospectively in 64 patients with FTD, retrospectively in 26 autopsied cases with FTD or Alzheimer's disease (AD), and in 13 healthy seniors. To validate our observations in vivo, we correlated CSF tau levels with cortical atrophy in 17 FTD patients using voxel-based morphometry analyses of high-resolution magnetic resonance imaging. CSF levels of tau, Abeta1-42, and iP differed significantly in FTD compared with AD. Individual patient analyses showed that 34% of FD patients had significantly low levels of CSF tau, although this was never seen in AD. A discriminant analysis based on CSF levels of tau, Abeta1-42, and iP was able to classify 88.5% of these patients in a manner that corresponds to their clinical or autopsy diagnosis. Magnetic resonance imaging studies showed that CSF tau levels correlate significantly with right frontal and left temporal cortical atrophy, brain regions known to be atrophic in patients with autopsy-proved FTD. We conclude that CSF tau levels are significantly reduced in many patients with FTD.     

Association of low plasma Abeta42/Abeta40 ratios with increased imminent risk for mild cognitive impairment and Alzheimer disease

BACKGROUND: To develop preventive therapy for Alzheimer disease (AD), it is essential to develop AD-related biomarkers that identify at-risk individuals in the same way that cholesterol levels identify persons at risk for heart disease. OBJECTIVE: To determine whether plasma levels of amyloid beta protein (Abeta40 and Abeta42) are useful for identifying cognitively normal elderly white subjects at increased risk for mild cognitive impairment (MCI) and AD. DESIGN: Using well-established sandwich enzyme-linked immunosorbent assays, plasma Abeta40 and Abeta42 levels were analyzed at baseline in a prospective, elderly white cohort followed up for 2 to 12 (median, 3.7) years to detect incident cases of MCI or AD. SETTING: Cognitively normal, community-based white volunteers recruited from primary care settings into the Mayo Rochester Alzheimer Disease Patient Registry. Patients We followed up 563 cognitively normal white volunteers (median age, 78 years; 62% female) who had at least 1 follow-up visit after measurement of baseline plasma Abeta levels. MAIN OUTCOME MEASURES: The primary outcome was time to development of MCI or AD. The secondary outcome was the annualized rate of cognitive change in patients for whom we had 2 Mattis Dementia Rating Scale evaluations 3 to 7 years apart. RESULTS: During follow-up, 53 subjects developed MCI or AD. Subjects with plasma Abeta42/Abeta40 ratios in the lower quartiles showed significantly greater risk of MCI or AD (P = .04, adjusted for age and apolipoprotein E genotype). Comparison of subjects with plasma Abeta42/Abeta40 ratios in the lowest vs the highest quartile gave a relative risk of 3.1 (95% confidence interval, 1.1-8.3). After adjusting for age and apolipoprotein E genotype, regression analysis using annualized changes in the Dementia Rating Scale scores as an outcome variable showed that participants with lower Abeta42/Abeta40 ratios had greater cognitive decline (P = .02). CONCLUSION: The plasma Abeta42/Abeta40 ratio may be a useful premorbid biomarker for identifying cognitively normal elderly white subjects who are at increased risk for developing MCI or AD.     

Cerebrospinal fluid isoprostanes are not related to inflammatory activity in relapsing-remitting multiple sclerosis

Oxidative stress leads to lipid peroxidation and may contribute to the pathogenesis of lesions in multiple sclerosis (MS), an autoimmune disease characterised by inflammatory as well as degenerative phenomena. We previously found that cerebrospinal fluid (CSF) levels of isoprostane 8-epi-PGF2alpha, a marker of free radical damage and lipid peroxidation in vivo, were elevated in MS patients. Such levels were correlated with the degree of disability and reduced in subjects under steroid therapy. Here we investigated weather the CSF isoprostane levels correlated with disease inflammatory activity. To this aim, we enrolled 41 relapsing-remitting (RR) MS patients who underwent at the same time full neurological examination, NMR-imaging brain scan and diagnostic CSF test. No evidence of correlation was found between 8-epi-PGF2alpha levels and the presence of gadolinium (Gd)-enhancing NMR lesions or the time elapsed since the last relapse. We suggest that isoprostanes are not useful as surrogate inflammatory markers in MS. However, they may represent a sensitive index of degenerative phenomena, which can persist also in the absence of inflammatory activity.     

Characterization of tau pathologies in gray and white matter of Guam parkinsonism-dementia complex

Guam parkinsonism-dementia complex (PDC) is a neurodegenerative tauopathy in ethnic Chamorro residents of the Mariana Islands that manifests clinically with parkinsonism as well as dementia and is characterized neuropathologically by prominent cortical neuron loss in association with extensive telencephalic neurofibrillary tau pathology. To further characterize cortical gray and white matter tau, alpha-synuclein and lipid peroxidation pathologies in Guam PDC, we examined the brains of 17 Chamorro PDC and control subjects using biochemical and immunohistological techniques. We observed insoluble tau pathology in both gray and white matter of PDC and Guam control cases, with frontal and temporal lobes being most severely affected. Using phosphorylation dependent anti-tau antibodies, abundant tau inclusions were detected by immunohistochemistry in both neuronal and glial cells of the neocortex, while less alpha-synuclein pathology was observed in more limited brain regions. Further, in sharp contrast to Alzheimer’s disease (AD), levels of the lipid peroxidation product 8, 12–iso-iPF_2α-VI isoprostane were not elevated in Guam PDC brains relative to controls. Thus, although the tau pathologies of Guam PDC share similarities with AD, the composite Guam PDC neuropathology profile of tau, alpha-synuclein and 8, 12-iso-iPF_2α-VI isoprostane reported here more closely resembles that seen in other tauopathies including frontotemporal dementias (FTDs), which may imply that Guam PDC and FTD tauopathies share underlying mechanisms of neurodegeneration.     

Safety and acceptability of the research lumbar puncture

Three hundred forty-two subjects underwent 428 research lumbar punctures for studies of cerebrospinal fluid (CSF) biomarkers. Subjects were 67 Alzheimer disease or mild cognitive impairment (AD/MCI) patients and 275 cognitively normal adults aged 21 to 88. Lumbar puncture was performed in the lateral decubitus or sitting position using the Sprotte 24 g atraumatic spinal needle. Up to 34 ml of cerebrospinal fluid were collected. Anxiety and pain experienced during lumbar puncture were rated on a visual analog scale. The frequency of any adverse event (11.7%), clinically significant adverse events (3.97%), and typical post-lumbar puncture headache (PLPHA) (0.93%) was low. Risk of post-lumbar puncture headache was unrelated to age, gender, position during lumbar puncture, ml of cerebrospinal fluid collected, or minutes of recumbent rest following lumbar puncture. The frequency of post-lumbar puncture headache was lower in AD/MCI (P = 0.03) than any other subject group. Anxiety and pain ratings were low. Younger subjects reported more anxiety than old (P = 0.001) and AD/MCI subjects (P = 0.008) and more pain than older normal subjects (P = 0.013). Pain ratings for women were higher than those for men (P = 0.006). Using the Sprotte 24 g spinal needle, research lumbar puncture can be performed with a very low rate of clinically significant adverse events and with good acceptability in cognitively impaired persons and cognitively normal adults of all ages.     

Peripheral oxidative stress biomarkers in mild cognitive impairment and Alzheimer's disease

Oxidative stress has been associated with normal aging and Alzheimer's disease (AD). However, little is known about oxidative stress in mild cognitive impairment (MCI) patients who present a high risk for developing AD. The aim of this study was to investigate plasma production of the lipid peroxidation marker, malonaldehyde (MDA) and to determine, in erythrocytes, the enzymatic antioxidant activity of catalase, glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione S-transferase (GST) in 33 individuals with MCI, 29 with mild probable AD and 26 healthy aged subjects. GR/GPx activity ratio was calculated to better assess antioxidant defenses. The relationship between oxidative stress and cognitive performance was also evaluated by the Mini Mental State Examination (MMSE). AD patients showed higher MDA levels than both MCI and healthy elderly subjects. MCI subjects also exhibited higher MDA levels compared to controls. Catalase and GPx activity were similar in MCI and healthy individuals but higher in AD. GR activity was lower in MCI and AD patients than in healthy aged subjects. Additionally, GR/GPx ratio was higher in healthy aged subjects, intermediate in MCI and lower in AD patients. No differences in GST activity were detected among the groups. MMSE was negatively associated with MDA levels (r = -0.31, p = 0.028) and positively correlated with GR/GPx ratio in AD patients (r = 0.68, p < 0.001). MDA levels were also negatively correlated to GR/GPx ratio (r = -0.31, p = 0.029) in the AD group. These results suggest that high lipid peroxidation and decreased antioxidant defenses may be present early in cognitive disorders.     

Cerebrospinal fluid sulfatide is decreased in subjects with incipient dementia

We recently noted a profound decline in brain sulfatides (ST) in subjects who died with incipient dementia due to Alzheimer's disease. Herein, we measured ST levels in cerebrospinal fluid in cognitively normal elderly and in subjects with mild cognitive impairment due to incipient demenia of the Alzheimer type. There was a significant decrease in cerebrospinal fluid ST and in the ST to phosphatidylinositol ratio in MCI subjects. The ST to phosphatidylinositol ratio accurately differentiated very mildly impaired subjects from controls on an individual basis. The cerebrospinal fluid ST to phosphatidylinositol ratio may be a very useful biomarker for the earliest clinical stage of Alzheimer's disease.     

Novel panel of cerebrospinal fluid biomarkers for the prediction of progression to Alzheimer dementia in patients with mild cognitive impairment

OBJECTIVE: To use proteomic analysis of cerebrospinal fluid to discover novel proteins and peptides able to differentiate between patients with stable mild cognitive impairment (MCI) and those who will progress to Alzheimer disease (AD). DESIGN: Baseline cerebrospinal fluid samples from patients with MCI and healthy controls were profiled using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. SETTING: Memory disorder clinic. PARTICIPANTS: Patients with MCI (n = 113), of whom 56 were cognitively stable and 57 progressed to AD with dementia during a 4- to 6-year follow-up, as well as 28 healthy controls who were followed up for 3 years. Main Outcome Measure During follow-up, 57 patients progressed to AD and 56 patients had stable MCI. Cerebrospinal fluid from these 2 groups of patients was compared using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry. RESULTS: We identified a panel of 17 potential biomarkers that could distinguish between patients with stable MCI and patients with MCI who progressed to AD. We have positively identified and characterized 5 of the potential biomarkers. CONCLUSIONS: Proteomic profiling of cerebrospinal fluid provided a novel panel of 17 potential biomarkers for prediction of MCI progression to AD. The 5 identified biomarkers are relevant to the pathogenesis of AD and could help gain an understanding of the molecular pathways in which they may function.     

Redox proteomic identification of 4-hydroxy-2-nonenal-modified brain proteins in amnestic mild cognitive impairment: insight into the role of lipid peroxidation in the progression and pathogenesis of Alzheimer's disease

Numerous investigations point to the importance of oxidative imbalance in mediating AD pathogenesis. Accumulated evidence indicates that lipid peroxidation is an early event during the evolution of the disease and occurs in patients with mild cognitive impairment (MCI). Because MCI represents a condition of increased risk for Alzheimer's disease (AD), early detection of disease markers is under investigation. Previously we showed that HNE-modified proteins, markers of lipid peroxidation, are elevated in MCI hippocampus and inferior parietal lobule compared to controls. Using a redox proteomic approach, we now report the identity of 11 HNE-modified proteins that had significantly elevated HNE levels in MCI patients compared with controls that span both brain regions: Neuropolypeptide h3, carbonyl reductase (NADPH), alpha-enolase, lactate dehydrogenase B, phosphoglycerate kinase, heat shock protein 70, ATP synthase alpha chain, pyruvate kinase, actin, elongation factor Tu, and translation initiation factor alpha. The enzyme activities of lactate dehydrogenase, ATP synthase, and pyruvate kinase were decreased in MCI subjects compared with controls, suggesting a direct correlation between oxidative damage and impaired enzyme activity. We suggest that impairment of target proteins through the production of HNE adducts leads to protein dysfunction and eventually neuronal death, thus contributing to the biological events that may lead MCI patients to progress to AD.     

Intrathecal chemokine synthesis in mild cognitive impairment and Alzheimer disease

BACKGROUND: Immunoreactivity for several chemokines and for their related receptors has been demonstrated in resident cells of the central nervous system, and the up-regulation of some of them is associated with pathological changes found in Alzheimer disease (AD). OBJECTIVE: To determine interferon-gamma-inducible protein 10 (IP-10), monocyte chemotactic protein 1 (MCP-1), and interleukin 8 (IL-8) levels in cerebrospinal fluid (CSF) from subjects with amnestic mild cognitive impairment (MCI) and patients with AD as compared with age-matched controls. PATIENTS: Thirty-eight subjects with amnestic MCI, 36 patients with AD, and 41 age-matched subjects with noninflammatory affections of the nervous system. DESIGN: Evaluation of CSF chemokine production at time of diagnosis of MCI and AD; correlation with clinical and personal data. Longitudinal evaluation of subjects with MCI until conversion to AD. RESULTS: Cerebrospinal fluid IP-10 concentration was significantly increased in patients with MCI and mild AD but not in patients with severe AD (Mini-Mental State Examination score <15), whereas MCP-1 and IL-8 levels were increased in patients with MCI and all patients with AD. A significant positive correlation between Mini-Mental State Examination score and CSF IP-10 or MCP-1 concentration was observed in patients with AD. No correlation between IP-10 levels and age was found, whereas MCP-1 and IL-8 levels correlated positively with age. Out of 38 subjects with MCI, 19 developed AD within a 1- to 3-year follow-up. CONCLUSIONS: The presence of inflammatory molecules is likely to be a very early event in AD pathogenesis, even preceding the clinical onset of the disease, as demonstrated by subjects with MCI who developed AD over time. Interferon-gamma-inducible protein 10 is specifically increased in MCI and seems to decrease with the progression of AD, whereas MCP-1 and IL-8 are up-regulated also in late stages of the disease, suggesting a role in phases in which neurodegeneration is prevalent.     

Increased Plasma Beta-Secretase 1 May Predict Conversion to Alzheimer’s Disease Dementia in Individuals With Mild Cognitive Impairment

Background

Increased beta-secretase 1 (BACE1) activity has consistently been detected in brain tissue and cerebrospinal fluid of subjects with mild cognitive impairment (MCI) and probable Alzheimer’s disease (AD) compared with control subjects. The collection of cerebrospinal fluid by lumbar puncture is invasive. We sought to identify the presence of plasma BACE1 activity and determine potential alterations in subjects with MCI with clinical follow-up examinations for 3 years using patients with diagnosed probable AD dementia compared with healthy control subjects.

Cerebrospinal fluid tau and beta-amyloid 42 proteins identify Alzheimer disease in subjects with mild cognitive impairment

CONTEXT: Cerebrospinal fluid tau protein and beta-amyloid 42 (Abeta42) protein are altered even in very mild Alzheimer disease (AD). So far, few data exist for subjects with mild cognitive impairment (MCI). OBJECTIVE: To investigate the potential of cerebrospinal fluid tau and Abeta42 for predicting progression from MCI to AD in a longitudinal study of 28 patients with MCI who received follow-up for 18 months. DESIGN: An 18-month prospective study. SETTING: Clinical follow-up study of community-residing subjects with MCI. MAIN OUTCOME MEASURES: Cerebrospinal fluid tau and Abeta42 concentrations were measured using enzyme-linked immunosorbent assay at baseline. The potential of both biomarkers was evaluated to predict the progression to dementia, the end point of this study, using multiple logistic regression analysis. RESULTS: Of 28 subjects with MCI, 12 progressed to dementia (2 to frontotemporal dementia; 10 to AD). Six subjects had progressive MCI, and 10 subjects showed stable MCI. Cerebrospinal fluid tau levels were significantly elevated in patients who progressed to probable AD (P =.002) and subjects with progressive MCI (P =.003) compared with subjects who had stable MCI. Cerebrospinal fluid Abeta42 levels were significantly lower in patients who progressed to probable AD (P =.007) and those with progressive MCI (P =.04) than in subjects with stable MCI. Logistic regression analysis identified elevated tau protein level as a predictor of cognitive deterioration (P =.02), whereas a delayed verbal recall score at baseline was significantly associated with the development of probable AD (P =.03). CONCLUSION: Our results indicate that altered tau and Abeta42 concentrations may be detectable in subjects who are clinically diagnosed as having MCI but demonstrate the pathological changes of AD.     

Sign of lipid peroxidation as measured in the urine of patients with probable Alzheimer's disease

Free radical-induced oxidative damage may be involved in the neurodegenerative process associated with Alzheimer's disease (AD). 8-Isoprostaglandin F(2alpha) (iPF(2alpha)-III) is an isoprostane derived from free radical-induced non-enzymatic oxidation of arachidonic acid. It is formed in vivo and is an indicator of lipid peroxidation. Measurements were made of iPF(2alpha)-III in the urine of patients with mild to moderate dementia associated with probable AD and compared to those in the urine of non-demented subjects, who were similar in age and gender. 2,3-Dinor thromboxane B(2) (dinor TXB(2)), a urinary metabolite of TXB(2) was also measured, and served as an indicator of the enzymatic transformation of a product of arachidonic acid. Enzyme linked immunoassays were used to measure iPF(2alpha)-III and dinor TXB(2) in the urine. The concentration of iPF(2alpha)-III was significantly elevated in urine of patients assessed to have mild to moderate dementia as compared to non-demented patients. The concentration of urinary dinor TXB(2) was also significantly elevated in the patients with dementia and probable AD as compared to the non-demented subjects. There was considerable overlap of values obtained for demented and non-demented patients for iPF(2alpha)-III and dinor TXB(2), respectively. The observed elevation of iPF(2alpha)-III suggests that patients with mild to moderate dementia associated with probable AD are experiencing significant oxidative stress. This finding is consistent with current data suggesting that oxidative stress may be occurring in patients with dementia and probable AD. The increase of dinor TXB(2) may indicate that enzymatic processes related to the metabolism of arachidonic acid-derived products are also increased in demented patients with probable AD.     

Evaluation of CSF biomarkers as predictors of Alzheimer's disease: a clinical follow-up study of 4.7 years

In this study, we determined the diagnostic accuracy of cerebrospinal fluid (CSF) biomarkers to predict development of Alzheimer's disease (AD) within five years in patients with mild cognitive impairment (MCI). To do so, the levels of tau, phosphorylated tau, Aβ42, Aβ40, Aβ38, sAβPPα, and sAβPPβ were analyzed in 327 CSF samples obtained at baseline from patients with AD (n = 94), MCI (n = 166), depressive disorder (n = 29), and cognitively healthy controls (n = 38). In the cohort with MCI at baseline, 33% subsequently developed AD and 16% developed other types of dementia; however, 51% were still cognitively stable after a followup of 4.7 years (range 3.0-7.2). Optimal cutoffs for each biomarker or combinations of biomarkers were defined in the AD, control, and depressive disorder groups. Several combinations resulted in sensitivity and specificity levels > 85% for differentiation of AD from controls and depressive disorder. Using the previously established cutoffs, a combination of Aβ42 and tau could predict future development of AD in MCI patients with a sensitivity of 88%, specificity 82%, positive predictive value 71%, and negative predictive value 94%. MCI patients with both low Aβ42 and high tau levels had a substantially increased risk of developing AD (OR 20; 95% CI 6-58), even after adjustment for confounding factors. Ultimately, CSF biomarkers can stratify MCI patients into those with very low or high risk for future development of AD. However, the specificities and positive predictive values are still too low to be able to diagnose AD before the patients fulfill the clinical criteria.     

Plasma level of chitinase 3-like 1 protein increases in patients with early Alzheimer’s disease

Previously, chitinase 3-like 1 (CHI3L1) protein level was increased in various inflammatory conditions and cancers. This study was aimed to evaluate the plasma CHI3L1 level as a potential prognostic biomarker for Alzheimer’s disease (AD). Forty-nine patients with mild cognitive impairment (MCI), 61 patients with mild to severe AD, and 35 healthy elderly controls were recruited for this study. They were given a comprehensive neuropsychological test battery including a mini-mental status examination (MMSE), clinical dementia rating (CDR), and neuropsychiatric inventory (NPI). The CHI3L1 levels were measured using a specific enzyme-linked immunosorbent assay in the plasma and cerebrospinal fluid (CSF). A significant increase in the mean plasma level of CHI3L1 was found in early AD patients compared to control subjects and MCI patients. No significant difference was found between MCI patients and controls. There was a significant positive correlation between CHI3L1 levels and neuropsychological test scores such as CDR and NPI in MCI and early AD patients. Our results demonstrate that CHI3L1 plasma levels are elevated in early AD compared to control or MCI patients. Thus, CHI3L1 plasma levels may be useful as a biomarker, reflecting disease severity in AD patients.