Plasma Abeta Levels Research Articles

Association of plasma abeta and tau levels in relation to cognition and brain structure in a diverse community

AbstractBackgroundEarly studies of mostly non‐Hispanic White groups suggest that plasma tau and abeta levels are associated with clinically relevant cognitive impairment. Given limited studies of more ethnically diverse communities, we chose to study 402 subjects from the UC Davis Alzheimer’s Disease Center.MethodThe subjects were diverse (14% White, 45% Black and 41% Hispanic), 61% women, average age of 76 + 7.3 years with 12 + 5 years of education with a spectrum of cognitive ability (66% cognitively normal, 19% MCI and 15% demented). Plasma samples were obtained within 0.3 + 0.8 years of cognitive and MRI assessments. Duplicate plasma samples were measured for tau, abeta 40 and 42 on a Quanterix SRX using SIMOA technology. Subjects with CV >20% or extreme values (>5 SD) were excluded. Analyses compared cross‐sectional associations between plasma abeta and tau levels and diagnosis adjusting for age, sex, race/ethnicity and education as well as associations with memory, executive function and structural MRI measures.ResultThe table summarizes mean values for Tau, abeta 40, 42 and the 42/40 ratio across diagnoses and race/ethnicity. Both abeta 42 and the 42/40 ratio differed significantly by clinical diagnosis. The abeta 42/40 ratio was significantly lower for non‐Hispanic whites than Blacks and Hispanics (Tukey HSD, p <0.05). Higher plasma tau levels were weakly negatively associated (beta =‐0.04 + 0.02, <0.05) whereas higher abeta 42/40 ratios were significantly positively associated (beta = 6.6 + 2.9, p =0.02) with executive function. Higher abeta 42/40 ratios were also significantly positively associated (beta = 7.1 + 3.4, p <0.05) with hippocampal and temporal lobe gray matter (beta = 146 + 46, p =0.002) volumes. Logistic regression predicting diagnostic category found that the abeta 42/40 ratio significantly differentiated the groups (chi sqr =17, p = 0.0002).ConclusionIn this study of diverse, community recruited individuals, plasma abeta 42 and the abeta 42/40 ratio were significant predictors of clinical diagnosis, cognition and MRI measures, indication that plasma levels of abeta measured have clinical implications in a diverse cohort where mixed pathologies are known to be common1. Reference: 1.Filshtein TJ, Dugger BN, Jin LW, et al. J Alzheimers Dis 2019.

Two distinct pathways leading to retinal degeneration in transgenic Drosophila melanogaster overexpressing human FUS

tau phosphorylation.Results: Six months high fat diet increased Abeta40 in the brains ofB6C wild type mice. On the other hand, high fat diet increased plasma Abeta levels in APP/PS1 mice, but not in wild type mice. Moreover, tau phosphorylation was highly increased in the brains of 18 months old APP+ ob/obmice.Conclusions:Tau phosphorylation is increased by diabetes in APP mice, suggesting that Abeta i s prerequisite, but insufficient to cause tau phosphorylation in vivo. A beta accumulation, insulin signaling and tau phosphorylation might play essential roles in the pathological interaction between AD and diabetes. Of note, a vicious cycle likely underlie the interaction between AD and diabetes. High fat diet-induced elevation of plasma Abeta level might be involved in this interaction between AD and diabetes.

Quantitation of plasma Abeta40 and Abeta42 levels using rabbit monoclonal antibodies

Previously we quantitated plasma Abeta40 and Abeta42 levels using a combination of mouse monoclonal antibody 6E10 as a capture antibody and rabbit polyclonal antibodies specific to Abeta as detection antibodies. Recently, we have produced rabbit monoclonal antibodies (Rabmab) to Abeta40 and Abeta42. Currently there is a great interest in the measurement of plasma Abeta levels at intervals in AD and elderly non-demented controls. Reports showed conflicting data and the reason is not known. We hypothesize that differences in antibody epitopes and affinity may have contributed to the variable findings. We examined 40 AD or control plasma samples using 1) a combination of Rabmab to Abeta as capture antibodies and 4G8 mouse monoclonal antibody as detecting antibody; and 2) mouse monoclonal antibody 6E10 as a capture antibody and Rabmab to Abeta as detecting antibodies in sandwich ELISA. There was a significant relation between Abeta40 levels of Rabmab to Abeta40 and rabbit polyclonal antibody to Abeta40 using 4G8 as detecting antibody (r = .67; p < 0.001), and Rabmab to Abeta42 and rabbit polyclonal antibody to Abeta42 using 4G8 as detecting antibody (r = .97; p < 0.001). Similarly there was a relation between Abeta levels using mouse monoclonal antibody 6E10 as capture antibody and Rabmab or polyclonal antibody as detecting antibodies. When the relationship between the levels using 4G8 and 6E10 were compared, there was a significant relation in Abeta40 levels (r = .63; p < .001) but not in Abeta42 levels (r = .19; p < .24). The data show that differences in capture or detecting antibodies may contribute to different findings among published studies.

Caffeine and Coffee as Therapeutics Against Alzheimer's Disease

Epidemiologic studies have increasingly suggested that caffeine/coffee could be an effective therapeutic against Alzheimer's disease (AD). We have utilized a transgenic mouse model for AD in well-controlled studies to determine if caffeine and/or coffee have beneficial actions to protect against or reverse AD-like cognitive impairment and AD pathology. AD mice given caffeine in their drinking water from young adulthood into older age showed protection against memory impairment and lower brain levels of the abnormal protein (amyloid-beta; Abeta) thought to be central to AD pathogenesis. Moreover, "aged" cognitively-impaired AD mice exhibited memory restoration and lower brain Abeta levels following only 1-2 months of caffeine treatment. We believe that the cognitive benefits of chronic caffeine administration in AD mice are due to caffeine itself, and not metabolites of caffeine; this, because our long-term administration of theophylline to AD mice provided no cognitive benefits. In acute studies involving AD mice, one oral caffeine treatment quickly reduced both brain and plasma Abeta levels - similarly rapid alterations in plasma Abeta levels were seen in humans following acute caffeine administration. "Caffeinated" coffee provided to AD mice also quickly decreased plasma Abeta levels, but not "decaffeinated" coffee, suggesting that caffeine is critical to decreasing blood Abeta levels. Caffeine appears to provide its disease-modifying effects through multiple mechanisms, including a direct reduction of Abeta production through suppression of both beta- and gamma-secretase levels. These results indicate a surprising ability of moderate caffeine intake (the human equivalent of 500 mg caffeine or 5 cups of coffee per day) to protect against or treat AD in a mouse model for the disease and a therapeutic potential for caffeine against AD in humans.

Concordant Association of Insulin Degrading Enzyme Gene (IDE) Variants with IDE mRNA, Aß, and Alzheimer's Disease

BackgroundThe insulin-degrading enzyme gene (IDE) is a strong functional and positional candidate for late onset Alzheimer's disease (LOAD).Methodology/Principal FindingsWe examined conserved regions of IDE and its 10 kb flanks in 269 AD cases and 252 controls thereby identifying 17 putative functional polymorphisms. These variants formed eleven haplotypes that were tagged with ten variants. Four of these showed significant association with IDE transcript levels in samples from 194 LOAD cerebella. The strongest, rs6583817, which has not previously been reported, showed unequivocal association (p = 1.5×10−8, fold-increase = 2.12,); the eleven haplotypes were also significantly associated with transcript levels (global p = 0.003). Using an in vitro dual luciferase reporter assay, we found that rs6583817 increases reporter gene expression in Be(2)-C (p = 0.006) and HepG2 (p = 0.02) cell lines. Furthermore, using data from a recent genome-wide association study of two Croatian isolated populations (n = 1,879), we identified a proxy for rs6583817 that associated significantly with decreased plasma Aβ40 levels (ß = −0.124, p = 0.011) and total measured plasma Aβ levels (b = −0.130, p = 0.009). Finally, rs6583817 was associated with decreased risk of LOAD in 3,891 AD cases and 3,605 controls. (OR = 0.87, p = 0.03), and the eleven IDE haplotypes (global p = 0.02) also showed significant association.ConclusionsThus, a previously unreported variant unequivocally associated with increased IDE expression was also associated with reduced plasma Aß40 and decreased LOAD susceptibility. Genetic association between LOAD and IDE has been difficult to replicate. Our findings suggest that targeted testing of expression SNPs (eSNPs) strongly associated with altered transcript levels in autopsy brain samples may be a powerful way to identify genetic associations with LOAD that would otherwise be difficult to detect.

Plasma β-amyloid as potential biomarker of Alzheimer disease: possibility of diagnostic tool for Alzheimer disease

Alzheimer disease (AD), which is characterized by progressive cognitive and behavioral deficit, is the most common form of dementia. The incidence of AD is increasing at an alarming rate, and has become a major public health concern in many countries. It is well known that the onset of AD is preceded by a long preclinical period. It is thus critical to establish diagnostic biomarkers that can predict the risk of developing AD prior to clinical manifestation of dementia, for effective prevention and early intervention. With the emergence of potential promising approaches to treat AD targeting the beta-amyloid (Abeta) pathway, such as gamma-secretase inhibitors and vaccine therapy, there is an urgent need for such diagnostic markers. Although cerebrospinal fluid (CSF) Abeta and tau protein levels are candidate biomarkers for AD, the invasive sampling procedure with associated complications limits their use in routine clinical practice. Plasma Abeta has been suggested as an inexpensive and non-invasive biomarker for AD. Although most previous cross-sectional studies on plasma Abeta level in humans failed to show a significant difference between individuals with AD compared to healthy older adults, many strategies are under investigation to improve the diagnostic potential of plasma Abeta. One promising approach is to modify the plasma Abeta level using some potential modulators. It is possible that a difference in plasma Abeta level might be unmasked by evaluating the response to stimulation by a modulator. Anti-Abeta antibody and Abeta binding proteins have been reported to be such modulators of plasma Abeta. In addition, the glucometabolic or hormonal status appears to modulate the plasma Abeta level. Our recent study has shown the possibility that glucose loading could be a novel simple strategy to modulate the plasma Abeta level, making it better suited for early diagnosis. This review summarizes the utility and limitations of current biomarkers of AD and discusses future strategies to improve the diagnostic potential of plasma Abeta.

Reduction of Aβ42 in brains of transgenic APPswe mice by 2‐3‐chlorophenylaminophenylacetate

1. Imbalanced generation of the Abeta42 peptide from the amyloid beta protein precursor (APP) is implicated in the pathogenesis of Alzheimer's disease. 2. The present study is the first to evaluate the ability of 2-[3-chlorophenylamino]phenylacetic acid (GLY-230), a new drug in clinical development for the treatment of vascular complications of diabetes, to modulate Abeta42 levels in transgenic mice expressing APP. 3. Oral administration of 7.5 mg/kg GLY-230 twice a day for 14 days to APPswe transgenic mice aged 3 months significantly reduced brain Abeta42 and increased plasma Abeta42 levels by 50 and 20%, respectively. 4. GLY-230 readily entered the brain after administration of a dose (7.5 mg/kg) that decreased brain Abeta42. 5. These results are the first to demonstrate that GLY-230, which exhibits antiglycation but no cyclo-oxygenase inhibitory properties, lowers brain Abeta42 levels in this experimental model of Alzheimer's disease.

Begacestat (GSI-953): A Novel, Selective Thiophene Sulfonamide Inhibitor of Amyloid Precursor Protein γ-Secretase for the Treatment of Alzheimer's Disease

The presenilin containing gamma-secretase complex is responsible for the regulated intramembraneous proteolysis of the amyloid precursor protein (APP), the Notch receptor, and a multitude of other substrates. gamma-Secretase catalyzes the final step in the generation of Abeta(40) and Abeta(42) peptides from APP. Amyloid beta-peptides (Abeta peptides) aggregate to form neurotoxic oligomers, senile plaques, and congophilic angiopathy, some of the cardinal pathologies associated with Alzheimer's disease. Although inhibition of this protease acting on APP may result in potentially therapeutic reductions of neurotoxic Abeta peptides, nonselective inhibition of the enzyme may cause severe adverse events as a result of impaired Notch receptor processing. Here, we report the preclinical pharmacological profile of GSI-953 (begacestat), a novel thiophene sulfonamide gamma-secretase inhibitor (GSI) that selectively inhibits cleavage of APP over Notch. This GSI inhibits Abeta production with low nanomolar potency in cellular and cell-free assays of gamma-secretase function, and displaces a tritiated analog of GSI-953 from enriched gamma-secretase enzyme complexes with similar potency. Cellular assays of Notch cleavage reveal that this compound is approximately 16-fold selective for the inhibition of APP cleavage. In the human APP-overexpressing Tg2576 transgenic mouse, treatment with this orally active compound results in a robust reduction in brain, plasma, and cerebral spinal fluid Abeta levels, and a reversal of contextual fear-conditioning deficits that are correlated with Abeta load. In healthy human volunteers, oral administration of a single dose of GSI-953 produces dose-dependent changes in plasma Abeta levels, confirming pharmacodynamic activity of GSI-953 in humans.

Caffeine Suppresses Amyloid-β Levels in Plasma and Brain of Alzheimer's Disease Transgenic Mice

Recent epidemiologic studies suggest that caffeine may be protective against Alzheimer's disease (AD). Supportive of this premise, our previous studies have shown that moderate caffeine administration protects/restores cognitive function and suppresses brain amyloid-beta (Abeta) production in AD transgenic mice. In the present study, we report that acute caffeine administration to both young adult and aged AD transgenic mice rapidly reduces Abeta levels in both brain interstitial fluid and plasma without affecting Abeta elimination. Long-term oral caffeine treatment to aged AD mice provided not only sustained reductions in plasma Abeta, but also decreases in both soluble and deposited Abeta in hippocampus and cortex. Irrespective of caffeine treatment, plasma Abeta levels did not correlate with brain Abeta levels or with cognitive performance in individual aged AD mice. Although higher plasma caffeine levels were strongly associated with lower plasma Abeta1-40 levels in aged AD mice, plasma caffeine levels were also not linked to cognitive performance. Plasma caffeine and theophylline levels were tightly correlated, both being associated with reduced inflammatory cytokine levels in hippocampus. Our conclusion is two-fold: first, that both plasma and brain Abeta levels are reduced by acute or chronic caffeine administration in several AD transgenic lines and ages, indicating a therapeutic value of caffeine against AD; and second, that plasma Abeta levels are not an accurate index of brain Abeta levels/deposition or cognitive performance in aged AD mice.

Protection against cognitive deficits and markers of neurodegeneration by long‐term oral administration of melatonin in a transgenic model of Alzheimer disease

The neurohormone melatonin has been reported to exert anti-beta-amyloid aggregation, antioxidant, and anti-inflammatory actions in various in vitro and animal models. To comprehensively determine the potential for long-term melatonin treatment to protect Alzheimer's transgenic mice against cognitive impairment and development of beta-amyloid (Abeta) neuropathology, we administered melatonin (100 mg/L drinking water) to APP + PS1 double transgenic (Tg) mice from 2-2.5 months of age to their killing at age 7.5 months. A comprehensive behavioral battery administered during the final 6 weeks of treatment revealed that Tg mice given melatonin were protected from cognitive impairment in a variety of tasks of working memory, spatial reference learning/memory, and basic mnemonic function; Tg control mice remained impaired in all of these cognitive tasks/domains. Immunoreactive Abeta deposition was significantly reduced in hippocampus (43%) and entorhinal cortex (37%) of melatonin-treated Tg mice. Although soluble and oligomeric forms of Abeta1-40 and 1-42 were unchanged in the hippocampus and cortex of the same melatonin-treated Tg mice, their plasma Abeta levels were elevated. These Abeta results, together with our concurrent demonstration that melatonin suppresses Abeta aggregation in brain homogenates, are consistent with a melatonin-facilitated removal of Abeta from the brain. Inflammatory cytokines such as tumor necrosis factor (TNF)-alpha were decreased in hippocampus (but not plasma) of Tg+ melatonin mice. Finally, the cortical mRNA expression of three antioxidant enzymes (SOD-1, glutathione peroxidase, and catalase) was significantly reduced to non-Tg levels by long-term melatonin treatment in Tg mice. Thus, melatonin's cognitive benefits could involve its anti-Abeta aggregation, anti-inflammatory, and/or antioxidant properties. Our findings provide support for long-term melatonin therapy as a primary or complementary strategy for abating the progression of Alzheimer disease.

Association of Cardiovascular Factors and Alzheimer's Disease Plasma Amyloid-β Protein in Subjective Memory Complainers

A strong link is indicated between cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD), which may be exacerbated by the major AD genetic risk factor apolipoprotein Eepsilon4 (APOEepsilon4). Since subjective memory complaint (SMC) may potentially be an early indicator for cognitive decline, we examined CVD risk factors in a cohort of SMC. As amyloid-beta (Abeta) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased LDL, reduced HDL, and increased body fat) would be associated with plasma Abeta levels. We explored this in 198 individuals with and without SMC (average age = 63 years). Correlations between Abeta40 and HDL were observed, which were stronger in non-APOEepsilon4 carriers (rho = -0.315, p < 0.001) and in SMC (rho = -0.322, p = 0.01). There was no relationship between percentage body fat and Abeta40 in this cohort. Age and HDL remained predictive for plasma Abeta40 using multivariate regression analysis. We report a novel negative association between HDL and Abeta, which if demonstrated to be causal has implications for the development of lifestyle interventions and/or novel therapeutics. The relationship between HDL and Abeta and the potential significance of such an association needs to be validated in a larger longitudinal study.

Plasma Aβ, homocysteine, and cognition

Amyloid-beta protein (Abeta) plays a key role in Alzheimer disease (AD) and is also implicated in cerebral small vessel disease. Serum total homocysteine (tHcy) is a risk factor for small vessel disease and cognitive impairment and correlates with plasma Abeta levels. To determine whether this association results from a common pathophysiologic mechanism, we investigated whether vitamin supplementation-induced reduction of tHcy influences plasma Abeta levels in the Vitamin Intervention in Stroke Prevention (VISP) study. Two groups of 150 patients treated with either the high-dose or low-dose formulation of pyridoxine, cobalamin, and folic acid in a randomized, double-blind fashion were selected among the participants in the VISP study without recurrent stroke during follow-up and in the highest 10% of the distribution for baseline tHcy levels. Concentrations of plasma Abeta with 40 (Abeta40) and 42 (Abeta42) amino acids were measured at baseline and at the 2-year visit. tHcy levels significantly decreased with vitamin supplementation in both groups. tHcy were strongly correlated with Abeta40 but not Abeta42 concentrations. There was no difference in the change in Abeta40, Abeta42 (p = 0.40, p = 0.35), or the Abeta42/Abeta40 ratio over time (p = 0.86) between treatment groups. Abeta measures were not associated with cognitive change. This double-blind randomized controlled trial of vitamin therapy demonstrates a strong correlation between serum tHcy and plasma Abeta40 concentrations in subjects with ischemic stroke. Treatment with high dose vitamins does not, however, influence plasma levels of Abeta, despite their effect on lowering tHcy. Our results suggest that although tHcy is associated with plasma Abeta40, they may be regulated by independent mechanisms.

Peripheral Abeta subspecies as risk biomarkers of Alzheimer's disease.

Plasma Abeta42 and Abeta40 levels are putative biomarkers for Alzheimer's disease (AD), but their significance and predictive value have been inconclusive. In AD transgenic models, plasma and cerebrospinal fluid levels of Abeta42 and Abeta40 increase with age but subsequently decrease when Abeta begins to accumulate in brain and with the onset of cognitive impairment. To determine the predictive value of Abeta levels in elderly populations, we investigated how plasma Abeta42, Abeta40, and a protofibrillar subspecies of Abeta42 changed over time and with the onset of cognitive impairment or AD. In a cohort of 1,125 elderly persons without dementia, 104 (9.2%) of the participants developed AD over 4.6 years of follow-up. Higher plasma Abeta42 levels at the onset of the study were associated with a threefold increased risk of AD. However, conversion to AD was accompanied by a significant decline in plasma Abeta42, a decreased Abeta42/Abeta40 ratio and, with the onset of cognitive impairment, decreased protofibrillar Abeta42 levels. Our results suggest individuals with elevated plasma Abeta42 are at increased risk of AD and that with the onset of disease, the decline in some forms of Abeta may reflect compartmentalization of Abeta peptides in the brain.

Maximizing the Potential of Plasma Amyloid-Beta as a Diagnostic Biomarker for Alzheimer’s Disease

Amyloid plaques are composed primarily of amyloid-beta (Abeta) peptides derived from proteolytic cleavage of amyloid precursor protein (APP) and are considered to play a pivotal role in Alzheimer's disease (AD) pathogenesis. Presently, AD is diagnosed after the onset of clinical manifestations. With the arrival of novel therapeutic agents for treatment of AD, there is an urgent need for biomarkers to detect early stages of AD. Measurement of plasma Abeta has been suggested as an inexpensive and non-invasive tool to diagnose AD and to monitor Abeta modifying therapies. However, the majority of cross-sectional studies on plasma Abeta levels in humans have not shown differences between individuals with AD compared to controls. Similarly, cross-sectional studies of mouse plasma Abeta have yielded inconsistent trends in different mouse models. However, longitudinal studies appear to be more promising in humans. Recently, efforts to modify plasma Abeta levels using modulators have shown some promise. In this review, we will summarize the present data on plasma Abeta in humans and mouse models of AD. We will discuss the potential of modulators of Abeta levels in plasma, including antibodies and insulin, and the challenges associated with measuring plasma Abeta. Modulators of plasma Abeta may provide an important tool to optimize plasma Abeta levels and may improve the diagnostic potential of this approach.

Luteinizing Hormone Levels Are Positively Correlated with Plasma Amyloid-β Protein Levels in Elderly Men

Dysregulation of the hypothalamic pituitary gonadal (HPG) axis during aging has been associated with increased risk of cognitive decline and developing dementia. Compared to controls, men with Alzheimer's disease (AD) have been shown to have lower serum testosterone levels and higher serum luteinizing hormone (LH) levels. As serum free testosterone concentration is negatively correlated with LH in older men, the independent contributions of these hormones to the pathogenesis of AD warrants further clarification. To explore this notion, we measured plasma amyloid-beta (Abeta), serum testosterone, serum LH and other biochemical parameters in 40 cognitively normal elderly men. Multiple linear regression analysis revealed that serum LH concentration is the only parameter that significantly correlates with plasma Abeta levels in these men (r=0.5, p=0.041). These results suggest that increased serum LH concentration, rather than lower serum free testosterone, is associated with the accumulation of Abeta in plasma. Larger, longitudinal human studies are needed to determine the significance of LH in the pathogenesis of AD.

Is Plasma Amyloid-&amp;#946; a Reliable Biomarker for Alzheimers Disease?

Over the past decade, a tremendous amount of consistent data have accumulated showing reduced levels of the 42 amino acid isoform of amyloid-beta (Abeta(42)) in cerebrospinal fluid (CSF) from patients with mature as well as incipient Alzheimer's disease (AD). However, as CSF analyses necessitate a spinal tap, which some consider hard to implement in the clinical routine and in clinical trials, there is a strong interest in the possible association of Abeta levels in plasma with AD. This review provides an update on the current status of research on plasma Abeta as a biomarker for AD in the context of recent patents in the field.

Plasma biomarkers of Alzheimer's disease

The importance of biomarkers of Alzheimer's disease is increasing. The present review aims to offer a general view of plasma biomarkers of Alzheimer's disease and to discuss their relevance and limitations. The broad overlap in the plasma amyloid beta protein (Abeta) levels between patients with Alzheimer's disease and control individuals indicates that the plasma Abeta level cannot differentiate cases of sporadic Alzheimer's disease from control cases. Although the significance of Abeta for diagnosing Alzheimer's disease is controversial, high plasma concentrations of Abeta40 and low plasma concentrations of Abeta42 indicate an increased risk of dementia. The usefulness of biomarkers in cerebrospinal fluid has been shown by numerous studies; this test is not commonly used, however, and blood biomarkers are therefore preferred. Increasing evidence shows that the plasma Abeta concentration may be a premorbid marker for the risk of Alzheimer's disease. It may be used for therapeutic monitoring, diagnosis of Abeta deposition in the brain, and also as a surrogate genetic marker to identify novel genetic determinants of Alzheimer's disease. A potential role of plasma Abeta concentration as a marker of incipient dementia warrants further investigation.

Plasma β Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men

Beta amyloid (Abeta) protein accumulates in the brains of individuals with Alzheimer disease (AD) and is detectable in cerebrospinal fluid and plasma. To examine plasma levels of Abeta peptides Abeta(40) and Abeta(42) as predictors of incident AD and other types of dementia. Prospective, population-based cohort study. The Uppsala Longitudinal Study of Adult Men. Plasma Abeta(40) and Abeta(42) levels were analyzed as predictors of incident AD in 1045 men at age 70 years and 680 men at age 77 years using Cox proportional hazards analyses. Alzheimer disease and other types of dementia were diagnosed by standardized screening, clinical evaluation, and medical record review. Hazard ratios of AD (primary outcome) and vascular dementia or other dementia (secondary outcomes) according to baseline levels of plasma Abeta(40) and Abeta(42). From the age of 77 years at baseline, 46 individuals developed AD at follow-up (median, 5.3 years). A low plasma Abeta(40) level at age 77 years was associated with higher incidence of AD. The multivariate-adjusted hazard ratio was 4.87 (95% confidence interval, 1.63-14.6) for the lowest Abeta(40) tertile compared with the highest tertile. On follow-up from age 70 years at baseline (median, 11.2 years), 82 individuals developed AD. Plasma Abeta(40) and Abeta(42) levels measured at age 70 years were not significantly associated with incident AD. Low plasma Abeta(40) levels predicted incident AD in elderly men independently of potential confounders. Plasma Abeta(42) levels were not significantly associated with AD incidence. The clinical value of Abeta measurement in plasma remains to be established in future studies.

Deglycosylated anti‐amyloid beta antibodies reduce microglial phagocytosis and cytokine production while retaining the capacity to induce amyloid beta sequestration

Accumulation of amyloid beta (Abeta) is a pathological hallmark of Alzheimer's disease, and lowering Abeta is a promising therapeutic approach. Intact anti-Abeta antibodies reduce brain Abeta through two pathways: enhanced microglial phagocytosis and Abeta transfer from the brain to the periphery (Abeta sequestration). While activation of microglia, which is essential for microglial phagocytosis, is necessarily accompanied by undesired neuroinflammatory events, the capacity for sequestration does not seem to be linked to such effects. We and other groups have found that simple Abeta binding agents are sufficient to reduce brain Abeta through the sequestration pathway. In this study, we aimed to eliminate potentially deleterious immune activation from antibodies without affecting the ability to induce sequestration. The glycan portion of immunoglobulin is critically involved in interactions with immune effectors including the Fc receptor and complement c1q; deglycosylation eliminates these interactions, while antigen (Abeta)-binding affinity is maintained. In this study, we investigated whether deglycosylated anti-Abeta antibodies reduce microglial phagocytosis and neuroinflammation without altering the capacity to induce Abeta sequestration. Deglycosylated antibodies maintained Abeta binding affinity. Deglycosylated antibodies did not enhance Abeta phagocytosis or cytokine release in primary cultured microglia, whereas intact antibodies did so significantly. Intravenous injection of deglycosylated antibodies elevated plasma Abeta levels and induced Abeta sequestration to a similar or greater degree compared with intact antibodies in an Alzheimer's transgenic mouse model without or with Abeta plaque pathology. We conclude that deglycosylated antibodies effectively induced Abeta sequestration without provoking neuroinflammation; thus, these deglycosylated antibodies may be optimal for sequestration therapy for Alzheimer's disease.

The normal equilibrium between CSF and plasma amyloid beta levels is disrupted in Alzheimer's disease

Amyloid-beta (Abeta) with 40 (Abeta40) and 42 (Abeta42) amino acids, the main components of amyloid plaques in the Alzheimer's disease (AD) brain, can be measured in human cerebrospinal fluid (CSF) and plasma. Whereas CSF Abeta42 is decreased in AD, some studies have reported changed plasma Abeta levels in AD and in subjects with mild cognitive impairment (MCI). To this date it is unclear if and how CSF and plasma levels of Abeta correlate with each other in healthy individuals, albeit earlier studies on AD patients found no correlation between CSF and plasma Abeta. We have measured Abeta40 and Abeta42 in paired CSF and plasma samples from patients with AD (n=39), MCI (n=29) and healthy control subjects (n=18). We observed a clear correlation between CSF and plasma levels for both Abeta40 and Abeta42 in healthy individuals, whereas no such correlation could be seen for AD or MCI cases. Similarly to other studies we also found low levels of Abeta42 in AD CSF, whereas there were no significant differences in plasma Abeta levels between the diagnostic groups. Our findings suggest that the normal equilibrium between CSF and plasma Abeta may be disrupted with the initiation of amyloid deposition in the brain.