Peripheral Aβ Research Articles

Identification of Spinal Circuits Transmitting and Gating Mechanical Pain

Pain information processing in the spinal cord has been postulated to rely on nociceptive transmission (T) neurons receiving inputs from nociceptors and Aβ mechanoreceptors, with Aβ inputs gated through feed-forward activation of spinal inhibitory neurons (INs). Here, we used intersectional genetic manipulations to identify these critical components of pain transduction. Marking and ablating six populations of spinal excitatory and inhibitory neurons, coupled with behavioral and electrophysiological analysis, showed that excitatory neurons expressing somatostatin (SOM) include T-type cells, whose ablation causes loss of mechanical pain. Inhibitory neurons marked by the expression of dynorphin (Dyn) represent INs, which are necessary to gate Aβ fibers from activating SOM(+) neurons to evoke pain. Therefore, peripheral mechanical nociceptors and Aβ mechanoreceptors, together with spinal SOM(+) excitatory and Dyn(+) inhibitory neurons, form a microcircuit that transmits and gates mechanical pain. PAPERCLIP:

Amyloid-β efflux from the central nervous system into the plasma.

The aim of this study was to measure the flux of amyloid-β (Aβ) across the human cerebral capillary bed to determine whether transport into the blood is a significant mechanism of clearance for Aβ produced in the central nervous system (CNS). Time-matched blood samples were simultaneously collected from a cerebral vein (including the sigmoid sinus, inferior petrosal sinus, and the internal jugular vein), femoral vein, and radial artery of patients undergoing inferior petrosal sinus sampling. For each plasma sample, Aβ concentration was assessed by 3 assays, and the venous to arterial Aβ concentration ratios were determined. Aβ concentration was increased by ∼7.5% in venous blood leaving the CNS capillary bed compared to arterial blood, indicating efflux from the CNS into the peripheral blood (p < 0.0001). There was no difference in peripheral venous Aβ concentration compared to arterial blood concentration. Our results are consistent with clearance of CNS-derived Aβ into the venous blood supply with no increase from a peripheral capillary bed. Modeling these results suggests that direct transport of Aβ across the blood-brain barrier accounts for ∼25% of Aβ clearance, and reabsorption of cerebrospinal fluid Aβ accounts for ∼25% of the total CNS Aβ clearance in humans. Ann Neurol 2014;76:837-844.

Sleep deficits in mild cognitive impairment are related to increased levels of plasma amyloid-β and cortical thinning

Evidence suggests that amyloid-beta (Aβ) depositions parallel sleep deficits in Alzheimer’s disease (AD). However, it remains unknown whether impaired sleep and changes in plasma Aβ levels are related in amnestic mild cognitive impairment (aMCI) subjects, and whether both markers are further associated with cortical thinning in canonical AD regions. To jointly address this issue, we investigated relationships between changes in physiological sleep and plasma Aβ concentrations in 21 healthy old (HO) adults and 21 aMCI subjects, and further assessed whether these two factors were associated with cortical loss in each group. aMCI, but not HO subjects, showed significant relationships between disrupted slow-wave sleep (SWS) and increased plasma levels of Aβ42. We also found that shortened rapid-eye movement (REM) sleep in aMCI correlated with thinning of the posterior cingulate, precuneus, and postcentral gyrus; whereas higher levels of Aβ40 and Aβ42 accounted for grey matter (GM) loss of posterior cingulate and entorhinal cortex, respectively. These results support preliminary relationships between Aβ burden and altered sleep physiology observed in animal models of AD amyloidosis, and provide precise cortical correlates of these changes in older adults with aMCI. Taken together, these findings open new research avenues on the combined role of sleep, peripheral Aβ levels and cortical integrity in tracking the progression from normal aging to early neurodegeneration.

Clearance of amyloid-beta in Alzheimer's disease: shifting the action site from center to periphery.

Amyloid-beta (Aβ) is suggested to play a causal role in the pathogenesis of Alzheimer's disease (AD). Immunotherapies are among the most promising Aβ-targeting therapeutic strategies for AD. But, to date, all clinical trials of this modality have not been successful including Aβ vaccination (AN1792), anti-Aβ antibodies (bapineuzumab, solanezumab and ponezumab), and intravenous immunoglobulin (IVIG). We propose that one reason for the failures of these clinical trials may be the adverse effects of targeting the central clearance of amyloid plaques. The potential adverse effects include enhanced neurotoxicity related to Aβ oligomerization from plaques, neuroinflammation related to opsonized Aβ phagocytosis, autoimmunity related to cross-binding of antibodies to amyloid precursor protein (APP) on the neuron membrane, and antibody-mediated vascular and neuroskeletal damage. Overall, the majority of the adverse effects seen in clinical trials were associated with the entry of antibodies into the brain. Finally, we propose that peripheral Aβ clearance would be effective and safe for future Aβ-targeting therapies.

Mathematical Model of Nerve Fiber Activation During Low Back Peripheral Nerve Field Stimulation: Analysis of Electrode Implant Depth

The lower back is the most common location of pain experienced by one-fifth of the European population reporting chronic pain. A peripheral nerve field stimulation system, which involves electrodes implanted subcutaneously in the painful area, has been shown to be efficacious for low back pain. Moreover, the predominant analgesic mechanism of action is thought to be via activation of peripheral Aβ fibers. Unfortunately, electrical stimulation also might coactivate Aδ fibers, causing pain or unpleasantness itself. The aim of this study was to investigate at which implant depth Aβ-fiber stimulation is maximized, and Aδ-fiber minimized, which in turn should lead to therapy optimization. A finite element model was used to estimate the electrical potential generated by a bipolar single-lead electrode implanted in the subcutaneous adipose tissue at depths of 5 mm to 30 mm below the skin surface. The model includes low back tissue; the epidermis, dermis, adipose, and muscle layers, and nerve fibers, which were programmed to branch randomly in the model in a fiber type-specific manner. Likewise, activation thresholds were specific to Aβ- and Aδ-fiber types and were estimated using a passive cable model. The stimulus-response functions showed that the skin area covered by Aβ-fiber activation was larger than the area covered by Aδ-fiber activation at all depths and all intensities. The skin area covered by Aδ-fiber activation was largest when the electrode was modeled to have a superficial location (5 mm below the skin surface), while the skin area covered by Aβ-fiber activation was largest at lower depths. The present mathematical model predicts an optimal implantation depth of 10 to 15 mm below the skin surface to achieve activation of the greatest area of Aβ fibers and the smallest area of Aδ fibers. This finding may act as a guide for peripheral nerve field stimulation implant depth to treat low back pain.

Immobilized amyloid Aβ peptides support platelet adhesion and activation

Accumulation of amyloidogenic Aβ peptides in the brain contributes to the onset of Alzheimer disease. Aβ peptide deposits are also present in blood vessel walls, mainly deriving from circulating platelets. However, their effect on platelet function is unclear. We demonstrate that immobilized Aβ peptides induce platelet adhesion and spreading through metalloproteinase-sensitive surface receptors. Aβ peptides also fasten platelet spreading on collagen, and support the time- and ADP-dependent activation of adherent platelets, leading to stimulation of several signalling proteins. Our results indicate a potential role for peripheral Aβ peptides in promoting platelet adhesion and activation in the initiation of thrombus formation.

Modest reductions in BACE1 activity significantly reduce beta-amyloid plaque load and neuroinflammation in a mouse model of Alzheimer's disease

Inhibiting the amyloidogenic processing of the amyloid precursor protein (APP) by blocking the activity of the β-site APP cleavage enzyme (BACE) has been extensively pursued as a therapeutic strategy for Alzheimer's disease (AD). Indeed, brief treatment with high doses of anti-BACE1 antibodies effectively reduced peripheral and central Aβ production in wild-type mice and nonhuman primates (Atwal et al., STM 2011), suggesting a potential therapeutic role for this antibody. However, it is still unclear what level of Aβ reduction could translate to a therapeutically meaningful impact on the progression of disease pathology if treatment were continued chronically. Therefore, to test the effectiveness of the anti-BACE1 antibodies for reducing/preventing A β plaque deposition and associated pathology, we treated transgenic mice expressing London mutant (V717I) human APP (hAPPlon) for four months starting at an age prior to the onset of plaque deposition. Female transgenic hAPPlon mice or non-transgenic littermate controls received either short-term treatment (3 IP injections, each separated by 4 days), with control antibody or anti-BACE1 antibodies (30mg/kg, 100mg/kg) starting at 2–3 months-of-age, or chronic treatment (weekly IP injections for 16 weeks) of a control antibody or anti-BACE1 antibody (100mg/kg), starting at 10.5 months-of-age. Serum, plasma and brain tissue was collected for PK/PD and pathology analysis. We found that short-term anti-BACE1 treatment (100mg/kg) modestly reduced guanidine-extracted total brain A β 40 and A β 42 levels by 17% and 31%, respectively, compared with control-treated hAPPlon mice when measured by ELISA. Chronic anti-BACE1 treatment significantly reduced A β plaques by ∼50% throughout the brain, compared with control-treated hAPPlon mice. This was associated with a reduction in total brain A β 40 and A β 42 levels by 73% and 55%, respectively. Plaque-associated neuroinflammation, as measured by microglia and astrocyte activation, was also significantly reduced. Modest but chronic inhibition of BACE1 activity with high affinity anti-BACE1 antibodies can significantly reduce A β plaque deposition and associated pathology in a mouse model of AD. This suggests that partial inhibition of BACE1 could be an effective therapeutic strategy in human AD patients as well.

Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease

Immunotherapy against amyloid-β(Aβ) may improve rodent cognitive function by reducing amyloid neuropathology and is being validated in clinical trials with positive preliminary results. However, for a complete understanding of the direct and long-term immunization responses in the aged patient, and also to avoid significant side effects, several key aspects remain to be clarified. Thus, to investigate brain Aβ clearance and Th2 responses in the elderly, and the reverse inflammatory events not found in the immunized rodent, better Alzheimer's disease (AD) models are required. In the aged familiar canine with a Cognitive Dysfunction Syndrome (CDS) we describe the rapid effectiveness and the full safety profile of a new active vaccine candidate for human AD prevention and treatment. In these aged animals, besidesa weak immune system, the antibody response activated a coordinated central and peripheral Aβ clearance, that rapidly improved their cognitive function in absence of any side effects. Our results also confirm the interest to use familiar dogs to develop innovative and reliable therapies for AD.

Enhanced proteolytic clearance of plasma Aβ by peripherally administered neprilysin does not result in reduced levels of brain Aβ in mice.

Accumulation of β-amyloid (Aβ) in the brain is believed to contribute to the pathology of Alzheimer's Disease (AD). Aβ levels are controlled by the production of Aβ from amyloid precursor protein, degradation by proteases, and peripheral clearance. In this study we sought to determine whether enhancing clearance of plasma Aβ with a peripherally administered Aβ-degrading protease would reduce brain Aβ levels through a peripheral sink. Neprilysin (NEP) is a zinc-dependent metalloprotease that is one of the key Aβ-degrading enzymes in the brain. We developed a NEP fusion protein with in vitro degradation of Aβ and a 10 day plasma half-life in mouse. Intravenous administration of NEP to wild-type and APP23 transgenic mice resulted in dose-dependent clearance of plasma Aβ. However, this did not correspond to reduced levels of soluble brain Aβ with treatment up to 5 weeks in WT mice or formic acid-extractable brain Aβ with 3 month treatment in aged APP23. In contrast, intracranial injection of NEP resulted in an acute decrease in soluble brain Aβ. We found no change in amyloid precursor protein gene expression in mice treated with intravenous NEP, suggesting that the lack of effects in the brain following this route of administration was not caused by compensatory upregulation of Aβ production. Taken together, these results suggest a lack of a robust peripheral Aβ efflux sink through which brain amyloid burdens can be therapeutically reduced.

CCL2 affects β-amyloidosis and progressive neurocognitive dysfunction in a mouse model of Alzheimer's disease

Neuroinflammation affects the pathobiology of Alzheimer's disease (AD). Notably, β-amyloid (Aβ) deposition induces microglial activation and the subsequent production of proinflammatory neurotoxic factors. In maintaining brain homeostasis, microglial plasticity also enables phenotypic transition between toxic and trophic activation states. One important control for such cell activation is through the CC-chemokine ligand 2 (CCL2) and its receptor, the CC-chemokine receptor 2. Both affect microglia and peripheral macrophage immune responses and for the latter, cell ingress across the blood–brain barrier. However, how CCL2-CC-chemokine receptor 2 signaling contributes to AD pathogenesis is not well understood. To this end, we now report that CCL2 deficiency influences behavioral abnormalities and disease progression in Aβ precursor protein/presenilin-1 double-transgenic mice. Here, increased cortical and hippocampal Aβ deposition is coincident with the formulation of Aβ oligomers. Deficits in peripheral Aβ clearance and in scavenger, neuroprogenitor, and microglial cell functions are linked to deficient Aβ uptake. All serve to accelerate memory dysfunction. Taken together, these data support a role of CCL2 in innate immune functions relevant to AD pathogenesis.

Muscle-Directed Anti-Aβ Single-Chain Antibody Delivery via AAV1 Reduces Cerebral Aβ Load in an Alzheimer’s Disease Mouse Model

We previously reported that anti-amyloid-beta (Aβ) single-chain antibody (scFv59) brain delivery via recombinant adeno-associated virus (rAAV) was effective in reducing cerebral Aβ load in an Alzheimer's disease (AD) mouse model without inducing inflammation. Here, we investigated the prophylactic effects and mechanism of a muscle-directed gene therapy modality in an AD mouse model. We injected rAAV serotype 1 encoding scFv59 into the right thigh muscles of 3-month-old mice. Nine months later, high levels of scFv59 expression were confirmed in the thigh muscles by both immunoblotting and immunohistochemistry. As controls, model mice were similarly injected with rAAV1 encoding antihuman immunodeficiency virus Gag antibody (scFvGag). AAV1-mediated scFv59 gene delivery was effective in decreasing Aβ deposits in the brain. Compared with the scFvGag group, levels of Aβ in cerebrospinal fluid (CSF) decreased significantly while Aβ in serum tended to increase in the scFv59 group. AAV1-mediated scFv59 gene delivery may alter the equilibrium of Aβ between the blood and brain, resulting in an increased efflux of Aβ from the brain owing to antibody-mediated sequestration/clearance of peripheral Aβ. Our results suggest that muscle-directed scFv59 delivery via rAAV1 may be a prophylactic option for AD and that levels of CSF Aβ may be used to evaluate the efficacy of anti-Aβ immunotherapy.

Immunotherapy for Alzheimer disease—the challenge of adverse effects

Amyloid-β (Aβ) plays a crucial part in the pathogenesis of Alzheimer disease (AD), making this peptide an attractive therapeutic target. However, clearance of brain Aβ in clinical trials of Aβ-specific antibodies did not improve cognition in patients with AD, leading to reassessment of the current therapeutic strategies. Moreover, current immunotherapies are associated with autoimmunity-related adverse effects, and mobilization of neurotoxic insoluble Aβ-oligomers. Despite the fact that antibodies to the N-terminal domain of Aβ can promote Aβ production, immunotherapies in ongoing clinical trials predominantly target this peptide region. Here, we address the challenges of adverse effects of immunotherapy for AD. We discuss available evidence regarding the mechanisms of both endogenous and exogenous Aβ-specific antibodies, with a view to developing optimal immunotherapy based on peripheral Aβ clearance, targeting of the toxic domain of Aβ, and improvement of antibody specificity. Such strategies should help to make immunotherapy a safe and efficacious disease-modifying treatment option for AD.

P1‐249: Role of BACE1 and BACE2 in the production of endogenous mouse Aß

The imbalance between Aβ production and/or clearance is hypothesized to be the major contributor to pathogenesis in Alzheimer's disease (AD). Inhibiting the sequential proteolytic cleavage of amyloid precursor protein (APP) by β- or γ-secretase blockade has been extensively pursued as a therapeutic strategy for AD treatment. The β-site APP cleavage enzyme (BACE) remains a popular target for small molecule inhibitors and antibodies because of its rate-limiting role in Aβ production. Targeting BACE1, versus its close homolog BACE2, is favored because BACE1 is highly expressed in neurons of the brain, whereas BACE2 is not. Although much is known about the role of BACE1 and BACE2 in processing human APP in in vitro and in vivo over-expression systems, less is known about their role in processing endogenous mouse APP in the brain and periphery. To determine the contribution of BACE1 and BACE2 to endogenous Aβ production in the brain and periphery, we measured brain and plasma Aβ40 levels by ELISA from BACE1ko, BACE2ko, and BACE1/2 double ko mice. Endogenous Aβ40 levels were measured in wild-type or BACE1ko mice to determine the selectivity of anti-BACE1 antibodies and small molecules against BACE1. In this study, we demonstrated that BACE1 contributes to ∼90% of endogenous brain and 50-60% of plasma Aβ40 production, whereas BACE2 does not contribute to either brain or plasma Aβ40 production. APPko mice had no detectable Aβ40 levels, demonstrating the specificity of the assay. Transient handling-induced increases in peripheral Aβ40 are mediated by BACE1, not BACE2. Anti-BACE1 antibodies are selective in inhibiting BACE1 activity, since no further reductions in Aβ40 levels were observed in BACE1 ko mice. BACE1 is the major β-secretase involved in the production of endogenous mouse Aβ in the brain and periphery, whereas BACE2 has little to no role. The remaining peripheral Aβ production in BACE1/2 ko mice suggests that there may be additional β-secretases yet to be identified.

Potential therapeutic system for Alzheimer’s disease: removal of blood Aβs by hemodialzyers and its effect on the cognitive functions of renal-failure patients

The pathological changes of Alzheimer's disease include the deposition of amyloid β protein (Aβ) as senile plaques in the brain. We hypothesized that the rapid removal of Aβs from the blood may act as a peripheral Aβ drainage sink from the brain. In this study, the plasma Aβ concentrations and the cognitive functions were investigated for in 57 patients on hemodailysis (69.4 ± 3.8 years), 26 renal-failure patients without hemodialysis (66.6 ± 14.7 years), and 17 age-matched healthy controls (66.6 ± 4.1 years). The concentrations of plasma Aβs increased along with the decline of renal functions. Moreover, the renal-failure patients without hemodialysis and with poorer renal functions showed lower cognitive functions. The plasma concentrations of Aβ(1-42) correlated with serum creatinine (P < 0.001) and Mini-Mental-State Examination scores (P = 0.017). The dialyzers effectively removed Aβs in the blood during hemodialysis sessions. The plasma Aβ concentrations showed steady or slightly decreasing along with duration of hemodialysis. The total amount of Aβs removed during a hemodialysis session was calculated to be comparable to the Aβs dissolved in the blood and the cerebrospinal fluid. The MMSE scores of the hemodialysis patients showed no clear decrease in longer hemodialysis duration. Therefore, the therapeutic approach for Alzheimer's disease by removing Aβs from the blood is worthy of further investigation, including whether or not Aβs in the brain decrease.

Characterization of Insulin Degrading Enzyme and Other Amyloid-β Degrading Proteases in Human Serum: A Role in Alzheimer's Disease?

Sporadic Alzheimer's disease (AD) patients have low amyloid-β peptide (Aβ) clearance in the central nervous system. The peripheral Aβ clearance may also be important but its role in AD remains unclear. We aimed to study the Aβ degrading proteases including insulin degrading enzyme (IDE), angiotensin converting enzyme (ACE) and others in blood. Using the fluorogenic substrate V (a substrate of IDE and other metalloproteases), we showed that human serum degraded the substrate V, and the activity was inhibited by adding increasing dose of Aβ. The existence of IDE activity was demonstrated by the inhibition of insulin, amylin, or EDTA, and further confirmed by immunocapture of IDE using monoclonal antibodies. The involvement of ACE was indicated by the ability of the ACE inhibitor, lisinopril, to inhibit the substrate V degradation. To test the variations of substrate V degradation in humans, we used serum samples from a homebound elderly population with cognitive diagnoses. Compared with the elderly who had normal cognition, those with probable AD and amnestic mild cognitive impairment (amnestic MCI) had lower peptidase activities. Probable AD or amnestic MCI as an outcome remained negatively associated with serum substrate V degradation activity after adjusting for the confounders. The elderly with probable AD had lower serum substrate V degradation activity compared with those who had vascular dementia. The blood proteases mediating Aβ degradation may be important for the AD pathogenesis. More studies are needed to specify each Aβ degrading protease in blood as a useful biomarker and a possible treatment target for AD.

Genetics of Alzheimer's disease: new evidences for an old hypothesis?

Alzheimer's disease (AD) is the prime cause of dementia and presents a strong genetic predisposition (60-80% of the attributable risk). In addition to APOE, a major recognized genetic determinant of AD, systematic, high-throughput genomic approaches have recently allowed the characterization of four new genetic determinants: CLU, CR1, PICALM and BIN1. Even if the complete picture of AD genetics is still not fully understood, the characterization of these new AD genetic determinants is probably going to strongly modify our perception of the pathophysiological process involved in AD. The new AD genetic landscape suggests that the common and late-onset forms of the disease are associated with a defect in peripheral Aβ peptide clearance, implying that the amyloid cascade hypothesis could be relevant not only in the AD monogenic forms.

Reduction of Alzheimer’s Disease Amyloid-β in Plasma by Hemodialysis and Its Relation to Cognitive Functions

Background/Aims: Rapid removal of plasma amyloid-β (Aβ) by blood purification may serve as a peripheral Aβ sink from the brain for Alzheimer’s disease therapy. We investigated the reduction of plasma Aβ during hemodialysis and cognitive states. Methods: Aβ concentrations and Mini-Mental State Examinations (MMSE) were investigated in 37 hemodialysis patients (68.9 ± 4.1 years). Results: The dialyzers effectively removed Aβ_1–40 and Aβ_1–42, 63.9 ± 14.4 and 51.6 ± 17.0% at 4 h dialysis, resulting in the reduction of Aβs in whole-body circulation by 51.1 ± 8.9 and 32.7 ± 12.0%, respectively. Although the plasma Aβs before dialysis (750.8 ± 171.3 pg/ml for Aβ_1–40) were higher than those reported for Alzheimer’s disease patients, the cognitive states of hemodialysis patients were relatively normal, especially of longer dialysis vintages. Conclusions: Dialyzers effectively reduced Aβs in whole-body circulation. Repeated rapid decrease of plasma Aβs might maintain cognitive state.

Piperazine sulfonamide BACE1 inhibitors: Design, synthesis, and in vivo characterization

With collaboration between chemistry, X-ray crystallography, and molecular modeling, we designed and synthesized a series of novel piperazine sulfonamide BACE1 inhibitors. Iterative exploration of the non-prime side and S2′ sub-pocket of the enzyme culminated in identification of an analog that potently lowers peripheral Aβ 40 in transgenic mice with a single subcutaneous dose.

Inhibition of Cortical Laser-Evoked Potentials by Transcutaneous Electrical Nerve Stimulation

Objectives. This study attempts to confirm the hypothesis that transcutaneous electrical stimulation (TENS) of peripheral Aβ fibers inhibits nociceptive processing, by quantifying the change of laser-evoked potential (LEP) components, using a 980-nm diode laser. Materials and Methods. Cutaneous heat stimuli were delivered to the dorsum of the right hand in 13 volunteers. LEPs and pain intensity ratings were recorded before, during, and after the use of TENS (110Hz) at the dorsolateral forearm. Area under the curve (AUC), LEP amplitudes (N2P2), and peak latencies (N2, P2) were calculated. The paired samples t-test was used for statistical analysis. Results. A significant reduction of LEP amplitudes and AUC was found during and after the use of TENS (p<0.05). After 10min of TENS this was associated with a clinically relevant decrease of pain intensity. Conclusions. Our data suggest that TENS inhibits nociceptive processing. Ten minutes of TENS exerts a clinically relevant pain reduction.

Serum β-Amyloid Correlates with Neuropsychological Impairment

ABSTRACT Aims: Evidence suggests a relationship between peripheral Aβ and AD. We hypothesized that higher levels of serum Aβ1–42 would be associated with memory impairment, thought to occur early in the disease, and rises in serum Aβ1–40, which occur later, would be associated with impairment in non-memory measures. Methods: Using a cross-sectional design, we examined the relationship of serum Aβ1–40, Aβ1–42, and the ratio of Aβ1–42/1–40 to neuropsychological measures in 40 cognitively normal controls, 13 MCI subjects, and 25 AD patients. Results: Serum Aβ1–42 and the ratio of Aβ1–42/1–40 were significantly higher in the MCI group compared to the controls. A significant relationship in the hypothesized direction (poorer scores associated with higher Aβ1–40 serum levels) was found between Aβ1–40 and measures of executive functions across the entire cohort of individuals tested and with measures of language and processing speed in the AD group. Regression analysis found that neuropsychological measures accounted for 26% of the variance in serum Aβ1–40, in the MCI/AD but not the controls. Furthermore that language and executive measures were significant predictors. Conclusions: Results provide preliminary data to partially support our hypotheses and suggest that changes in serum Aβ levels may be attributed to pathological changes within the brain.