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Objective Higher levels of physical activity (PA) reduce the risk of cognitive impairment, but the underlying mechanisms are unclear. Using longitudinal data from the Cardiovascular Health Study, we examined whether PA predicted plasma Aβ levels and risk for cognitive decline 9–13 years later. Methods Linear and logistic regressions (controlling for APOE status, age, gender, body mass index, cardiovascular disease, brain white matter lesions, and cystatin C levels) tested associations between PA, Aβ, and cognitive impairment in a sample of 149 cognitively normal older adults (mean age 83 years). Results More PA at baseline predicted lower levels of Aβ 9–13 years later. Higher Aβ levels at year 9 predicted greater risk for cognitive impairment at year 13. Levels of Aβ at year 9 mediated the relationship between PA and cognitive impairment. Interpretation Greater PA may reduce plasma levels of a neurotoxic peptide at an age when the risk for cognitive impairment is especially high.

Little is known whether cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) can predict both memory decline and associated longitudinal medial temporal lobe (MTL) gray matter (GM) reductions in cognitively healthy individuals. Fifty-seven normal elderly subjects received comprehensive evaluation at baseline and 2 years later. The baseline phosphorylated tau(231) (p-tau(231)), total tau, the amyloid beta (Aβ) Aβ42/Aβ40, t-tau/Aβ42 and p-tau(231)/Aβ42 ratios were examined as predictors of memory change and reductions in the global and MTL GM, determined from T1-weighted MRI. Twenty out of 57 participants experienced reduced memory performance at follow-up. The group with decreased memory performance showed higher baseline p-tau(231) (Z=-2.2, p=0.03), lower Aβ42/Aβ40 (t=-2.2 [55], p=0.04) and greater longitudinal MTL GM reductions (t([52])=-2.70, p=0.01). Higher baseline p-tau(231) was also associated with the absolute decrease in memory scores (rho=-0.30, p=0.02) and with longitudinal MTL GM reduction (F([2,52])=4.4, p=0.04, age corrected). Our results indicate that in normal individuals, elevated p-tau(231), a marker of neurofibrillary pathology is related to both a decrease in declarative memory and progressive atrophy of the MTL, suggesting its diagnostic potential in preclinical stage.

Objective: To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aβ in patients with mild cognitive impairment (MCI) and similarly aged controls. Methods: In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP nd ) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aβ levels measured in duplicate was analyzed. Results: Plasma Aβ42/Aβ40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aβ40 ( p = 0.3) and Aβ42 ( p = 0.06) levels did not differ between the 2 groups. PiB BP nd was increased in MCI compared to controls in the cingulate ( p = 0.02), parietal ( p = 0.02), and total brain ( p = 0.03), but not in prefrontal cortex ( p = 0.08) or parahippocampal gyrus ( p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aβ42/Aβ40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01 p ≤ 0.05). These associations between PiB binding and the Aβ42/Aβ40 ratio were strongest in PiB-positive subjects and within the MCI group. Conclusions: Though cross-sectional, the findings support the “sink” hypothesis that increased brain Aβ is accompanied by lower peripheral levels of Aβ, particularly the Aβ42/Aβ40 ratio in patients with MCI. The association between PiB binding and the plasma Aβ42/Aβ40 ratio suggests possible use of plasma Aβ combined with PiB binding as a risk biomarker with potential clinical application.

A variable poly-T polymorphism in the TOMM40 gene, which is in linkage disequilibrium with APOE, was recently implicated with increased risk and earlier onset age for late-onset Alzheimer's disease in APOE ε3 carriers. To elucidate potential neurobiological mechanisms underlying this association, we compared the effect of TOMM40 poly-T variants to the effect of APOE, an established LOAD-risk modulator, on cerebrospinal fluid (CSF) amyloid beta (Aβ) and tau levels, in cognitively intact elderly subjects. APOE ε4 carriers showed significant reductions in Aβ 1-42 levels compared to non-ε4 carriers, but no differences were detected across TOMM40 variants. Neither Aβ 1-40 nor tau levels were affected by APOE or TOMM40.

Epidemiology and imaging studies showed that cognitively normal (NL) individuals with a maternal history (MH) of late-onset Alzheimer's disease (LOAD) might be at increased risk for Alzheimer's disease (AD) compared with NL with a paternal history (PH) and NL with a negative family history of LOAD (NH). With a panel of cerebrospinal fluid (CSF) markers, this study examined whether NL MH showed evidence for AD pathology compared with PH and NH.Fifty-nine 40-80-year-old NL subjects were examined, including 23 MH and 14 PH whose parents had a clinician-certified diagnosis of LOAD and 22 NH. All subjects completed clinical neuropsychological examinations and a lumbar puncture to measure CSF levels of amyloid-beta (Aβ(40), Aβ(42), Aβ(42/40)), total and hyperphosphorylated tau (T-Tau and P-Tau(231); markers of axonal degeneration and neurofibrillary tangles, respectively), and F₂-isoprostanes (IsoP) (a marker of oxidative stress).Groups were comparable for demographic and neuropsychological measures. The MH subjects showed higher IsoP and reduced Aβ(42/40) CSF levels compared with NH and with PH (p values ≤ .05), whereas no differences were found between NH and PH. No group differences were found for P-Tau(231) and T-Tau. The IsoP and Aβ(42/40) levels were correlated only within the MH group (R² = .32, p = .005) and discriminated MH from the other subjects with 70% accuracy (relative risk = 3.7%, 95% confidence interval = 1.6-9.7, p.001). Results remained significant controlling for age, gender, education, and apolipoprotein E genotype.Adult children of LOAD-affected mothers express a pathobiological phenotype characterized by Aβ-associated oxidative stress consistent with AD, which might reflect increased risk for developing the disease.

Impaired glucose regulation is a defining characteristic of type 2 diabetes mellitus (T2DM) pathology and has been linked to increased risk of cognitive impairment and dementia. Although the benefits of aerobic exercise for physical health are well-documented, exercise effects on cognition have not been examined for older adults with poor glucose regulation associated with prediabetes and early T2DM. Using a randomized controlled design, twenty-eight adults (57–83 y old) meeting 2-h tolerance test criteria for glucose intolerance completed 6 months of aerobic exercise or stretching, which served as the control. The primary cognitive outcomes included measures of executive function (Trails B, Task Switching, Stroop, Self-ordered Pointing Test, and Verbal Fluency). Other outcomes included memory performance (Story Recall, List Learning), measures of cardiorespiratory fitness obtained via maximal-graded exercise treadmill test, glucose disposal during hyperinsulinemic-euglycemic clamp, body fat, and fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulin-like growth factor-1, amyloid-β (Aβ40 and Aβ42). Six months of aerobic exercise improved executive function (MANCOVA, p = 0.04), cardiorespiratory fitness (MANOVA, p = 0.03), and insulin sensitivity (p = 0.05). Across all subjects, 6-month changes in cardiorespiratory fitness and insulin sensitivity were positively correlated (p = 0.01). For Aβ42, plasma levels tended to decrease for the aerobic group relative to controls (p = 0.07). The results of our study using rigorous controlled methodology suggest a cognition-enhancing effect of aerobic exercise for older glucose intolerant adults. Although replication in a larger sample is needed, our findings potentially have important therapeutic implications for a growing number of adults at increased risk of cognitive decline.

While cerebrospinal fluid (CSF) biomarkers are of use in the prediction and diagnosis of Alzheimer’s disease our understanding of the background effects of age and the ApoE genotype is limited. Seventy-eight community-based normal volunteers (mean age 60 ± 10 years, range 36–86) were examined to determine the relationships between CSF measures of total tau (T-tau), hyperphosphorylated tau (P-tau 231), amyloid beta (Aβ42/Aβ40 ratio), and isoprostane (IP) with age and ApoE genotype. The results showed that age by ε4 genotype interactions were found for P-tau231 (β = 1.82; p < 0.05) and IP (β = 1.6; p < 0.05). T-tau CSF concentration increased with age. The increasing CSF concentrations of P-tau and IP in ε4 carriers suggest that early tauopathy and oxidative stress may be related to the increased risk for AD. The data also suggest that T-tau changes are more age dependent than Aβ changes. The evidence that P-tau231 and IP are the earliest markers for the neuronal damage related to AD awaits longitudinal study. © 2007 Elsevier Inc. All rights reserved.

Objectives—To longitudinally evaluate five cerebrospinal fluid (CSF) biomarkers in the transition from Mild Cognitive Impairment (MCI) to Alzheimer’s disease (AD) Methods—A baseline and 2-year follow-up clinical and CSF study of 86 subjects, including 22 MCI patients that declined to AD (MCI-AD), 43 MCI that did not deteriorate (MCI-MCI) and 21 controls (NL-NL). All subjects were studied for total and phosphorylated tau (T-tau, P-tau231), amyloid beta (Aβ) Aβ42/Aβ40 ratio, isoprostane (IP) as well as P-tau231/Aβ42/40 and T-tau/Aβ42/40 ratios. Results—At baseline and at follow-up MCI-AD showed higher levels P-tau231, T-tau, IP, Ptau231/Aβ42/40 and T-tau/Aβ42/40 ratios and lower Aβ42/Aβ40 than MCI-MCI or NL-NL. Baseline P-tau231 best predicted MCI-AD (80%, p

We examined whether cerebral metabolic rates for glucose (CMRglc) on 2-[(18)F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET) and cerebrospinal fluid (CSF) markers of Alzheimer's disease (AD) are altered in cognitively normal apolipoprotein E (ApoE) E4 carriers with subjective memory complaints (SMC).Twenty-eight middle-aged normal subjects (NL) were examined, including 13 E4 carriers (E4+; 6 with SMC [SMC+] and 7 without SMC [SMC-]) and 15 noncarriers (E4-; 7 SMC+ and 8 SMC-). Subjects received an FDG-PET scan and a lumbar puncture to measure CSF total (T-Tau) and hyperphosphorylated tau(231) (P-Tau), 40 and 42 amino acid forms of beta-amyloid (Abeta40 and Abeta42), and F(2)-isoprostane (IP).As compared with E4-, E4+ subjects showed decreased CMRglc in AD-related brain regions and associated higher CSF IP, P-Tau, T-Tau, and P-Tau/Abeta42 levels (p's.05). As compared with SMC-, SMC+ subjects showed reduced parietotemporal and parahippocampal gyrus (PHG) CMRglc. A significant ApoE by SMC status interaction was found, with the E4+/SMC+ showing the lowest PHG CMRglc and the highest CSF IP, P-Tau, and P-Tau/Abeta42 levels as compared with all other subgroups (p'sor = .05). The combination of CSF and CMRglc measures significantly improved the accuracy of either measures alone in discriminating ApoE groups (86% accuracy, odds ratio [OR] = 4.1, p.001) and E4+/SMC+ from all other subgroups (86% accuracy, OR = 3.7, p = .005). Parahippocampal gyrus CMRglc was the most accurate discriminator of SMC groups (75% accuracy, OR = 2.4, p.001).Normal E4 carriers with SMC show altered AD-related CSF and FDG-PET measures. Longitudinal studies are needed to assess whether these brain abnormalities foreshadow clinical decline.

Alzheimer disease (AD) is a neurodegenerative disease that affects cognition, behavior and function. The etiology of the disease is unknown, however, the Primary Risk Factors for AD are aging, and family history. Neurofibrillary tangles (NFT) and amyloid-bearing neuritic plaques in the limbic and cerebral cortices are the characteristic neuropathologic lesions in brains of patients with AD. The NFT is mainly composed of hyprephosphorylated tau, whereas the major component of the neuritic plaques is the amyloid beta (Abeta) protein. The clinical diagnosis of probable AD is based on history, physical examination, neuropsychological testing, laboratory studies and neuroimaging techniques. However, there is no specific laboratory marker to support the diagnosis of definite AD or monitoring the progression of the disease. Several biochemical markers related to neuropathology have been identified in cerebrospinal fluid (CSF). We describe the studies of CSF or blood levels of amyloid beta protein in patients with AD and age-matched nondemented controls. Due to the heterogeneity and complex nature of the disease, it is highly unlikely that that a single marker specific for AD will be found.

Obesity and overweight, well known risk factors for cardiovascular disease and type 2 diabetes, are now associated with Alzheimer's disease (AD). It remains to be determined if obesity and overweight contribute to the risk of developing AD through modulating levels of amyloid-beta (Abeta), a key molecule in AD pathogenesis. Thus, we investigated whether there were any associations between plasma Abeta levels and body mass index (BMI) or fat mass (FM) in a group of 18 healthy adults. A statistically significant correlation was found between BMI, FM, and plasma levels of Abeta42 (BMI r = 0.602, P = 0.008; FM r = 0.547, P = 0.019), the longer, more pathogenic form of Abeta, but not with plasma levels of the shorter, less pathogenic Abeta40. Although not significant, positive correlations between plasma levels of Abeta42 and levels of insulin and the inflammatory marker C-reactive protein (CRP), along with an inverse trend between plasma Abeta42 levels and levels of high density lipoprotein (HDL) were answered. These results suggest that proteins implicated in inflammation, cardiovascular disease and type 2 diabetes, which in turn are risk factors for AD, may contribute to the associations between BMI/FM and plasma Abeta42 levels. Longitudinal studies involving larger cohorts are required to determine if elevated body fat may predispose individuals to AD through increasing Abeta42 levels throughout early to late adulthood.

Objective: To compare proteins related to Alzheimer disease ( AD) in the frontal cortex and cerebellum of subjects with early-onset AD (EOAD) with or without presenilin 1 (PS1) mutations with sporadic late-onset AD ( LOAD) and nondemented control subjects. Methods: Immunohistochemistry, immunoblot analysis, and ELISA were used to detect and assess protein levels in brain. Results: In EOAD and to a lesser extent in LOAD, there was increased amyloid beta (Abeta) deposition (by immunohistochemistry), increased soluble Abeta (by immunoblot analysis), and specific increases in Abeta(40) and Abeta(42) ( by ELISA) in the frontal cortex and, in some cases, in the cerebellum. Surprisingly, immunoblot analysis revealed reduced levels of PS1 in many of the subjects with EOAD with or without PS1 mutations. In those PS1 mutation-bearing subjects with the highest Abeta, PS1 was barely, if at all, detectable. This decrease in PS1 was specific and not attributable solely to neuronal loss because amyloid precursor protein (APP) and the PS1-interacting protein beta-catenin levels were unchanged. Conclusions: This study shows that in the frontal cortex and cerebellum from Alzheimer disease patients harboring certain presenilin 1 mutations, high levels of amyloid beta are associated with low levels of presenilin 1. The study provides the premise for further investigation of mechanisms underlying the downregulation of presenilin 1, which may have considerable pathogenic and therapeutic relevance.

Background: Plasma amyloid β-peptide (Aβ) 40 and Aβ42 levels are increased in persons with mutations causing early-onset familial Alzheimer’s disease (AD). Plasma Aβ42 levels were also used to link microsatellite genetic markers to a putative AD genetic locus on chromosome 10 and were observed in patients with incipient sporadic AD. Methods: The authors measured plasma Aβ40 and Aβ42 levels using a sandwich ELISA after the initial examination of 530 individuals participating in an epidemiologic study of aging and dementia. Participants were examined at 18-month intervals, and plasma Aβ40 and Aβ42 levels were repeated in 307 subjects 3 years after baseline. Results: Compared with individuals who never developed AD, patients with AD at baseline and those who developed AD during the follow-up had significantly higher Aβ42, but not Aβ40, plasma levels. The risk of AD in the highest quartile of plasma Aβ42 was increased by more than twofold over that in the lowest quartile. The highest plasma Aβ42 levels were observed in patients with AD who died during the follow-up. Plasma Aβ42, but not Aβ40, levels decreased over time in patients with newly acquired AD. Conclusions: Plasma Aβ40 and Aβ42 increase with age and are strongly correlated with each other. Plasma Aβ40 and Aβ42 levels are elevated in some patients before and during the early stages of AD but decline thereafter. High plasma Aβ42 levels may also be associated with mortality in patients with AD.

Mutations in the gene encoding presenilin 1 (PS-1) account for 50% of early-onset familial Alzheimer’s disease (EOFAD) cases. In this study, we identified two missense mutations in the coding sequence of the presenilin (PS-1) gene in two EOFAD pedigrees. AD was confirmed in one pedigree by autopsy. Mutation analysis of PCR products amplified from genomic DNA templates showed two novel PS-1 mutations resulting in Gln222His and Tyr256Ser. The two novel mutations are located within predicted transmembrane domains five (TM-5) and six (TM-6), respectively, and are associated with very early ages of onset. The Tyr256Ser is associated with one of the youngest age of AD onset, 25 years, which is consistent with a drastic change in function of the altered PS-1 protein. A morphometric analysis of the cortical degenerative changes of the Tyr256Ser case, showed severe involvement of the primary motor cortex, which correlated well with the pyramidal changes, including tetraspasticity. Immunoblot analysis showed the Tyr256Ser case had the greatest expression of Aβ1–40 and Aβ1–42, which was confirmed by ELISA, compared to other PS-1 mutant FAD cases and age-matched controls and, thus, contributes to the severity of the disease pathology.

Rapid communication Biological markers for therapeutic trials in Alzheimer’s disease Proceedings of the biological markers working group; NIA initiative on neuroimaging in Alzheimer’s disease Richard A. Frank a,∗, Douglas Galasko b,1, Harald Hampel c,2, John Hardy d,3, Mony J. de Leon e,4, Pankaj D. Mehta f,5, Joseph Rogers g,6, Eric Siemers h,7, John Q. Trojanowski i,8 a Pharmacia Corporation, Mailstop 134, Peapack, NJ 07977, USA b Department of Neurosciences, UCSD, VA Medical Center, 3350 LaJolla Village Drive, SanDiego, CA 92161, USA c Department of Psychiatry, Alzheimer Memorial Center and Geriatric Psychiatry Branch, Ludwig-Maximilian University, Nussbaumstr. 7, 80336 Munich, Germany d Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Building 10, Room 6C103, MSC1589, Bethesda, MD 20892, USA e Department of Psychiatry, Center for Brain Health, NYU School of Medicine, Millhauser Wing HN400, 560 First Ave., New York, NY 10016, USA f Division of Immunology, Department of Developmental Neurobiology, Institute for Basic Research in Developmental Disabilities, 1050 Forest Hill Road, Staten Island, NY 10314, USA g Sun Health Research Institute, 10515 West Santa Fe Drive, Sun City, AZ 85351, USA h Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA i Department of Pathology and Laboratory Medicine, Institute on Aging, Alzheimer’s Disease Center, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, HUP, Maloney 3rd Floor, 36th and Spruce Streets, Philadelphia, PA 19104-4283, USA

Mutations in the amyloid precursor protein and presenilin 1 and 2 genes result in elevated plasma levels of the amyloid beta-peptide species terminating at amino acid residue 42 (A beta1-42). In a longitudinal study of unrelated elderly individuals, those who subsequently developed Alzheimer's disease had higher plasma levels of A beta1-42 at entry than did those who remained free of dementia. The results indicate that elevated plasma levels of the released A beta peptide A beta1-42 may be detected several years before the onset of symptoms, supporting that extracellular A beta1-42 plays an important role in the pathogenesis of late-onset Alzheimer's disease.

Objective: To test whether the concentrations of amyloid-β (Aβ)40, Aβ42, apolipoprotein E (apoE) and transthyretin in the CSF of normal individuals, are linked to three factors which modulate the risk of Alzheimer’s disease (AD): chronological age, gender, and the presence of the apoE4 allele. Methods and results: Proteins were measured by enzyme-linked immunosorbent assays except for transthyretin, which was assayed by radial immunodiffusion. The apoE phenotype was determined by isoelectric focusing. While the CSF levels of Aβ42, apoE, and transthyretin are reported to be reduced in AD, we found no relationship between age, gender, or apoE phenotype and the level of any of these proteins in the CSF of nondemented individuals. The concentration of Aβ40 was not modulated by gender or apoE phenotype, but did decline significantly with age. Conclusion: These results indicate that the changes observed in the CSF of AD patients are specific to the disease itself rather than the known risk factors.

The ideal biomarker for Alzheimer's disease (AD) should detect a fundamental feature of neuropathology and be validated in neuropathologically-confirmed cases: it should have a sensitivity >80% for detecting AD and a specificity of >80% for distinguishing other dementias: it should be reliable, reproducible non-invasive, simple to perform, and inexpensive. Recommended steps to establish a biomarker include confirmation by at least two independent studies conducted by qualified investigators with the results published in peer-reviewed journals. Our review of current candidate markers indicates that for suspected early-onset familial AD. it is appropriate to search for mutations in the presenilin 1, presenilin 2, and amyloid precursor protein genes. Individuals with these mutations typically have increased levels of the amyloid Aβ 42 peptide in plasma and decreased levels of APPs in cerebrospinal fluid. In late-onset and sporadic AD. these measures are not useful. but detecting an apolipoprotein E e4 allele can add confidence to the clinical diagnosis. Among the other proposed molecular and biochemical markers for sporadic AD. cerebrospinal fluid assays showing low levels of Aβ 42 and high levels of tau come closest to fulfilling criteria for a useful biomarker.

This report examines plasma amyloid β proteins Aβ40 and Aβ42 and apolipoprotein E (apoE) levels and their relationships with age in non-demented older adults with (N = 32) or without the apoE-e4 allele (N = 94). Aβ levels did not differ between the groups whereas the e4 allele was associated with a significant reduction in plasma apoE. In subjects with the e4 allele, increasing age was associated with significant reduction in plasma Aβ40. Subjects without the e4 allele showed a significant positive correlation between Aβ40 and Aβ42 levels. There was also a significant correlation between plasma Aβ40 and apoE levels in all subjects.

Objective: To evaluate the relations between PET Pittsburgh compound B (PiB-PET) binding (amyloid imaging) and plasma Aβ in patients with mild cognitive impairment (MCI) and similarly aged controls. Methods: In 20 patients with MCI and 19 cognitively intact controls (case-control study), PiB binding potential (BP nd ) was assessed in 4 regions, and total brain excluding cerebellum, referenced to cerebellar binding. The mean of plasma Aβ levels measured in duplicate was analyzed. Results: Plasma Aβ42/Aβ40 ratio was decreased in MCI compared to controls (mean 0.15 SD 0.04 vs mean 0.19 SD 0.07, p = 0.03) but Aβ40 ( p = 0.3) and Aβ42 ( p = 0.06) levels did not differ between the 2 groups. PiB BP nd was increased in MCI compared to controls in the cingulate ( p = 0.02), parietal ( p = 0.02), and total brain ( p = 0.03), but not in prefrontal cortex ( p = 0.08) or parahippocampal gyrus ( p = 0.07). Linear regression analyses adjusting for age, sex, and cognitive test scores showed that low Aβ42/Aβ40 ratio was associated with high cingulate, parietal, and total brain PiB binding (0.01 p ≤ 0.05). These associations between PiB binding and the Aβ42/Aβ40 ratio were strongest in PiB-positive subjects and within the MCI group. Conclusions: Though cross-sectional, the findings support the “sink” hypothesis that increased brain Aβ is accompanied by lower peripheral levels of Aβ, particularly the Aβ42/Aβ40 ratio in patients with MCI. The association between PiB binding and the plasma Aβ42/Aβ40 ratio suggests possible use of plasma Aβ combined with PiB binding as a risk biomarker with potential clinical application.

Plasma amyloid-β (Aβ) level could be useful as a non-invasive biomarker in Alzheimer's disease research. We compared a multiplex electrochemiluminescence detection method with a well established ELISA method for plasma Aβ quantification. Compared to the ELISA method, the electrochemiluminescence detection method demonstrates a statistically significant, but modest correlation. The reasons for this may include the differences in the affinities of antibodies, and purity and source of Aβ peptides used as standards. However, the advantages of electrochemiluminescence detection technology include short processing time and small sample volume. This comparison demonstrates the need for a further study in optimizing this system.

Objectives To examine the effects of aerobic exercise on cognition and other biomarkers associated with Alzheimer disease pathology for older adults with mild cognitive impairment, and assess the role of sex as a predictor of response. Design Six-month, randomized, controlled, clinical trial. Setting Veterans Affairs Puget Sound Health Care System clinical research unit. Participants Thirty-three adults (17 women) with amnestic mild cognitive impairment ranging in age from 55 to 85 years (mean age, 70 years). Intervention Participants were randomized either to a high-intensity aerobic exercise or stretching control group. The aerobic group exercised under the supervision of a fitness trainer at 75% to 85% of heart rate reserve for 45 to 60 min/d, 4 d/wk for 6 months. The control group carried out supervised stretching activities according to the same schedule but maintained their heart rate at or below 50% of their heart rate reserve. Before and after the study, glucometabolic and treadmill tests were performed and fat distribution was assessed using dual-energy x-ray absorptiometry. At baseline, month 3, and month 6, blood was collected for assay and cognitive tests were administered. Main Outcome Measures Performance measures on Symbol-Digit Modalities, Verbal Fluency, Stroop, Trails B, Task Switching, Story Recall, and List Learning. Fasting plasma levels of insulin, cortisol, brain-derived neurotrophic factor, insulinlike growth factor-I, and β-amyloids 40 and 42. Results Six months of high-intensity aerobic exercise had sex-specific effects on cognition, glucose metabolism, and hypothalamic-pituitary-adrenal axis and trophic activity despite comparable gains in cardiorespiratory fitness and body fat reduction. For women, aerobic exercise improved performance on multiple tests of executive function, increased glucose disposal during the metabolic clamp, and reduced fasting plasma levels of insulin, cortisol, and brain-derived neurotrophic factor. For men, aerobic exercise increased plasma levels of insulinlike growth factor I and had a favorable effect only on Trails B performance. Conclusions This study provides support, using rigorous controlled methodology, for a potent nonpharmacologic intervention that improves executive control processes for older women at high risk of cognitive decline. Moreover, our results suggest that a sex bias in cognitive response may relate to sex-based differences in glucometabolic and hypothalamic-pituitary-adrenal axis responses to aerobic exercise.

Alzheimer's disease (AD) is the major form of age-related dementia worldwide, accounting for more than two-thirds of all dementia cases. The disease is characterized by a progressive loss of cognitive and intellectual functioning (Gilman, 1997). A number of risk factors for AD have been identified. The prevalence of AD increases with age, diabetes, depression, family history of Parkinson's disease and following head injury or exposure to solvents (Jorm et al., 1991; van Duijn et al., 1991; Ott et al., 1995; Yoshitake et al., 1995; Devanand et al., 1996). Published research further suggests that low education levels are associated with increased prevalence of clinical AD (Gatz et al., 2001; Qiu et al., 2001; Ravaglia et al., 2002). Women also have a higher risk for developing the disease than men, with the risk being markedly increased following menopause (Sherwin, 2002; Sherwin 2003). Additionally, slightly more severe cognitive deficits have been reported in AD in women compared to men (Buckwalter et al., 1993, Henderson and Buckwalter, 1994). These epidemiological trends may be a consequence of reproductive hormonal changes. Specifically, menopause results in a marked diminution in gonadal estrogen production in women (see Sherwin, 2003, for a review). Estrogen plays a pivotal role in the maintenance and function of neuronal circuits in the brain and in resistance to neuronal damage (McEwen, 2001). The neuroprotective properties of estrogen are thought to be mediated at least in part by anti-amyloidogenic, anti-oxidative and ant-inflammatory mechanisms (reviewed in Barron et al., 2006a). However, limited and somewhat mixed data exist regarding the association between endogenous levels of estrogen and cognitive decline (Manly et al., 2000; Schupf et al., 2003). Based on some of our own findings, we here consider the factors that may be useful in predicting memory decline as a risk factor for Alzheimer's disease in older post-menopausal women.

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.

Identifying biomarkers of Alzheimer's disease (AD) risk will be critical to effective AD prevention. Levels of circulating amyloid-beta (Abeta) 40 and 42 may be candidate biomarkers. However, properties of plasma Abeta assays must be established. Using five different protocols, blinded samples were used to assess: intra-assay reproducibility; impact of EDTA vs. heparin anticoagulant tubes; and effect of time-to-blood processing. In addition, percent recovery of known Abeta concentrations in spiked samples was assessed. Median intra-assay coefficients of variation for the assay protocols ranged from 6-24% for Abeta(40), and 8-14% for Abeta(42). There were no systematic differences in reproducibility by collection method. Plasma concentrations of Abeta (particularly Abeta(42) appeared stable in whole blood kept in ice packs and processed as long as 24 hours after collection. Recovery of expected concentrations was modest, ranging from -24% to 44% recovery of Abeta(40), and 17% to 61% of Abeta(42). In conclusion, across five protocols, plasma Abeta(40) and Abeta(42) levels were measured with generally low error, and measurements appeared similar in blood collected in EDTA versus heparin. While these preliminary findings suggest that measuring plasma Abeta(40) and Abeta(42) may be feasible in varied research settings, additional work in this area is necessary.

The pathogenesis of Alzheimer's disease (AD) is thought to be related to the accumulation of amyloid β (Aβ) in amyloid deposits and toxic oligomeric species. Immunomodulation is emerging as an effective means of shifting the equilibrium from Aβ accumulation to clearance; however, excessive cell mediated inflammation and cerebral microhemorrhages are two forms of toxicity which can occur with this approach. Vaccination studies have so far mainly targeted the adaptive immune system. In the present study, we have stimulated the innate immune system via the Toll-like receptor 9 (TLR9) with cytosine-guanosine-containing DNA oligodeoxynucleotides in Tg2576 AD model transgenic mice. This treatment produced a 66% and 80% reduction in the cortical (p= 0.0001) and vascular (p= 0.0039) amyloid burden, respectively, compared with nontreated AD mice. This was in association with significant reductions in Aβ42, Aβ40, and Aβ oligomer levels. We also show that treated Tg mice performed similarly to wild-type mice on a radial arm maze. Our data suggest that stimulation of innate immunity via TLR9 is highly effective at reducing the parenchymal and vascular amyloid burden, along with Aβ oligomers, without apparent toxicity.

Little is known of combined utility of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) biomarkers for prediction of Alzheimer's disease (AD) and longitudinal data is scarce. We examined these biomarkers at baseline and longitudinally in incipient AD. Forty-five subjects [21 controls (NL-NL), 16 stable MCI (MCI-MCI), 8 MCI who declined to AD (MCI-AD)] received MRI and lumbar puncture at baseline and after 2 years. CSF measures included total and phosphorylated tau (T-tau, P-tau(231)), amyloid-beta (Abeta(42)/Abeta(40)) and isoprostane. Voxel-based morphometry identified gray matter concentration (GMC) differences best distinguishing study groups and individual GMC values were calculated. Rate of medial temporal lobe (MTL) atrophy was examined using regional boundary shift (rBS) method. At baseline, for MRI, MCI-AD showed reduced GMC-MTL, and for CSF higher CSF T-tau, P-tau(231), IP and lower Abeta(42)/Abeta(40) as compared with MCI-MCI or NL-NL. Longitudinally, rBS-MTL atrophy was higher in MCI-AD than in either MCI-MCI or NL-NL, particularly in the left hemisphere. CSF data showed longitudinally greater increases of isoprostane in MCI-AD as compared with NL-NL. Combining baseline CSF-P-tau(231) and GMC-MTL significantly increased overall prediction of AD from 74% to 84% (p(step)

Multiple sclerosis (MS) is one of the most common demyelinating diseases of the central nervous system affecting adults between the ages of 20 and 40 years. Clinically, it is characterized by episodes of exacerbations and remissions. Although the cause of MS is unknown, it is generally believed that one or more infectious agents triggers an autoimmune response that causes myelin destruction. There is no known cure for this disease; however, early diagnosis is helpful in the management of patients with MS. The diagnosis of MS is commonly made on the basis of established clinical criteria. No specific laboratory diagnostic test exists, but detection of abnormalities in cerebrospinal fluid (CSF) is a useful aid to support the clinical diagnosis of MS. This review describes the most common CSF abnormalities. These include (a) elevation of immunoglobulin G (IgG), IgG index and IgG synthesis rate; and (b) detection of oligoclonal IgG bands in the CSF by electrophoresis and isoelectric-focusing procedures.

Background: Current research indicates a strong link between obesity and overweight, cardiovascular disease (CVD) and risk for developing Alzheimer's disease (AD). This may be exacerbated in people who possess the major AD genetic risk factor apolipoprotein Eϵ4 (APOEϵ4). The biological mechanisms underlying these associations are still unclear. Methods: Since subjective memory complaint (SMC) may be a potential early indicator for cognitive decline, it was pertinent to examine these risk factors in a cohort of SMC to determine their clinical significance. Methods: Since subjective memory complaint (SMC) may be a potential early indicator for cognitive decline, it was pertinent to examine these risk factors in a cohort of SMC to determine their clinical significance. As beta amyloid (Aβ) is considered to play a central role in AD, we hypothesized that the CVD risk profile (increased low density lipoprotein-LDL and reduced high density lipoprotein-HDL) may be associated with raised plasma Aβ levels. We also hypothesized that the CVD risk profile may be associated with poorer cognition, as assessed using a neuropsychological battery. We explored this association in 198 individuals from a study of SMC (average age⫽ 63 years). Results: A positive correlation between Aβ 40 and triglycerides (rho⫽ 0.147, p⫽ 0.020) and a negative correlation between Aβ 40 and HDL was observed. The latter was stronger in those who do not possess the APOEe4 allele (rho⫽ -0.315, p⫽0.00). Age and HDL remained predictive for plasma A ␤ 40 using multivariate regression analysis. HDL levels were also positively correlated with cognitive performance. Conclusions: The negative association between HDL and A ␤ is reported here for the first time and has implications for the development of novel therapeutics that complement LDL lowering approaches. Our findings confirm the close association between lipid and Aβ metabolism and emphasize the importance of the APOEe4 allele in modulating AD risk. The role of HDL as a predictor of cognitive decline needs to be assessed in a larger longitudinal study.

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.

Recent research studies associate elevated gonadotropin levels with dementia. Specifically, an age associated increase in levels of luteinizing hormone has been linked to an increased risk of Alzheimer's disease. The objective of this study was to investigate the association between gonadotropin levels and cognition in older, healthy postmenopausal women. Cognitive functioning was compared with plasma levels of estradiol, luteinizing hormone, follicle stimulating hormone, Abeta40 and APOE genetic status in 649 community-dwelling, non-demented older women residing in Western Australia. High endogenous luteinizing hormone levels were associated with a lower cognitive score, especially in older women and in those women that were depressed. Unexpectedly, disproportionately well preserved cognitive functioning was found for the oldest women who had high endogenous levels of follicle stimulating hormone. The findings indicate that gonadotropins can impact upon cognitive functioning in older postmenopausal women, and that luteinizing hormone and follicle stimulating hormone may exert contrasting effects. Taken together, the findings have important implications for the development of possible preventive strategies for dementia.

Our results show that a lack of taurine in the diet of cats results in a significant leukopenia, a shift in the percentage of polymorphonuclear and mononuclear leukocytes, an increase in the absolute count of mononuclear leukocytes, and a change in the sedimentation characteristics of white cells. Functional studies of polymorphonuclear cells isolated from cats fed taurine-free diets show a significant decrease in the respiratory burst as measured by chemiluminescence as well as a decrease in phagocytosis of Staphylococcus epidermis compared to cats fed the same diet containing taurine. In addition, serum gamma globulin in cats fed taurine-free diets was significantly increased compared to taurine-supplemented cats, indicating that other immune cells may be affected by taurine deficiency. Histological examination of lymph nodes and spleen revealed regression of follicular centers with depletion of reticular cells, mature and immature lymphocytes (B cell areas), as well as mild extravascular hemolysis. These results indicate that there are profound immunologic consequences in cats with prolonged taurine deficiency.

BACKGROUND: Little solid information is available on the possible risks for neuronal injury in amateur boxing. OBJECTIVE: To determine whether amateur boxing and severity of hits are associated with elevated levels of biochemical markers for neuronal injury in cerebrospinal fluid. DESIGN: Longitudinal study. SETTING: Referral center specializing in evaluation of neurodegenerative disorders. PARTICIPANTS: Fourteen amateur boxers (11 men and three women) and 10 healthy male nonathletic control subjects. INTERVENTIONS: The boxers underwent lumbar puncture 7–10 days and 3 months after a bout. The control subjects underwent LP once. MAIN OUTCOME MEASURES: Neurofilament light protein, total tau, glial fibrillary acidic protein, phosphorylated tau, and beta-amyloid protein 1–40 (Abeta([1–40])) and 1–42 (Abeta([1–42])) concentrations in cerebrospinal fluid were measured. RESULTS: Increased levels after a bout compared with after 3 months of rest from boxing were found for two markers for neuronal and axonal injury, neurofilament light protein (mean±SD, 845±1140 vs 208±108 ng/L; P=0.008) and total tau (mean±SD, 449±176 vs 306±78 ng/L; P=0.006), and for the astroglial injury marker glial fibrillary acidic protein (mean±SD, 541±199 vs 405±138 ng/L; P=0.003). The increase was significantly higher among boxers who had received many hits (>15) or high-impact hits to the head compared with boxers who reported few hits. In the boxers, concentrations of neurofilament light protein and glial fibrillary acidic protein, but not total tau, were significantly elevated after a bout compared with the nonathletic control subjects. With the exception of neurofilament light protein, there were no significant differences between boxers after 3 months of rest from boxing and the nonathletic control subjects. CONCLUSIONS: Amateur boxing is associated with acute neuronal and astroglial injury. If verified in longitudinal studies with extensive follow-up regarding the clinical outcome, analyses of cerebrospinal fluid may provide a scientific basis for medical counseling of athletes after boxing or head injury.

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

Objective Longitudinal changes in plasma beta amyloid protein 1-42 and 1-40 (Aβ42 and Aβ40) levels and possible relationships with cognitive decline and apolipoprotein (APOE) genotype were studied in healthy elderly individuals. Methods Authors determined cognitive level and plasma Aβ40 and Aβ42 levels twice, approximately 4 years apart, in 34 elderly subjects. Results Analyses revealed a selective reduction in Aβ42 levels at follow-up, which were not modulated by the ɛ4 allele. Greater reductions and higher baseline plasma Aβ42 levels were associated with reductions in cognitive scores. Conclusions Alterations in plasma Aβ42 levels may be associated with subtle cognitive decline in elderly subjects without dementia.

We quantitated amyloid beta peptide (A beta) 38, A beta40 and A beta42 levels in matched CSF and plasma from Alzheimer disease (AD) patients and controls. CSF A beta38 and A beta40 levels were similar in AD patients and in controls; however, they were higher in controls with APOE upsilon4 allele than those without. CSF A beta42 levels were lower in AD patients than in controls. The CSF A beta38/42 ratio was higher in AD patients than controls, consistent with the previously reported higher A beta40/42 ratio. A beta38, A beta40 and A beta42 levels in plasma were similar in AD patients and in controls and showed no relationship to levels in CSF. Our findings suggest that the increased CSF A beta38/42 ratio found in AD patients is derived entirely from reduction of CSF A beta42 levels.

Early endosomes are a major site of amyloid precursor protein (APP) processing and a convergence point for molecules of pathologic relevance to Alzheimer's disease (AD). Neuronal endosome enlargement, reflecting altered endocytic function, is a disease-specific response that develops years before the earliest stage of AD and Down syndrome (DS). We examined how endocytic dysfunction is related to Abeta accumulation and distribution in early stage AD and DS. We found by ELISA and immunocytochemistry that the appearance of enlarged endosomes coincided with an initial rise in soluble Abeta40 and Abeta42 peptides, which preceded amyloid deposition. Double-immunofluorescence using numerous Abeta antibodies showed that intracellular Abeta localized principally to rab5-positive endosomes in neurons from AD brains and was prominent in enlarged endosomes. Abeta was not detectable in neurons from normal controls and was diminished after amyloid deposition in neuropathologically confirmed AD. These studies support growing evidence that endosomal pathology contributes significantly to Abeta overproduction and accumulation in sporadic AD and in AD associated with DS and may signify earlier disease-relevant disturbances of the signaling functions of endosomes.

The carboxy-terminal ends of the 40- and 42-amino acids amyloid beta-protein (Abeta) may be generated by the action of at least two different proteases termed gamma(40)- and gamma(42)-secretase, respectively. To examine the cleavage specificity of the two proteases, we treated amyloid precursor protein (APP)-transfected cell cultures with several dipeptidyl aldehydes including N-benzyloxycarbonyl-Leu-leucinal (Z-LL-CHO) and the newly synthesized N-benzyloxycarbonyl-Val-leucinal (Z-VL-CHO). All dipeptidyl aldehydes tested inhibited production of both Abeta1-40 and Abeta1-42. Changes in the P1 and P2 residues of these aldehydes, however, indicated that the amino acids occupying these positions are important for the efficient inhibition of gamma-secretases. Peptidyl aldehydes inhibit both cysteine and serine proteases, suggesting that the two gamma-secretases belong to one of these mechanistic classes. To differentiate between the two classes of proteases, we treated our cultures with the specific cysteine protease inhibitor E-64d. This agent inhibited production of secreted Abeta1-40, with a concomitant accumulation of its cellular precursor indicating that gamma(40)-secretase is a cysteine protease. In contrast, this treatment increased production of secreted Abeta1-42. No inhibition of Abeta production was observed with the potent calpain inhibitor I (acetyl-Leu-Leu-norleucinal), suggesting that calpain is not involved. Together, these results indicate that gamma(40)-secretase is a cysteine protease distinct from calpain, whereas gamma(42)-secretase may be a serine protease. In addition, the two secretases may compete for the same substrate. Dipeptidyl aldehyde treatment of cultures transfected with APP carrying the Swedish mutation resulted in the accumulation of the beta-secretase C-terminal APP fragment and a decrease of the alpha-secretase C-terminal APP fragment, indicating that this mutation shifts APP cleavage from the alpha-secretase site to the beta-secretase site.

Levels of soluble amyloid beta protein (sAbeta), amyloid beta precursor protein (APP) and apolipoprotein E (apoE) were examined in cerebrospinal fluid (CSF) obtained twice, at baseline and after 3-year follow-up, from 25 patients with probable Alzheimer's disease (AD). Levels of sAbeta and apoE from patients with the apoE4 allele decreased with time, whereas the levels were similar in patients without apoE4 allele. Changes of sAbeta and apoE concentrations correlated significantly with those of mini-mental state examination (MMSE) scores. Levels of sAbeta did not change with time in patients with mild dementia, whereas they decreased significantly in patients with moderate dementia. ApoE concentrations decreased in both groups whereas APP levels were similar. We conclude that measurements of CSF sAbeta and apoE levels may be helpful in monitoring progression of the disease.

Estradiol has potent favorable effects on brain function and behavior in animals while in human trials, the results are inconsistent. A number of potential mediating variables influencing response to estradiol have been proposed to account for this variability, one of which includes stress. We conducted a placebo-controlled study to examine joint and independent effects of estradiol and elevated levels of the stress hormone cortisol on cognition and biomarkers of aging and neurodegenerative disease. Thirty-nine healthy postmenopausal women (56-84 yrs) received 0.10 mg/d of transdermal 17β-estradiol (E2) or placebo for eight weeks. During the last four days of the trial, subjects also received 90 mg/d (30 mg TID) of oral hydrocortisone (CORT) to induce stress-level elevations in cortisol, or a matched placebo. The four groups thus included Placebo (placebo patch/placebo pill), CORT-alone (placebo patch/hydrocortisone), E2-alone (estradiol patch/placebo pill), and E2+CORT (estradiol patch/hydrocortisone). Eight weeks of E2 increased plasma estradiol by 167%, and four days of CORT increased plasma cortisol by 119%. Overall, E2 had favorable effects on verbal memory (p=0.03), working memory (p=0.02), and selective attention (p=0.04), and the magnitude of these effects was attenuated for E2+CORT. E2-alone and E2+CORT had opposing effects on plasma levels of the amyloid-β (Aβ) biomarker (Aβ40/42 ratio, p

Brain autopsy data from persons with DS showed that the neuropathology of Alzheimer disease (AD) is always present in DS 40 years of age and older. The core protein of the neuritic plaque is Aβ protein. Studies have suppoted the role of immune abnormalities and inflammation in the pathogenesis of DS. We hypothesized that the levels of TNFα and Cystatin C would be higher in DS than controls, and would correlate with Aβ levels. The study included 40 persons with DS (44±8 years old) and age-matched controls. Plasma levels of Aβ40 and Aβ42 , TNFα and Cystatin C were quantitated by using an ELISA. Aβ40 and Aβ42, TNFα and Cystatin C levels were higher in DS than controls (p

The Alzheimer disease (AD) and Down syndrome (DS) neuritic plaques consist of a central amyloid core surrounded by a spherical cluster of dystrophic degenerating and regenerating neuntes. The main component of the plaque amyloid is a small protein (βA4 protein) which derives from a larger amyloid precursor protein (APP). It has been proposed that the neuritic regeneration associated with the neuritic plaques takes place in the presence of a milieu of neurotrophic factors. It is, therefore, important to determine the effect of various neurotrophic factors on the metabolism of APP. Using antisera against specific APP sequences we determined that, in PC 12 cell cultures, nerve growth factor (NGF), basic fibroblast growth factor (bFGF), and epidermal growth factor (EGF) stimulate the secretion of at least two different APP isoforms, both of which derive from the Kunitz protease inhibitor (KPI) containing βAPP and both of which differ in their degree of glycosylation. In addition, bFGF induced the appearance of a novel APP isoform in the human astrocytoma cell line HBT 14. Immunoblots using specific monoclonal and polyclonal antibodies indicated that the NGFsecreted APP form is cleaved from its precursor within the first ten amino acids that immediately follow the transmembrane region. A similarly reactive APP form has been detected in human cerebrospinal fluid. These results suggest that normal metabolism of APP involves cleavage within the βA4 protein sequence, thus preventing amyloid formation. Furthermore, they suggest that production of the amyloid protein in AD and DS may involve a defect in the enzymic system involved in the cleavage of the secreted forms of APP. This could cause degradation of the precursor through alternative and possibly nonspecific pathways, thus initiating the process leading to amyloid deposition.