0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Original Contribution |

Age but Not Diagnosis Is the Main Predictor of Plasma Amyloid β-Protein Levels FREE

Hiroaki Fukumoto, PhD; Marsha Tennis, RN; Joseph J. Locascio, PhD; Bradley T. Hyman, MD, PhD; John H. Growdon, MD; Michael C. Irizarry, MD
[+] Author Affiliations

From the Department of Neurology, Massachusetts General Hospital, Boston.


Arch Neurol. 2003;60(7):958-964. doi:10.1001/archneur.60.7.958.
Text Size: A A A
Published online

Background  Plasma amyloid β-protein Aβ42 levels are increased in patients with familial Alzheimer disease (AD) mutations, and high levels reportedly identify individuals at risk to develop AD.

Objectives  To determine whether there are characteristic changes in plasma Aβ40 and Aβ42 levels in sporadic AD, and to examine the relationship of plasma Aβ measures with clinical, demographic, and genetic variables in a prospectively characterized outpatient clinic population.

Patients  A total of 371 outpatients with sporadic AD (n = 146), mild cognitive impairment (n = 37), or Parkinson disease (n = 96) and nondemented control cases (n = 92).

Methods  We collected plasma samples and determined Aβ40 and Aβ42 levels by sandwich enzyme-linked immunosorbent assay with the use of the capture antibody BNT77 (anti–Aβ11-28) and the detector antibodies horseradish peroxidase–linked BA27 (anti-Aβ40) and BC05 (anti-Aβ42).

Results  Mean Aβ40 and Aβ42 levels increased significantly with age in each diagnostic group. When covaried for age, mean plasma levels of Aβ40 and Aβ42 did not differ significantly among the 4 diagnostic groups. Within the mild cognitive impairment and AD groups, Aβ40 and Aβ42 levels did not correlate with duration of memory impairment or with cognitive test scores. The Aβ measures were not influenced by family history of AD, apolipoprotein E genotype, or current medication use of cholinesterase inhibitors, vitamin E, statins, nonsteroidal anti-inflammatory drugs, or estrogen.

Conclusions  Plasma Aβ measures increase with age, but, in contrast to reports on familial AD, plasma Aβ measures were neither sensitive nor specific for the clinical diagnosis of mild cognitive impairment or sporadic AD.

Figures in this Article

AMYLOID β-PROTEIN (Aβ) is a major component of amyloid plaques in brain of patients with Alzheimer disease (AD). Amyloid β-protein is derived from the β-secretase pathway of amyloid precursor protein (APP) processing by the enzymatic activity of the β-site APP cleaving enzyme—which releases the N-terminus of Aβ from APP—and a presenilin-dependent γ-secretase activity that releases the C-terminus of Aβ from the membrane.1 The most common forms of Aβ contain 40 (Aβ40) or 42 (Aβ42) amino acids. The Aβ42 is more fibrillogenic and deposits early in amyloid plaques.2,3 In addition to being deposited in the brain, Aβ can be detected in cerebrospinal fluid (CSF) and plasma, leading to the analysis of Aβ levels in these fluids as biomarkers of the cerebral amyloidosis in AD.

Cerebrospinal fluid Aβ42 level is reduced in AD47 and is inversely proportional to dementia severity in some studies.8 Plasma Aβ42 level is increased in patients with familial AD mutations.9,10 Studies of Aβ40 and Aβ42 in plasma of patients with sporadic AD have been equivocal, some suggesting increased Aβ40 or Aβ42 levels in AD or preclinical AD,11,12 but others showing no change.9,10,13,14 Sensitive measurement of plasma Aβ levels in a large patient group is required to clarify the clinical, demographic, and genetic factors that influence plasma Aβ levels, and as a prerequisite for proposing plasma Aβ as a biomarker for diagnosis, progression, and treatment effects. The principal goal of this study, therefore, was to determine the sensitivity and specificity of plasma Aβ40 and Aβ42 levels for the diagnosis of AD. A related goal was to examine the relationship of plasma Aβ measures with disease severity, medication use, apolipoprotein E (APOE) genotype, and other demographic variables in a prospectively characterized outpatient clinic population.

PATIENTS

Plasma samples were collected from patients in the Memory and Movement Disorders Units of Massachusetts General Hospital, Boston, with a diagnosis of AD,15 mild cognitive impairment (MCI),16 nondemented Parkinson disease (PD), and no dementia. Informed consent was obtained from the patient and caregiver by a staff physician. The study was approved by the Massachusetts General Hospital Institutional Review Board. The following anonymized data were available for each case: (1) subject demographics, including date of birth, age, sex, race, education, family history of AD (defined as first-degree relative with AD), and family history of dementia; (2) clinical characteristics, including diagnosis, onset of disease, disease duration, Blessed Dementia Scale–Information-Memory-Concentration (BDS-IMC) score,17 the Clinical Dementia Rating Scale score,18 and Hoehn and Yahr PD severity scale score19; (3) current medication use, including cholinesterase inhibitors, estrogen, carbidopa-levodopa, dopamine agonists, anticholinergics, anti-inflammatory medications, hypoglycemic agents, antioxidants, aspirin, and statins; and (4) protocol notes, including last meal, processing details, and protocol violations.

BLOOD COLLECTION

From each patient, 22.5 mL of blood was collected in three 7.5-mL polypropylene sterile plunger tubes (S-Monovette; Sarstedt, Newton, NC), containing potassium EDTA, by a trained phlebotomist. The blood samples were cooled to 4°C for 15 minutes. A serum-plasma separator was added (Sure-Sep II; Organon, West Orange, NJ). In rapid succession, the samples were centrifuged at 3300 rpm (1380g) for 15 minutes and aliquoted in 960-µL quantities into polypropylene tubes containing 40 µL of a protease inhibitor cocktail (Complete, 1 tablet in 2 mL of phosphate-buffered saline; Roche, Indianapolis, Ind), then frozen on dry ice. The samples were stored at −80°C until ready for use.

PLASMA PRETREATMENT

To block cross-reaction of unidentified components of human plasma with the enzyme-linked immunosorbent assay (ELISA), plasma was precleared with mouse IgG1 κ (Sigma-Aldrich Corp, St Louis, Mo) cross-linked to agarose beads (CNBr-activated Sepharose 4B; Amersham Biosciences, Piscataway, NJ).10 Preclearing was performed by diluting 300 µL of each plasma sample with 525 µL of sample buffer (20mM phosphate, 400mM sodium chloride, 2mM EDTA, 10% blocking agent [Block Ace Liquid; Dainippon Pharmaceutical, Osaka, Japan], 0.2% bovine serum albumin, 0.0765% 3-{[3-cholamidopropyl]dimethylammonio}-1-propanesulfonate [CHAPS], pH 7.2), and 75 µL of the agarose beads covalently cross-linked to nonspecific mouse IgG1 κ. After incubation for 2 hours at 4°C, the beads were removed by centrifugation.

SANDWICH Aβ ELISA

For this assay,10 96-well microtiter plates (Maxisorp Black; Nalge Nunc, Rochester, NY) were coated with the capture antibody—5-µg/mL BNT77 (mouse IgA anti–Aβ 11-28; Takeda Chemical Industries, Osaka, Japan)—and blocked with blocking buffer (25% Block Ace Liquid in phosphate-buffered saline) for 6 hours. Pretreated plasma samples (100 µL, in triplicate) were incubated in BNT77-coated wells containing 50 µL of sample buffer overnight at 4°C. The plates were washed 4 times with phosphate-buffered saline, then reacted with horseradish peroxidase–conjugated detector antibodies (BA27 mouse IgG2 anti-Aβ40, 1:1000; BC05 mouse IgG1 anti-Aβ42, 1:1000, 0.5 µg/mL; Takeda Chemical Industries) in 75 µL of sample buffer for 4 hours at room temperature. After 6 washes with phosphate-buffered saline, horseradish peroxidase enzyme activity was measured with a fluorogenic substrate (Quanta Blu; Pierce, Rockford, Ill) on a fluorometer (Wallac Victor2 1420 Multilabel Counter; Perkin-Elmer, Boston, Mass) with a 320-nm excitation filter and 400-nm emission filter. Each plate contained known concentrations of human synthetic Aβ 1-40 and Aβ 1-42 (Bachem, King of Prussia, Pa) in sample buffer to construct a log-log standard curve. These ELISAs can detect N-terminally truncated β-site APP cleaving enzyme–cleaved Aβ species (Aβ 11-40/42) as well as full-length Aβ (Aβ 1-40/42), but not α-secretase cleaved products (p3; Aβ 17-40/42).20

STATISTICAL ANALYSIS

Within groups, Aβ variables were regressed on age, sex, duration of illness, and BDS-IMC score. Significant factors (age and sex) were included in an analysis of covariance with Aβ measures as dependent variables comparing diagnostic groups with nondemented controls, as well as other demographic and clinical variables. Most of the analyses in this study were well powered. For continuous factors, with the sample sizes of 92 to 146 in the control, PD, and AD cases, and a 2-tailed test at P = .05, the power was 80% to detect a population correlation of approximately r = 0.25 to 0.29. Only for the MCI group with a sample size of 37 was the power weaker, at 70% to detect a correlation of r = 0.4. Power for between-group comparisons was 80% to detect differences of approximately 0.4 SD (0.5 SD for MCI). There were few or no missing values for medication use and demographic variables, so power was similarly strong for analyses involving them.

STANDARDIZATION OF ELISA

The sensitivity and specificity of the antibodies and the ELISA have been published.10 In our hands, the ELISA had a sensitivity of 1 pmol/L for Aβ40 and Aβ42. The recovery of exogenous Aβ40 and Aβ42 added to plasma was greater than 90%, irrespective of the presence or absence of the IgG1 κ resin, indicating that these ELISAs can detect both free Aβ and Aβ bound to plasma proteins.10,21 Repeated measures of frozen aliquots of the same sample yielded SDs less than 10%, and correlation of repeated measures of samples showed r2>0.96.

DEMOGRAPHICS

Plasma samples were collected from 371 outpatients with a diagnosis of sporadic AD (n = 146), MCI (n = 37), nondemented control cases (n = 92), and PD (n = 96) (Table 1). Relative to the control group, the patients with AD were significantly older (P<.001), had fewer years of education (P<.001), had a greater family history of AD (P = .03), and had a greater APOE ϵ4 allele frequency (0.38 vs 0.11). Relative to the control group, the MCI group had a greater APOE ϵ4 allele frequency (0.39 vs 0.11), and the PD group had a significantly higher proportion of men (P<.001).

Table Graphic Jump LocationCase Demorgraphics and Plasma Amyloid β-Protein Levels
ANALYSIS OF Aβ LEVELS WITH AGE, SEX, DURATION OF ILLNESS, AND BDS-IMC

By regression analysis, we found that the most robust determinant for Aβ40 and Aβ42 levels in each diagnostic group was age (Figure 1). Other effects were seen only in single diagnostic groups. Within the AD and MCI groups, there was no association of Aβ measures with duration of illness or severity of dementia, as estimated by the BDS-IMC scores (Figure 2).

Place holder to copy figure label and caption
Figure 1.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels in relation to age and sex in the nondemented control group. Age had a significant positive relation to Aβ40 (P<.001) and Aβ42 (P = .005). Sex had a significant relation to Aβ40 (P = .02) and a marginal relation to Aβ42 (P = .07), in both cases women having a higher mean than men. Age had similar positive relations to Aβ measures in all diagnostic groups. Best-fit lines are indicated for men (solid lines) and women (dashed lines).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Amyloid proteins Aβ40 (A and C) and Aβ42 (B and D) according to clinical measures of dementia severity. Duration of illness (A and B) and Blessed Dementia Scale–Information-Memory-Concentration score (BDS-IMC, scored from 0 to 37 mistakes) (C and D) had no correlation with Aβ measures in the Alzheimer disease (AD) and mild cognitive impairment (MCI) groups. Aβ variables were regressed on age, sex, duration of illness, and the BDS-IMC. Best-fit lines are indicated for AD (solid lines) and MCI (dashed lines).

Graphic Jump Location

For the control group, the Aβ variables (Aβ40, Aβ42, and the ratio of Aβ42 to total Aβ [Aβ42/Aβ]) were regressed on age and sex. Age had a significant positive relation to Aβ40 (P<.001) and Aβ42 (P = .005). Sex had a significant relation to Aβ40 (P = .02), with women having a higher mean than men. For the AD group, Aβ variables were regressed on age, sex, duration of illness, and the BDS-IMC scores. The only significant effects were that age had a positive relation to Aβ40 (P = .001) and to Aβ42 (P = .01). For the MCI group, as for the AD group, Aβ variables were regressed on age, sex, duration of illness, and the BDS-IMC. The only significant effect was that age had a positive relation with Aβ40 (P<.01). For the PD group, as for other diagnostic groups, Aβ variables were regressed on age, sex, duration of illness, and the BDS-IMC. The only significant effects were that age had a positive relation with Aβ40 (P<.001) and with Aβ42 (P = .01), and duration of PD had a weak positive relation for Aβ40 (P<.05). Pursuant to these findings, age and sex were included as covariates in the group comparisons that follow.

ANALYSIS OF Aβ LEVELS BETWEEN GROUPS

After covarying for age, there was no significant difference in Aβ measures between diagnostic groups (Table 1). Analyses of covariance were run with the Aβ variables as dependent variables comparing AD vs control groups crossed with a sex factor and including age as a covariate. The only significant effects involving group comparisons were significant interactions between sex and diagnostic group for Aβ40 (P = .04) and for Aβ42 (P = .04). In both cases, the interaction was due to the control group having a higher mean than the AD group among women, with the reverse situation occurring among men. The MCI and control groups as well as the PD and control groups were compared with the same analysis of covariance used to compare the AD and control groups. No significant effects involving diagnostic group were found.

SECONDARY ANALYSES

To determine whether other genetic or clinical features affect Aβ measures, we evaluated the number of APOE ϵ4 alleles, family history of dementia, family history of AD, and medication use.

Number of APOE ϵ4 alleles (0, 1, or 2) was crossed with sex and diagnostic group (AD and MCI only; PD and control subjects were not included because there were too few individuals who were homozygotes for APOE ϵ4), and age was covaried. Dependent variables were Aβ40, Aβ42, and Aβ42/Aβ. No significant effects involving APOEϵ4were found (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels (mean ± SD) according to apolipoprotein E (APOE) genotype and diagnosis. Number of APOE ϵ4 alleles was crossed with sex and diagnostic group, and age was covaried. No significant effects involving ϵ4 were found. AD indicates Alzheimer disease; MCI, mild cognitive impairment; and PD, Parkinson disease.

Graphic Jump Location

Presence or absence of family history of dementia and of family history of AD were crossed with sex and diagnostic group (AD, PD, MCI, and controls), and age was covaried. Dependent variables were Aβ40, Aβ42, and Aβ42/Aβ. No effects involving family history were significant except for complex higher-order interactions involving sex and diagnostic group (Figure 4).

Place holder to copy figure label and caption
Figure 4.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels (mean ± SD) according to family history of Alzheimer disease (FH AD). Presence or absence of family history of Alzheimer disease was crossed with sex and diagnostic group, and age was covaried. No effects involving family history of Alzheimer disease were significant except for complex higher-order interactions involving sex and diagnostic group. MCI indicates mild cognitive impairment; PD, Parkinson disease.

Graphic Jump Location

Whether or not participants were taking various medications was analyzed in relation to Aβ40, Aβ42, and Aβ42/Aβ. In separate analyses, the medications were cholinesterase inhibitors, anti-inflammatory drugs, antioxidants, estrogen, and statins. Only data for women were analyzed in the case of estrogen. Medication use was crossed with diagnostic group and sex, and age was covaried. In each analysis, only diagnostic groups with sufficient numbers of participants taking the medication were included. No effects involving medications were found to be significant (Figure 5).

Place holder to copy figure label and caption
Figure 5.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) according to medication use in nondemented control subjects (for statins, estrogen [women only], nonsteroidal anti-inflammatory drugs [NSAIDS], and antioxidants) and patients with Alzheimer disease (AD) (for anticholinesterase inhibitors [AchE-I]). Medication use was crossed with diagnostic group and sex, and age was covaried. No effects involving medications were found to be significant when all diagnostic groups were analyzed, except for an occasional higher-order interaction involving sex and diagnostic group.

Graphic Jump Location

Since amyloid plaques are a fundamental feature of AD neuropathology, and Aβ can be detected in CSF and plasma, Aβ measures in biological fluids are compelling candidate biomarkers for AD diagnosis and progression.22 The combination of low Aβ42 level and elevated tau protein in CSF has modest sensitivity and specificity for diagnosing AD.6 Plasma Aβ or Aβ42 is increased in familial AD with presenilin or APP mutations as well as in Down syndrome with APP triplication,9,10,23 but, on the basis of our study and others, these plasma measures do not reliably differentiate sporadic AD from control cases.9,10,13,14

We collected plasma samples from a cohort of 371 patients, and specifically studied patients with MCI and a neurodegenerative control group of nondemented patients with PD, in addition to AD and neurologically normal controls. This large and diverse sample allowed us to examine which genetic, demographic, and clinical factors were significantly associated with the variance in plasma Aβ levels. The results of our study indicate that the primary influence on plasma Aβ40 and Aβ42 levels is age rather than diagnosis, with higher Aβ40 and Aβ42 levels in older patients regardless of diagnostic category. This effect of age is consistent with the findings of Younkin et al24 and Mayeux et al.11 After controlling for age, there was no significant difference in Aβ levels among the diagnoses. Studies using similar antibodies to our assay (either BAN50 or BNT77 capture antibodies and BA27/BC05 detector antibodies) and others (3D6 capture antibody and 21F12 anti-Aβ42 detector antibody) also found no significant differences between AD and control cases.9,10,13,14 In contrast, ELISAs using 6E10 capture with R162/R164 or R165 detector antibodies have detected elevated plasma Aβ measures in AD or incipient AD, with a large overlap with non-AD cases.11,12 Our study did not detect elevated Aβ measures in MCI cases, which could be considered preclinical AD; however, it is important to note that in the study by Mayeux et al,11 elevated Aβ levels were present before any cognitive impairment in those who subsequently became demented.

In secondary analyses, we investigated other factors associated with AD risk and therapy, including education, sex, family history of dementia, family history of AD, APOE genotype, and use of classes of medications. When age was covaried, no significant effects were found for medication use, APOE genotype, or family history of dementia. Within the AD and MCI groups, plasma Aβ level did not correlate with duration or severity of memory impairment. These results indicate that the variance in plasma Aβ levels in late-onset AD is largely related to age, although we cannot rule out other genetic factors besides APOE, PS-1, and APP, since there is evidence that plasma Aβ levels behave like heritable traits (independent of diagnosis or family history of AD).25,26

Few published studies have correlated plasma Aβ levels with medication use. Our cross-sectional results with statins are consistent with another cross-sectional study finding that plasma levels of Aβ were not associated with statin use,27 and with a study indicating no association of CSF Aβ42 levels with statin use28; however, lovastatin reduced serum Aβ levels in a dose-dependent manner during 3 months in a placebo-controlled study of hypercholesterolemic patients,29 and simvastatin treatment for 26 weeks showed a trend toward reduced CSF Aβ40 levels.30 We did not detect significant effects on plasma Aβ by commonly used current medication classes for AD—cholinesterase inhibitors and antioxidants (eg, vitamin E)—as well as by putative preventive agents against the development of AD—estrogen, nonsteroidal anti-inflammatory drugs, and statins.31 While large class effects on plasma Aβ were not found in this analysis, we cannot rule out individual medication effects. Specific medications within the nonsteroidal anti-inflammatory drug and statin classes may differ in effects on APP processing and AD risk. For instance, in a study of the nonsteroidal anti-inflammatory drugs, ibuprofen, sulindac sulfide, and indomethacin were more effective than naproxen, aspirin, and celecoxib in reducing Aβ42 production in cell culture.32 Among the statins, a reduced prevalence of AD was associated with lovastatin and pravastatin but not simvastatin.33 However, insufficient numbers of our sample population took any single medication to allow subclass analysis of this sort. Some classes of medications may affect AD risk without affecting APP metabolism and Aβ levels, such as cholinesterase inhibitors and antioxidants.

Besides these clinical, demographic, and genetic factors, the physiologic processes that affect plasma Aβ levels are unknown, in particular where Aβ in plasma is synthesized and metabolized. Studies in APP transgenic mice suggest an equilibrium between Aβ deposited in brain, soluble Aβ in CSF, and Aβ in plasma: in aging Tg2576 APP KN670-1ML mice, age-related Aβ deposition in the brain is associated with a reduction in CSF and plasma Aβ levels.34 The Aβ injected intraventricularly in rats is cleared into the blood,35 intravenously administered Aβ can enter mouse brain,36 and peripheral administration of Aβ antibodies in APP transgenic mice can bind Aβ from the CSF-brain compartment.37 Studies in humans have failed to demonstrate, however, correlation of CSF Aβ levels and plasma Aβ levels.38 Alternatively, extracerebral sources such as platelets are a source of Aβ in plasma.39 The age-related increase of Aβ species in plasma may be a peripheral reflection of increases in Aβ production or reduction in Aβ clearance in the brain leading to increased Aβ deposition and AD with aging; changes in the central or peripheral activity of Aβ synthetic enzymes (eg, β-secretase or γ-secretase) or Aβ catabolic enzymes (eg, insulin-degrading enzyme or neprilysin) with aging remain to be clarified.

This study demonstrates that age is the principal correlate of plasma Aβ levels, rather than diagnosis, medication use, or APOE genotype. Therefore, plasma Aβ is not a reliably sensitive or specific biomarker of AD or MCI diagnosis in cross-sectional study. Longitudinal analysis of plasma in the course of a double-blind placebo-controlled study of specific drugs could detect more sensitive effects of medications on plasma Aβ measures in individual patients. Clinical follow-up of individuals in our study is also under way to determine whether these baseline levels of Aβ40, Aβ42, or Aβ42/Aβ predict future cognitive decline, as suggested by the results of Mayeux et al11 and the studies of familial AD with PS-1 and APP mutations.911 Serial measurement of population-based samples could also determine whether the pattern of change in Aβ levels in plasma is predictive of conversion to AD or progression of established AD.40

Corresponding author and reprints: Michael C. Irizarry, MD, Alzheimer Disease Research Unit, Massachusetts General Hospital–East, B114-2010, 11416th St, Charlestown, MA 02129 (e-mail: mirizarry@partners.org).

Accepted for publication November 14, 2002.

Author contributions: Study concept and design (Drs Fukumoto, Hyman, Growdon, and Irizarry and Ms Tennis); acquisition of data (Drs Fukumoto, Hyman, and Irizarry and Ms Tennis); analysis and interpretation of data (Drs Fukumoto, Locascio, Hyman, Growdon, and Irizarry); drafting of the manuscript (Drs Fukumoto, Locascio, Hyman, and Irizarry); critical revision of the manuscript for important intellectual content (Drs Fukumoto, Locascio, Hyman, Growdon, and Irizarry and Ms Tennis); statistical expertise (Drs Locascio, Hyman, and Irizarry); obtained funding (Drs Hyman, Growdon, and Irizarry); administrative, technical, and material support (Drs Fukumoto, Growdon, and Irizarry and Ms Tennis); study supervision (Drs Fukumoto, Hyman, Growdon, and Irizarry and Ms Tennis).

This study was supported by grants AG00793 and AG05134 from the National Institutes of Health, Bethesda, Md, and the Lawrence J. and Anne Cable Rubenstein Foundation. Dr Fukumoto's salary is supported by Takeda Chemical Industries, Osaka, Japan.

We thank Marisa Dreisbach, Kerri Anne Giglio, Bonnie Cheung, Sarah McKenzie Hallen, Lue Davis, and Ellen Valentine for phlebotomy collection, sample processing, and administrative support.

Walter  JKaether  CSteiner  HHaass  C The cell biology of Alzheimer's disease: uncovering the secrets of secretases. Curr Opin Neurobiol.2001;11:585-590.
PubMed
Gravina  SAHo  LEckman  CB  et al Amyloid beta protein (Aβ) in Alzheimer's disease brain. J Biol Chem.1995;270:7013-7016.
PubMed
Iwatsubo  TMann  DMOdaka  ASuzuki  NIhara  Y Amyloid beta protein (Aβ) deposition. Ann Neurol.1995;37:294-299.
PubMed
Tamaoka  ASawamura  NFukushima  T  et al Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci.1997;148:41-45.
PubMed
Andreasen  NHesse  CDavidsson  P  et al Cerebrospinal fluid β-amyloid(1-42) in Alzheimer disease. Arch Neurol.1999;56:673-680.
PubMed
Galasko  DChang  LMotter  R  et al High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol.1998;55:937-945.
PubMed
Motter  RVigo-Pelfrey  CKholodenko  D  et al Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol.1995;38:643-648.
PubMed
Nitsch  RMRebeck  GWDeng  M  et al Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease. Ann Neurol.1995;37:512-518.
PubMed
Scheuner  DEckman  CJensen  M  et al Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med.1996;2:864-870.
PubMed
Kosaka  TImagawa  MSeki  K  et al The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at Aβ42(43). Neurology.1997;48:741-745.
PubMed
Mayeux  RTang  MXJacobs  DM  et al Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease. Ann Neurol.1999;46:412-416.
PubMed
Mehta  PDPirttila  TMehta  SPSersen  EAAisen  PSWisniewski  HM Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease. Arch Neurol.2000;57:100-105.
PubMed
Tamaoka  AFukushima  TSawamura  N  et al Amyloid beta protein in plasma from patients with sporadic Alzheimer's disease. J Neurol Sci.1996;141:65-68.
PubMed
Vanderstichele  HVan Kerschaver  EHesse  C  et al Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma. Amyloid.2000;7:245-258.
PubMed
McKhann  GDrachman  DFolstein  M  et al Clinical diagnosis of Alzheimer's disease. Neurology.1984;34:939-944.
PubMed
Petersen  RCStevens  JCGanguli  MTangalos  EGCummings  JLDeKosky  ST Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology.2001;56:1133-1142.
PubMed
Blessed  GTomlinson  BERoth  M The association between quantitative measures of dementia and senile change in the cerebral gray matter of elderly subjects. Br J Psychiatry.1968;114:797-811.
PubMed
Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology.1993;43:2412-2414.
PubMed
Hoehn  MMYahr  MD Parkinsonism. Neurology.1967;17:427-442.
PubMed
Fukumoto  HTomita  TMatsunaga  HIshibashi  YSaido  TCIwatsubo  T Primary cultures of neuronal and non-neuronal rat brain cells secrete similar proportions of amyloid beta peptides ending at Aβ40 and Aβ42. Neuroreport.1999;10:2965-2969.
PubMed
Kuo  YMKokjohn  TAKalback  W  et al Amyloid-beta peptides interact with plasma proteins and erythrocytes. Biochem Biophys Res Commun.2000;268:750-756.
PubMed
Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group Consensus report of the Working Group on "Molecular and Biochemical Markers of Alzheimer's Disease." Neurobiol Aging.1998;19:109-116.
PubMed
Schupf  NPatel  BSilverman  W  et al Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in adults with Down syndrome. Neurosci Lett.2001;301:199-203.
PubMed
Younkin  SGEckman  CBErtekin-Taner  N  et al Genetic elevation of plasma amyloid β protein in typical late onset Alzheimer's disease [abstract]. Abstr Soc Neurosci.1998;24:263.
Ertekin-Taner  NGraff-Radford  NYounkin  LH  et al Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science.2000;290:2303-2304.
PubMed
Ertekin-Taner  NGraff-Radford  NYounkin  LH  et al Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees. Genet Epidemiol.2001;21:19-30.
PubMed
Tokuda  TTamaoka  AMatsuno  S  et al Plasma levels of amyloid beta proteins did not differ between subjects taking statins and those not taking statins. Ann Neurol.2001;49:546-547.
PubMed
Fassbender  KStroick  MBertsch  T  et al Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology.2002;59:1257-1258.
PubMed
Buxbaum  JDCullen  EIFriedhoff  LT Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front Biosci.2002;7:a50-a59.
PubMed
Simons  MSchwarzler  FLutjohann  D  et al Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol.2002;52:346-350.
PubMed
Irizarry  MCHyman  BT Alzheimer disease therapeutics. J Neuropathol Exp Neurol.2001;60:923-928.
PubMed
Weggen  SEriksen  JLDas  P  et al A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature.2001;414:212-216.
PubMed
Wolozin  BKellman  WRuosseau  PCelesia  GGSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol.2000;57:1439-1443.
PubMed
Kawarabayashi  TYounkin  LHSaido  TCShoji  MAshe  KHYounkin  SG Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci.2001;21:372-381.
PubMed
Ghersi-Egea  JFGorevic  PDGhiso  JFrangione  BPatlak  CSFenstermacher  JD Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem.1996;67:880-883.
PubMed
Maness  LMBanks  WAPodlisny  MBSelkoe  DJKastin  AJ Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci.1994;55:1643-1650.
PubMed
DeMattos  RBBales  KRCummins  DJPaul  SMHoltzman  DM Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science.2002;295:2264-2267.
PubMed
Mehta  PDPirttila  TPatrick  BABarshatzky  MMehta  SP Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett.2001;304:102-106.
PubMed
Chen  MInestrosa  NCRoss  GSFernandez  HL Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun.1995;213:96-103.
PubMed
Graff-Radford  NErtekin-Taner  NJadeja  NYounkin  LYounkin  S Evidence that plasma amyloid beta protein may be useful as a premorbid biomarker for Alzheimer's disease [abstract]. Neurobiol Aging.2002;23:S384.

Figures

Place holder to copy figure label and caption
Figure 1.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels in relation to age and sex in the nondemented control group. Age had a significant positive relation to Aβ40 (P<.001) and Aβ42 (P = .005). Sex had a significant relation to Aβ40 (P = .02) and a marginal relation to Aβ42 (P = .07), in both cases women having a higher mean than men. Age had similar positive relations to Aβ measures in all diagnostic groups. Best-fit lines are indicated for men (solid lines) and women (dashed lines).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Amyloid proteins Aβ40 (A and C) and Aβ42 (B and D) according to clinical measures of dementia severity. Duration of illness (A and B) and Blessed Dementia Scale–Information-Memory-Concentration score (BDS-IMC, scored from 0 to 37 mistakes) (C and D) had no correlation with Aβ measures in the Alzheimer disease (AD) and mild cognitive impairment (MCI) groups. Aβ variables were regressed on age, sex, duration of illness, and the BDS-IMC. Best-fit lines are indicated for AD (solid lines) and MCI (dashed lines).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels (mean ± SD) according to apolipoprotein E (APOE) genotype and diagnosis. Number of APOE ϵ4 alleles was crossed with sex and diagnostic group, and age was covaried. No significant effects involving ϵ4 were found. AD indicates Alzheimer disease; MCI, mild cognitive impairment; and PD, Parkinson disease.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) levels (mean ± SD) according to family history of Alzheimer disease (FH AD). Presence or absence of family history of Alzheimer disease was crossed with sex and diagnostic group, and age was covaried. No effects involving family history of Alzheimer disease were significant except for complex higher-order interactions involving sex and diagnostic group. MCI indicates mild cognitive impairment; PD, Parkinson disease.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Amyloid β-proteins Aβ40 (A) and Aβ42 (B) according to medication use in nondemented control subjects (for statins, estrogen [women only], nonsteroidal anti-inflammatory drugs [NSAIDS], and antioxidants) and patients with Alzheimer disease (AD) (for anticholinesterase inhibitors [AchE-I]). Medication use was crossed with diagnostic group and sex, and age was covaried. No effects involving medications were found to be significant when all diagnostic groups were analyzed, except for an occasional higher-order interaction involving sex and diagnostic group.

Graphic Jump Location

Tables

Table Graphic Jump LocationCase Demorgraphics and Plasma Amyloid β-Protein Levels

References

Walter  JKaether  CSteiner  HHaass  C The cell biology of Alzheimer's disease: uncovering the secrets of secretases. Curr Opin Neurobiol.2001;11:585-590.
PubMed
Gravina  SAHo  LEckman  CB  et al Amyloid beta protein (Aβ) in Alzheimer's disease brain. J Biol Chem.1995;270:7013-7016.
PubMed
Iwatsubo  TMann  DMOdaka  ASuzuki  NIhara  Y Amyloid beta protein (Aβ) deposition. Ann Neurol.1995;37:294-299.
PubMed
Tamaoka  ASawamura  NFukushima  T  et al Amyloid beta protein 42(43) in cerebrospinal fluid of patients with Alzheimer's disease. J Neurol Sci.1997;148:41-45.
PubMed
Andreasen  NHesse  CDavidsson  P  et al Cerebrospinal fluid β-amyloid(1-42) in Alzheimer disease. Arch Neurol.1999;56:673-680.
PubMed
Galasko  DChang  LMotter  R  et al High cerebrospinal fluid tau and low amyloid β42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol.1998;55:937-945.
PubMed
Motter  RVigo-Pelfrey  CKholodenko  D  et al Reduction of beta-amyloid peptide42 in the cerebrospinal fluid of patients with Alzheimer's disease. Ann Neurol.1995;38:643-648.
PubMed
Nitsch  RMRebeck  GWDeng  M  et al Cerebrospinal fluid levels of amyloid beta-protein in Alzheimer's disease. Ann Neurol.1995;37:512-518.
PubMed
Scheuner  DEckman  CJensen  M  et al Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer's disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer's disease. Nat Med.1996;2:864-870.
PubMed
Kosaka  TImagawa  MSeki  K  et al The beta APP717 Alzheimer mutation increases the percentage of plasma amyloid-beta protein ending at Aβ42(43). Neurology.1997;48:741-745.
PubMed
Mayeux  RTang  MXJacobs  DM  et al Plasma amyloid beta-peptide 1-42 and incipient Alzheimer's disease. Ann Neurol.1999;46:412-416.
PubMed
Mehta  PDPirttila  TMehta  SPSersen  EAAisen  PSWisniewski  HM Plasma and cerebrospinal fluid levels of amyloid beta proteins 1-40 and 1-42 in Alzheimer disease. Arch Neurol.2000;57:100-105.
PubMed
Tamaoka  AFukushima  TSawamura  N  et al Amyloid beta protein in plasma from patients with sporadic Alzheimer's disease. J Neurol Sci.1996;141:65-68.
PubMed
Vanderstichele  HVan Kerschaver  EHesse  C  et al Standardization of measurement of beta-amyloid(1-42) in cerebrospinal fluid and plasma. Amyloid.2000;7:245-258.
PubMed
McKhann  GDrachman  DFolstein  M  et al Clinical diagnosis of Alzheimer's disease. Neurology.1984;34:939-944.
PubMed
Petersen  RCStevens  JCGanguli  MTangalos  EGCummings  JLDeKosky  ST Practice parameter: early detection of dementia: mild cognitive impairment (an evidence-based review). Neurology.2001;56:1133-1142.
PubMed
Blessed  GTomlinson  BERoth  M The association between quantitative measures of dementia and senile change in the cerebral gray matter of elderly subjects. Br J Psychiatry.1968;114:797-811.
PubMed
Morris  JC The Clinical Dementia Rating (CDR): current version and scoring rules. Neurology.1993;43:2412-2414.
PubMed
Hoehn  MMYahr  MD Parkinsonism. Neurology.1967;17:427-442.
PubMed
Fukumoto  HTomita  TMatsunaga  HIshibashi  YSaido  TCIwatsubo  T Primary cultures of neuronal and non-neuronal rat brain cells secrete similar proportions of amyloid beta peptides ending at Aβ40 and Aβ42. Neuroreport.1999;10:2965-2969.
PubMed
Kuo  YMKokjohn  TAKalback  W  et al Amyloid-beta peptides interact with plasma proteins and erythrocytes. Biochem Biophys Res Commun.2000;268:750-756.
PubMed
Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group Consensus report of the Working Group on "Molecular and Biochemical Markers of Alzheimer's Disease." Neurobiol Aging.1998;19:109-116.
PubMed
Schupf  NPatel  BSilverman  W  et al Elevated plasma amyloid beta-peptide 1-42 and onset of dementia in adults with Down syndrome. Neurosci Lett.2001;301:199-203.
PubMed
Younkin  SGEckman  CBErtekin-Taner  N  et al Genetic elevation of plasma amyloid β protein in typical late onset Alzheimer's disease [abstract]. Abstr Soc Neurosci.1998;24:263.
Ertekin-Taner  NGraff-Radford  NYounkin  LH  et al Linkage of plasma Aβ42 to a quantitative locus on chromosome 10 in late-onset Alzheimer's disease pedigrees. Science.2000;290:2303-2304.
PubMed
Ertekin-Taner  NGraff-Radford  NYounkin  LH  et al Heritability of plasma amyloid beta in typical late-onset Alzheimer's disease pedigrees. Genet Epidemiol.2001;21:19-30.
PubMed
Tokuda  TTamaoka  AMatsuno  S  et al Plasma levels of amyloid beta proteins did not differ between subjects taking statins and those not taking statins. Ann Neurol.2001;49:546-547.
PubMed
Fassbender  KStroick  MBertsch  T  et al Effects of statins on human cerebral cholesterol metabolism and secretion of Alzheimer amyloid peptide. Neurology.2002;59:1257-1258.
PubMed
Buxbaum  JDCullen  EIFriedhoff  LT Pharmacological concentrations of the HMG-CoA reductase inhibitor lovastatin decrease the formation of the Alzheimer beta-amyloid peptide in vitro and in patients. Front Biosci.2002;7:a50-a59.
PubMed
Simons  MSchwarzler  FLutjohann  D  et al Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann Neurol.2002;52:346-350.
PubMed
Irizarry  MCHyman  BT Alzheimer disease therapeutics. J Neuropathol Exp Neurol.2001;60:923-928.
PubMed
Weggen  SEriksen  JLDas  P  et al A subset of NSAIDs lower amyloidogenic Aβ42 independently of cyclooxygenase activity. Nature.2001;414:212-216.
PubMed
Wolozin  BKellman  WRuosseau  PCelesia  GGSiegel  G Decreased prevalence of Alzheimer disease associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors. Arch Neurol.2000;57:1439-1443.
PubMed
Kawarabayashi  TYounkin  LHSaido  TCShoji  MAshe  KHYounkin  SG Age-dependent changes in brain, CSF, and plasma amyloid (beta) protein in the Tg2576 transgenic mouse model of Alzheimer's disease. J Neurosci.2001;21:372-381.
PubMed
Ghersi-Egea  JFGorevic  PDGhiso  JFrangione  BPatlak  CSFenstermacher  JD Fate of cerebrospinal fluid-borne amyloid beta-peptide: rapid clearance into blood and appreciable accumulation by cerebral arteries. J Neurochem.1996;67:880-883.
PubMed
Maness  LMBanks  WAPodlisny  MBSelkoe  DJKastin  AJ Passage of human amyloid beta-protein 1-40 across the murine blood-brain barrier. Life Sci.1994;55:1643-1650.
PubMed
DeMattos  RBBales  KRCummins  DJPaul  SMHoltzman  DM Brain to plasma amyloid-beta efflux: a measure of brain amyloid burden in a mouse model of Alzheimer's disease. Science.2002;295:2264-2267.
PubMed
Mehta  PDPirttila  TPatrick  BABarshatzky  MMehta  SP Amyloid beta protein 1-40 and 1-42 levels in matched cerebrospinal fluid and plasma from patients with Alzheimer disease. Neurosci Lett.2001;304:102-106.
PubMed
Chen  MInestrosa  NCRoss  GSFernandez  HL Platelets are the primary source of amyloid beta-peptide in human blood. Biochem Biophys Res Commun.1995;213:96-103.
PubMed
Graff-Radford  NErtekin-Taner  NJadeja  NYounkin  LYounkin  S Evidence that plasma amyloid beta protein may be useful as a premorbid biomarker for Alzheimer's disease [abstract]. Neurobiol Aging.2002;23:S384.

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Web of Science® Times Cited: 136

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics