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Age but Not Diagnosis Is the Main Predictor of Plasma Amyloid  -Protein Levels
Hiroaki Fukumoto, PhD;
Marsha Tennis, RN;
Joseph J. Locascio, PhD;
Bradley T. Hyman, MD, PhD;
John H. Growdon, MD;
Michael C. Irizarry, MD
Arch Neurol. 2003;60:958-964.
ABSTRACT
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Background Plasma amyloid  -protein A42 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 A40 and A42 levels in sporadic AD, and to examine the relationship of plasma A 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 A40 and A42 levels by sandwich enzyme-linked immunosorbent assay with the use of the capture antibody BNT77 (anti–A11-28) and the detector antibodies horseradish peroxidase–linked BA27 (anti-A40) and BC05 (anti-A42).
Results Mean A40 and A42 levels increased significantly with age in each diagnostic group. When covaried for age, mean plasma levels of A40 and A42 did not differ significantly among the 4 diagnostic groups. Within the mild cognitive impairment and AD groups, A40 and A42 levels did not correlate with duration of memory impairment or with cognitive test scores. The A 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 A measures increase with age, but, in contrast to reports on familial AD, plasma A measures were neither sensitive nor specific for the clinical diagnosis of mild cognitive impairment or sporadic AD.
INTRODUCTION
AMYLOID -PROTEIN (A) is a major component of amyloid plaques in brain of patients with Alzheimer disease (AD). Amyloid -protein is derived from the -secretase pathway of amyloid precursor protein (APP) processing by the enzymatic activity of the -site APP cleaving enzyme—which releases the N-terminus of A from APP—and a presenilin-dependent  -secretase activity that releases the C-terminus of A from the membrane.1 The most common forms of A contain 40 (A40) or 42 (A42) amino acids. The A42 is more fibrillogenic and deposits early in amyloid plaques.2-3 In addition to being deposited in the brain, A can be detected in cerebrospinal fluid (CSF) and plasma, leading to the analysis of A levels in these fluids as biomarkers of the cerebral amyloidosis in AD.
Cerebrospinal fluid A42 level is reduced in AD4-7 and is inversely proportional to dementia severity in some studies.8 Plasma A42 level is increased in patients with familial AD mutations.9-10 Studies of A40 and A42 in plasma of patients with sporadic AD have been equivocal, some suggesting increased A40 or A42 levels in AD or preclinical AD,11-12 but others showing no change.9-10,13-14 Sensitive measurement of plasma A levels in a large patient group is required to clarify the clinical, demographic, and genetic factors that influence plasma A levels, and as a prerequisite for proposing plasma A 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 A40 and A42 levels for the diagnosis of AD. A related goal was to examine the relationship of plasma A measures with disease severity, medication use, apolipoprotein E (APOE) genotype, and other demographic variables in a prospectively characterized outpatient clinic population.
METHODS
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  (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 . After incubation for 2 hours at 4°C, the beads were removed by centrifugation.
SANDWICH A 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–A 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-A40, 1:1000; BC05 mouse IgG1 anti-A42, 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 A 1-40 and A 1-42 (Bachem, King of Prussia, Pa) in sample buffer to construct a log-log standard curve. These ELISAs can detect N-terminally truncated -site APP cleaving enzyme–cleaved A species (A 11-40/42) as well as full-length A (A 1-40/42), but not  -secretase cleaved products (p3; A 17-40/42).20
STATISTICAL ANALYSIS
Within groups, A 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 A 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.
RESULTS
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 A40 and A42. The recovery of exogenous A40 and A42 added to plasma was greater than 90%, irrespective of the presence or absence of the IgG1 resin, indicating that these ELISAs can detect both free A and A 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  4 allele frequency (0.38 vs 0.11). Relative to the control group, the MCI group had a greater APOE 4 allele frequency (0.39 vs 0.11), and the PD group had a significantly higher proportion of men (P<.001).
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Case Demorgraphics and Plasma Amyloid -Protein Levels
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ANALYSIS OF A LEVELS WITH AGE, SEX, DURATION OF ILLNESS, AND BDS-IMC
By regression analysis, we found that the most robust determinant for A40 and A42 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 A measures with duration of illness or severity of dementia, as estimated by the BDS-IMC scores (Figure 2).
For the control group, the A variables (A40, A42, and the ratio of A42 to total A [A42/A]) were regressed on age and sex. Age had a significant positive relation to A40 (P<.001) and A42 (P = .005). Sex had a significant relation to A40 (P = .02), with women having a higher mean than men. For the AD group, A 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 A40 (P = .001) and to A42 (P = .01). For the MCI group, as for the AD group, A 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 A40 (P<.01). For the PD group, as for other diagnostic groups, A 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 A40 (P<.001) and with A42 (P = .01), and duration of PD had a weak positive relation for A40 (P<.05). Pursuant to these findings, age and sex were included as covariates in the group comparisons that follow.
ANALYSIS OF A LEVELS BETWEEN GROUPS
After covarying for age, there was no significant difference in A measures between diagnostic groups (Table 1). Analyses of covariance were run with the A 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 A40 (P = .04) and for A42 (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 A measures, we evaluated the number of APOE 4 alleles, family history of dementia, family history of AD, and medication use.
Number of APOE 4 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 4), and age was covaried. Dependent variables were A40, A42, and A42/A. No significant effects involving APOE 4were found (Figure 3).
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 A40, A42, and A42/A. No effects involving family history were significant except for complex higher-order interactions involving sex and diagnostic group (Figure 4).
Whether or not participants were taking various medications was analyzed in relation to A40, A42, and A42/A. 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).
COMMENT
Since amyloid plaques are a fundamental feature of AD neuropathology, and A can be detected in CSF and plasma, A measures in biological fluids are compelling candidate biomarkers for AD diagnosis and progression.22 The combination of low A42 level and elevated tau protein in CSF has modest sensitivity and specificity for diagnosing AD.6 Plasma A or A42 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 A levels. The results of our study indicate that the primary influence on plasma A40 and A42 levels is age rather than diagnosis, with higher A40 and A42 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 A 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-A42 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 A measures in AD or incipient AD, with a large overlap with non-AD cases.11-12 Our study did not detect elevated A 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 A 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 A level did not correlate with duration or severity of memory impairment. These results indicate that the variance in plasma A 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 A levels behave like heritable traits (independent of diagnosis or family history of AD).25-26
Few published studies have correlated plasma A levels with medication use. Our cross-sectional results with statins are consistent with another cross-sectional study finding that plasma levels of A were not associated with statin use,27 and with a study indicating no association of CSF A42 levels with statin use28; however, lovastatin reduced serum A 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 A40 levels.30 We did not detect significant effects on plasma A 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 A 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 A42 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 A levels, such as cholinesterase inhibitors and antioxidants.
Besides these clinical, demographic, and genetic factors, the physiologic processes that affect plasma A levels are unknown, in particular where A in plasma is synthesized and metabolized. Studies in APP transgenic mice suggest an equilibrium between A deposited in brain, soluble A in CSF, and A in plasma: in aging Tg2576 APP KN670-1ML mice, age-related A deposition in the brain is associated with a reduction in CSF and plasma A levels.34 The A injected intraventricularly in rats is cleared into the blood,35 intravenously administered A can enter mouse brain,36 and peripheral administration of A antibodies in APP transgenic mice can bind A from the CSF-brain compartment.37 Studies in humans have failed to demonstrate, however, correlation of CSF A levels and plasma A levels.38 Alternatively, extracerebral sources such as platelets are a source of A in plasma.39 The age-related increase of A species in plasma may be a peripheral reflection of increases in A production or reduction in A clearance in the brain leading to increased A deposition and AD with aging; changes in the central or peripheral activity of A synthetic enzymes (eg, -secretase or -secretase) or A 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 A levels, rather than diagnosis, medication use, or APOE genotype. Therefore, plasma A 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 A measures in individual patients. Clinical follow-up of individuals in our study is also under way to determine whether these baseline levels of A40, A42, or A42/A 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.9-11 Serial measurement of population-based samples could also determine whether the pattern of change in A levels in plasma is predictive of conversion to AD or progression of established AD.40
AUTHOR INFORMATION
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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{at}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.
From the Department of Neurology, Massachusetts General Hospital, Boston.
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Neurology 2008;71:85-92.
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The Clinical Significance of Plasmatic Amyloid A{beta}-40 Peptide Levels in Alzheimer's Disease Patients Treated With Galantamine
Modrego et al.
AM J ALZHEIMERS DIS OTHER DEMEN 2008;23:286-290.
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Plasma Amyloid {beta}-Protein and C-reactive Protein in Relation to the Rate of Progression of Alzheimer Disease
Locascio et al.
Arch Neurol 2008;65:776-785.
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Plasma amyloid levels and the risk of AD in normal subjects in the Cardiovascular Health Study
Lopez et al.
Neurology 2008;70:1664-1671.
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Amyloid-Associated Depression: A Prodromal Depression of Alzheimer Disease?
Sun et al.
Arch Gen Psychiatry 2008;65:542-550.
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Complement-Associated Deposits in the Human Retina
Seth et al.
IOVS 2008;49:743-750.
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Plasma {beta} Amyloid and the Risk of Alzheimer Disease and Dementia in Elderly Men: A Prospective, Population-Based Cohort Study
Sundelof et al.
Arch Neurol 2008;65:256-263.
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Association of Low Plasma Abeta42/Abeta40 Ratios With Increased Imminent Risk for Mild Cognitive Impairment and Alzheimer Disease
Graff-Radford et al.
Arch Neurol 2007;64:354-362.
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Excess of nonceruloplasmin serum copper in AD correlates with MMSE, CSF {beta}-amyloid, and h-tau.
Squitti et al.
Neurology 2006;67:76-82.
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Effect of apolipoprotein e on the cerebral load of latent herpes simplex virus type 1 DNA.
Burgos et al.
J. Virol. 2006;80:5383-5387.
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Differential modulation of plasma {beta}-amyloid by insulin in patients with Alzheimer disease
Kulstad et al.
Neurology 2006;66:1506-1510.
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Interaction of the Cytosolic Domains of sorLA/LR11 with the Amyloid Precursor Protein (APP) and beta-Secretase beta-Site APP-Cleaving Enzyme
Spoelgen et al.
J. Neurosci. 2006;26:418-428.
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Plasma {beta}-amyloid and white matter lesions in AD, MCI, and cerebral amyloid angiopathy
Gurol et al.
Neurology 2006;66:23-29.
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Association of homocysteine with plasma amyloid {beta} protein in aging and neurodegenerative disease
Irizarry et al.
Neurology 2005;65:1402-1408.
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Autoantibodies to Redox-modified Oligomeric A{beta} Are Attenuated in the Plasma of Alzheimer's Disease Patients
Moir et al.
J. Biol. Chem. 2005;280:17458-17463.
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