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Alzheimer's Research & Therapy
Published in: Alzheimer's Research & Therapy 1/2017

Open Access 01-12-2017 | Research

Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults

Authors: Ge Li, Jane B. Shofer, Eric C. Petrie, Chang-En Yu, Charles W. Wilkinson, Dianne P. Figlewicz, Andrew Shutes-David, Jing Zhang, Thomas J. Montine, Murray A. Raskind, Joseph F. Quinn, Douglas R. Galasko, Elaine R. Peskind

Published in: Alzheimer's Research & Therapy | Issue 1/2017

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Abstract

Background

This study sought to evaluate gender and APOE genotype-related differences in the concentrations of cerebrospinal fluid (CSF) biomarkers for Alzheimer’s disease (AD) and cerebrovascular injury across the life span of cognitively normal adults.

Methods

CSF amyloid beta1–42 (Aβ42), phospho-tau-181 (p-tau181), and total tau were measured in 331 participants who were between the ages of 21 and 100. CSF E-selectin and vascular cell adhesion protein 1 (VCAM1) were measured in 249 participants who were between the ages of 50 and 100.

Results

CSF total tau and p-tau181 increased with age over the adult life span (p < 0.01) with no gender differences in those increases. CSF Aβ42 concentration varied according to age, gender, and APOE genotype (interaction of age × gender × ε4, p = 0.047). CSF VCAM1, but not E-selectin, increased with age (p < 0.01), but both were elevated in men compared to women (p < 0.01).

Conclusions

Female APOE-ε4 carriers appear at higher risk for AD after age 50. In contrast, men may experience a relatively higher rate of cerebrovascular injury in middle and early old age.
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Literature
1.
Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, Dartigues JF, Kragh-Sorensen P, Baldereschi M, Brayne C, et al. Gender differences in the incidence of AD and vascular dementia: The EURODEM Studies. EURODEM Incidence Research Group. Neurol. 1999;53:1992–7.CrossRef
2.
Miech RA, Breitner JC, Zandi PP, Khachaturian AS, Anthony JC, Mayer L. Incidence of AD may decline in the early 90s for men, later for women: The Cache County study. Neurology. 2002;58:209–18.CrossRefPubMed
3.
Kukull WA, Higdon R, Bowen JD, McCormick WC, Teri L, Schellenberg GD, van Belle G, Jolley L, Larson EB. Dementia and Alzheimer disease incidence: a prospective cohort study. Arch Neurol. 2002;59:1737–46.CrossRefPubMed
4.
Chene G, Beiser A, Au R, Preis SR, Wolf PA, Dufouil C, Seshadri S. Gender and incidence of dementia in the Framingham Heart Study from mid-adult life. Alzheimers Dement. 2015;11:310–20.CrossRefPubMed
5.
Henderson VW. Estrogen, cognition, and a woman's risk of Alzheimer's disease. Am J Med. 1997;103:11S–8S.CrossRefPubMed
6.
Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002;288:2123–9.CrossRefPubMed
7.
Li G, Sokal I, Quinn JF, Leverenz JB, Brodey M, Schellenberg GD, Kaye JA, Raskind MA, Zhang J, Peskind ER, Montine TJ. CSF tau/Abeta42 ratio for increased risk of mild cognitive impairment: a follow-up study. Neurology. 2007;69:631–9.CrossRefPubMed
8.
Fagan AM, Roe CM, Xiong C, Mintun MA, Morris JC, Holtzman DM. Cerebrospinal fluid tau/beta-amyloid(42) ratio as a prediction of cognitive decline in nondemented older adults. Arch Neurol. 2007;64:343–9.CrossRefPubMed
9.
Fagan AM, Mintun MA, Mach RH, Lee SY, Dence CS, Shah AR, LaRossa GN, Spinner ML, Klunk WE, Mathis CA, et al. Inverse relation between in vivo amyloid imaging load and cerebrospinal fluid Abeta42 in humans. Ann Neurol. 2006;59:512–9.CrossRefPubMed
10.
Fleisher AS, Chen K, Quiroz YT, Jakimovich LJ, Gutierrez Gomez M, Langois CM, Langbaum JB, Roontiva A, Thiyyagura P, Lee W, et al. Associations between biomarkers and age in the presenilin 1 E280A autosomal dominant Alzheimer disease kindred: a cross-sectional study. JAMA Neurol. 2015;72:316–24.CrossRefPubMedPubMedCentral
11.
Li G, Xiong K, Korff A, Pan C, Quinn J, Galasko D, Liu C, Montine TJ, Peskind E, Zhang J. Increased CSF E-selectin in clinical Alzheimer’s disease without altered CSF Abeta 42 and Tau. J Alzheimers Dis. 2015;47:883–7 in press.
12.
Ewers M, Mielke MM, Hampel H. Blood-based biomarkers of microvascular pathology in Alzheimer's disease. Exp Gerontol. 2010;45:75–9.CrossRefPubMed
13.
Kawamura T, Umemura T, Kanai A, Nagashima M, Nakamura N, Uno T, Nakayama M, Sano T, Hamada Y, Nakamura J, Hotta N. Soluble adhesion molecules and C-reactive protein in the progression of silent cerebral infarction in patients with type 2 diabetes mellitus. Metabolism. 2006;55:461–6.CrossRefPubMed
14.
Kawamura T, Umemura T, Kanai A, Uno T, Matsumae H, Sano T, Sakamoto N, Sakakibara T, Nakamura J, Hotta N. The incidence and characteristics of silent cerebral infarction in elderly diabetic patients: association with serum-soluble adhesion molecules. Diabetologia. 1998;41:911–7.CrossRefPubMed
15.
Li G, Millard SP, Peskind ER, Zhang J, Yu CE, Leverenz JB, Mayer C, Shofer JS, Raskind MA, Quinn JF, et al. Cross-sectional and longitudinal relationships between cerebrospinal fluid biomarkers and cognitive function in people without cognitive impairment from across the adult life span. JAMA Neurol. 2014;71:742–51.CrossRefPubMedPubMedCentral
16.
Peskind ER, Riekse R, Quinn JF, Kaye J, Clark CM, Farlow MR, Decarli C, Chabal C, Vavrek D, Raskind MA, Galasko D. Safety and acceptability of the research lumbar puncture. Alzheimer Dis Assoc Disord. 2005;19:220–5.CrossRefPubMed
17.
Mattsson N, Andreasson U, Persson S, Arai H, Batish SD, Bernardini S, Bocchio-Chiavetto L, Blankenstein MA, Carrillo MC, Chalbot S, et al. The Alzheimer's Association external quality control program for cerebrospinal fluid biomarkers. Alzheimers Dement. 2011;7:386–95. e386.CrossRefPubMedPubMedCentral
18.
Pan C, Korff A, Galasko D, Ginghina C, Peskind E, Li G, Quinn J, Montine TJ, Cain K, Shi M, Zhang J. Diagnostic values of cerebrospinal fluid T-Tau and Abeta42 using meso scale discovery assays for Alzheimer's disease. J Alzheimers Dis. 2015;45:709–19.PubMedPubMedCentral
19.
Hixson JE, Vernier DT. Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI. J Lipid Res. 1990;31:545–8.PubMed
20.
Harrell FEJ. Regression modeling stratigies with applications to linear models, logistic regression and survival analysis. New York: Springer; 2001.
21.
Davison AC, Hinkley DV. Bootstrap methods and their applications. Cambridge: Cambridge University Press; 1997.CrossRef
22.
Team RC. R: a language and environment for statistical computing. R Foundation for Statistical Computing: Vienna; 2012.
23.
Harrell Jr F. rms: Regression modeling strategies. In R package, 36-0 edition. R Foundation for Statistical Computing: Vienna; 2012.
24.
Canty A, Ripley B. boot: Bootstrap R (S-Plus) functions. In R package, 13-13 edition. R Foundation for Statistical Computing: Vienna; 2014.
25.
Vlassenko AG, McCue L, Jasielec MS, Su Y, Gordon BA, Xiong C, Holtzman DM, Benzinger TL, Morris JC, Fagan AM. Imaging and cerebrospinal fluid biomarkers in early preclinical alzheimer disease. Ann Neurol. 2016;80:379–87.CrossRefPubMed
26.
Peskind ER, Li G, Shofer J, Quinn JF, Kaye JA, Clark CM, Farlow MR, DeCarli C, Raskind MA, Schellenberg GD, et al. Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol. 2006;63:936–9.CrossRefPubMed
27.
Sutphen CL, Jasielec MS, Shah AR, Macy EM, Xiong C, Vlassenko AG, Benzinger TL, Stoops EE, Vanderstichele HM, Brix B, et al. Longitudinal cerebrospinal fluid biomarker changes in preclinical Alzheimer disease during middle age. JAMA Neurol. 2015;72(9):1029–42.CrossRefPubMedPubMedCentral
28.
Jack Jr CR, Wiste HJ, Weigand SD, Knopman DS, Vemuri P, Mielke MM, Lowe V, Senjem ML, Gunter JL, Machulda MM, et al. Age, sex, and APOE epsilon4 effects on memory, brain structure, and beta-amyloid across the adult life span. JAMA Neurol. 2015;72:511–9.CrossRefPubMedPubMedCentral
29.
Resnick SM, Bilgel M, Moghekar A, An Y, Cai Q, Wang MC, Thambisetty M, Prince JL, Zhou Y, Soldan A, et al. Changes in Abeta biomarkers and associations with APOE genotype in 2 longitudinal cohorts. Neurobiol Aging. 2015;36:2333–9.CrossRefPubMedPubMedCentral
30.
Zhao Q, Lu J, Yao Z, Wang S, Zhu L, Wang J, Chen B. Upregulation of Abeta42 in the brain and bodily fluids of rhesus monkeys with aging. J Mol Neurosci. 2017;61:79–87.CrossRefPubMed
31.
Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, Holtzman DM, Morris JC, Goate AM. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007;61:446–53.CrossRefPubMed
32.
Altmann A, Tian L, Henderson VW, Greicius MD. Alzheimer's Disease Neuroimaging Initiative I: sex modifies the APOE-related risk of developing Alzheimer disease. Ann Neurol. 2014;75:563–73.CrossRefPubMedPubMedCentral
33.
Sampedro F, Vilaplana E, de Leon MJ, Alcolea D, Pegueroles J, Montal V, Carmona-Iragui M, Sala I, Sanchez-Saudinos MB, Anton-Aguirre S, et al. APOE-by-sex interactions on brain structure and metabolism in healthy elderly controls. Oncotarget. 2015;6:26663–74.CrossRefPubMedPubMedCentral
34.
Sonnen JA, Larson EB, Haneuse S, Woltjer R, Li G, Crane PK, Craft S, Montine TJ. Neuropathology in the adult changes in thought study: a review. J Alzheimers Dis. 2009;18:703–11.CrossRefPubMedPubMedCentral
35.
White L, Petrovitch H, Hardman J, Nelson J, Davis DG, Ross GW, Masaki K, Launer L, Markesbery WR. Cerebrovascular pathology and dementia in autopsied Honolulu-Asia Aging Study participants. Ann N Y Acad Sci. 2002;977:9–23.CrossRefPubMed
36.
Wang LY, Larson EB, Sonnen JA, Shofer JB, McCormick W, Bowen JD, Montine TJ, Li G. Blood pressure and brain injury in older adults: findings from a community-based autopsy study. J Am Geriatr Soc. 2009;57:1975–81.CrossRefPubMedPubMedCentral
37.
Sonnen JA, Larson EB, Brickell K, Crane PK, Woltjer R, Montine TJ, Craft S. Different patterns of cerebral injury in dementia with or without diabetes. Arch Neurol. 2009;66:315–22.CrossRefPubMedPubMedCentral
38.
Wildman RP, Kaplan R, Manson JE, Rajkovic A, Connelly SA, Mackey RH, Tinker LF, Curb JD, Eaton CB, Wassertheil-Smoller S. Body size phenotypes and inflammation in the Women's Health Initiative Observational Study. Obesity (Silver Spring). 2011;19:1482–91.CrossRef
39.
Huang Z, Yin Q, Sun W, Zhu W, Li Y, Liu W, Xiao L, Duan Z, Cai Q, Liu D, et al. Microbleeds in ischemic stroke are associated with lower serum adiponectin and higher soluble E-selectin levels. J Neurol Sci. 2013;334:83–7.CrossRefPubMed
40.
Koran ME, Wagener M, Hohman TJ, Alzheimer's NI. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2016;11(1):205–13.CrossRef
Metadata
Title
Cerebrospinal fluid biomarkers for Alzheimer's and vascular disease vary by age, gender, and APOE genotype in cognitively normal adults
Authors
Ge Li
Jane B. Shofer
Eric C. Petrie
Chang-En Yu
Charles W. Wilkinson
Dianne P. Figlewicz
Andrew Shutes-David
Jing Zhang
Thomas J. Montine
Murray A. Raskind
Joseph F. Quinn
Douglas R. Galasko
Elaine R. Peskind
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Alzheimer's Research & Therapy / Issue 1/2017
Electronic ISSN: 1758-9193
DOI
https://doi.org/10.1186/s13195-017-0271-9

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