White Matter Lesion Load Increases the Risk of Low CSF Aβ42 in Apolipoprotein E-ɛ4 Carriers Attending a Memory Clinic
Vidar Stenset MD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorDag Hofoss PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorLisbeth Johnsen MSc
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAudun Elnaes Berstad MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAnne Negaard MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAnders Skinningsrud MD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorLeif Gjerstad MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorTormod Fladby MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorVidar Stenset MD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorDag Hofoss PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorLisbeth Johnsen MSc
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAudun Elnaes Berstad MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAnne Negaard MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorAnders Skinningsrud MD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorLeif Gjerstad MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorTormod Fladby MD, PhD
From the Departments of Neurology (VS, LJ, TF), Radiology (AEB, AN), and Multidisciplinary Medical Laboratory (AS), Akershus University Hospital, Lørenskog, Norway; Faculty Division, Akershus University Hospital, University of Oslo, Oslo, Norway (VS, TF); Department of Neurosurgery, Oslo University Hospital Ullevål, Oslo, Norway (VS); Helse Øst Health Services Research Centre, Akershus University Hospital, University of Oslo, Oslo, Norway (DH), Department of Neurology, Oslo University Hospital Rikshospitalet (LG), Oslo, Norway; and Medical Faculty, University of Oslo, Oslo, Norway (LG).
Search for more papers by this authorJ Neuroimaging 2011;21:e78-e82.
Abstract
ABSTRACT
BACKGROUND
White matter lesions (WMLs) are age-related manifestations of ischemic cerebrovascular disease and increase the risk for Alzheimer's disease (AD). The apolipoprotein E (ApoE) ɛ4 allele is a risk factor for late onset AD and has been related to low cerebrospinal fluid (CSF) Aβ42 levels and to cerebrovascular disease. The present study analyzed the relationship between WMLs, ApoE-ɛ4 genotype, and low CSF Aβ42.
METHODS
A total of 235 memory clinic attenders were stratified in 3 groups according to WML load. WMLs were rated on axial T2 magnetic resonance imaging images. Group 1 had no or only small amounts of periventricular (PV) or subcortical (SC) WMLs, WML group 2 had high amounts of PV WMLs and low amounts of SC WMLs, and WML group 3 had high amounts of both PV and SC WMLs. In each WML group, ApoE-ɛ4 genotype was used in logistic regression as a predictor for low CSF Aβ42 (cutoff ≤450 ng/L). Results: The odds ratio (OR) of having low CSF Aβ42 was significantly increased in the presence of ApoE-ɛ4 only in WML group 3 (OR 3.69, P= .009).
CONCLUSION
A high WML load may interact with the ApoE-ɛ4 genotype and increase the risk for reduced CSF Aβ42 in patients attending a memory clinic.
References
- 1 De la Torre JC. Alzheimer disease as a vascular disorder: nosological evidence. Stroke 2002; 33(4): 1152-1162.
- 2 Lewis H, Beher D, Cookson N, et al. Quantification of Alzheimer pathology in ageing and dementia: age-related accumulation of amyloid-beta(42) peptide in vascular dementia. Neuropathol Appl Neurobiol 2006; 32(2): 103-118.
- 3 Sun X, He G, Qing H, et al. Hypoxia facilitates Alzheimer's disease pathogenesis by up-regulating BACE1 gene expression. Proc Natl Acad Sci USA 2006; 103(49): 18727-18732.
- 4 Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer's disease in late onset families. Science 1993; 261(5123): 921-923.
- 5 Farrer LA, Cupples LA, Haines JL, et al. Effects of age, sex, and ethnicity on the association between apolipoprotein E genotype and Alzheimer disease. A meta-analysis. APOE and Alzheimer Disease Meta Analysis Consortium. JAMA 1997; 278(16): 1349-1356.
- 6 Holtzman DM, Bales KR, Tenkova T, et al. Apolipoprotein E isoform-dependent amyloid deposition and neuritic degeneration in a mouse model of Alzheimer's disease. Proc Natl Acad Sci USA 2000; 97(6): 2892-2897.
- 7 McCarron MO, Delong D, Alberts MJ. APOE genotype as a risk factor for ischemic cerebrovascular disease: a meta-analysis. Neurology 1999; 53(6): 1308-1311.
- 8 Yip AG, McKee AC, Green RC, et al. APOE, vascular pathology, and the AD brain. Neurology 2005; 65(2): 259-265.
- 9 Bronge L, Fernaeus SE, Blomberg M, et al. White matter lesions in Alzheimer patients are influenced by apolipoprotein E genotype. Dement Geriatr Cogn Disord 1999; 10(2): 89-96.
- 10 Hirono N, Yasuda M, Tanimukai S, et al. Effect of the apolipoprotein E epsilon4 allele on white matter hyperintensities in dementia. Stroke 2000; 31(6): 1263-1268.
- 11 Blennow K, Hampel H. CSF markers for incipient Alzheimer's disease. Lancet Neurol 2003; 2(10): 605-613.
- 12 Galasko D, Chang L, Motter R, et al. High cerebrospinal fluid tau and low amyloid beta42 levels in the clinical diagnosis of Alzheimer disease and relation to apolipoprotein E genotype. Arch Neurol 1998; 55(7): 937-945.
- 13 de Groot JC, de Leeuw FE, Oudkerk M, et al. Cerebral white matter lesions and depressive symptoms in elderly adults. Arch Gen Psychiatry 2000; 57(11): 1071-1076.
- 14 Stenset V, Hofoss D, Berstad AE, et al. White matter lesion subtypes and cognitive deficits in patients with memory impairment. Dement Geriatr Cogn Disord 2008; 26(5): 424-431.
- 15 Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001; 32(6): 1318-1322.
- 16 Stenset V, Hofoss D, Johnsen L, et al. White matter lesion severity is associated with reduced cognitive performances in patients with normal CSF Abeta42 levels. Acta Neurol Scand 2008; 118(6): 373-378.
- 17 Gorelick PB. Risk factors for vascular dementia and Alzheimer disease. Stroke 2004; 35(11 Suppl 1): 2620-2622.
- 18 Bouwman FH, Schoonenboom NS, Verwey NA, et al. CSF biomarker levels in early and late onset alzheimer's disease. Neurobiol Aging 2008; 30(12): 1895-1901.
- 19 Peskind ER, Li G, Shofer J, et al. Age and apolipoprotein E*4 allele effects on cerebrospinal fluid beta-amyloid 42 in adults with normal cognition. Arch Neurol 2006; 63(7): 936-939.
- 20 Masana Y, Motozaki T. Emergence and progress of white matter lesion in brain check-up. Acta Neurol Scand 2003; 107(3): 187-194.
- 21 Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer's disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007; 6(8): 734-746.
- 22 Nihashi T, Inao S, Kajita Y, et al. Expression and distribution of beta amyloid precursor protein and beta amyloid peptide in reactive astrocytes after transient middle cerebral artery occlusion. Acta Neurochir (Wien) 2001; 143(3): 287-295.
- 23 Akiguchi I, Tomimoto H, Suenaga T, et al. Alterations in glia and axons in the brains of Binswanger's disease patients. Stroke 1997; 28(7): 1423-1429.
- 24 Sanan DA, Weisgraber KH, Russell SJ, et al. Apolipoprotein E associates with beta amyloid peptide of Alzheimer's disease to form novel monofibrils. Isoform apoE4 associates more efficiently than apoE3. J Clin Invest 1994; 94(2): 860-869.
- 25 Selkoe DJ. Alzheimer's disease. In: RN Rosenberg, S Prusiner, S DiMauro, R Barchi, eds. The Molecular and Genetic Basis of Neurologic and Psychiatric Disease. Philadelphia , PA : Butterworth and Heinemann; 2003; 331-342.
- 26 Strittmatter WJ, Weisgraber KH, Huang DY, et al. Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset alzheimer disease. Proc Natl Acad Sci USA 1993; 90(17): 8098-8102.
- 27 Badan I, Buchhold B, Hamm A, et al. Accelerated glial reactivity to stroke in aged rats correlates with reduced functional recovery. J Cereb Blood Flow Metab 2003; 23(7): 845-854.
- 28 Lai AY, Todd KG. Microglia in cerebral ischemia: molecular actions and interactions. Can J Physiol Pharmacol 2006; 84(1): 49-59.
- 29 Niwa M, Inao S, Takayasu M, et al. Time course of expression of three nitric oxide synthase isoforms after transient middle cerebral artery occlusion in rats. Neurol Med Chir (Tokyo) 2001; 41(2): 63-72; discussion 72-73.
- 30 Suenaga T, Ohnishi K, Nishimura M, et al. Bundles of amyloid precursor protein-immunoreactive axons in human cerebrovascular white matter lesions. Acta Neuropathol 1994; 87(5): 450-455.
- 31 Koo EH, Sisodia SS, Archer DR, et al. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci USA. 1990; 87(4): 1561-1565.
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