title: Associations between cerebral small-vessel disease and Alzheimer disease pathology as measured by cerebrospinal fluid biomarkers.
abstract: OBJECTIVE
  It remains unclear if and how associations between cerebral small-vessel disease and Alzheimer disease (AD) pathology lead to cognitive decline and dementia.
  
  
  OBJECTIVE
  To determine associations between small-vessel disease and AD pathology.
  
  
  METHODS
  Cross-sectional study from January 2002 to December 2012 using the memory clinic-based Amsterdam Dementia Cohort. The study included 914 consecutive patients with available cerebrospinal fluid (CSF) and magnetic resonance imaging; 547 were patients diagnosed as having AD (54% female, mean [SD], 67 [8]; Mini-Mental State Examination score, mean [SD], 21 [5]), 30 were patients diagnosed as having vascular dementia (37% female, mean [SD], 76 [9]; Mini-Mental State Examination score, mean [SD], 24 [4]), and 337 were control participants with subjective memory complaints (42% female, mean [SD], 59 [59]; Mini-Mental State Examination score, mean [SD], 28 [2]). Linear regressions were performed with CSF biomarkers (log transformed) as dependent variables and magnetic resonance imaging measures (dichotomized) as independent, adjusted for sex, age, mediotemporal lobe atrophy, and diagnosis. An interaction term for diagnosis by magnetic resonance imaging measures was used for estimates per diagnostic group.
  
  
  METHODS
  We examined the associations of magnetic resonance imaging white matter hyperintensities (WMH), lacunes, microbleeds with CSF β-amyloid 42 (Aβ42), total tau, and tau phosphorylated at threonine 181 (P-tau181) as well as for a subset of apolipoprotein E (APOE) ε4 carriers and noncarriers.
  
  
  RESULTS
  Microbleed presence was associated with lower CSF Aβ42 in AD and vascular dementia (standardized beta = -0.09, P = .003; standardized beta = -0.30, P = .01), and higher CSF tau in controls (standardized beta = 0.10, P = .03). There were no effects for P-tau181. The presence of WMH was associated with lower Aβ42 in control participants and patients with vascular dementia (standardized beta = -0.18, P = .002; standardized beta = -0.32, P = .02) but not in patients with AD. There were no effects for tau or P-tau181. The presence of lacunes was associated with higher Aβ42 in vascular dementia (standardized beta = 0.17, P = .07) and lower tau in AD (standardized beta = -0.07, P = .05) but there were no effects for Aβ42 or P-tau181. Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to ε4 carriers.
  
  
  CONCLUSIONS
  Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E ε4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Maartje I
authors.initials: MI
authors.lastname: Kester
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Jeroen D C
authors.initials: JD
authors.lastname: Goos
authors.affiliation: Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Teunissen
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Marije R
authors.initials: MR
authors.lastname: Benedictus
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Femke H
authors.initials: FH
authors.lastname: Bouwman
authors.affiliation: Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Mike P
authors.initials: MP
authors.lastname: Wattjes
authors.affiliation: Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Frederik
authors.initials: F
authors.lastname: Barkhof
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Philip
authors.initials: P
authors.lastname: Scheltens
authors.affiliation: Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands.
authors.forename: Wiesje M
authors.initials: WM
authors.lastname: van der Flier
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000134:cerebrospinal fluid / Q000378:metabolism; D015415:Biomarkers / Q000134:cerebrospinal fluid / Q000378:metabolism; D059345:Cerebral Small Vessel Diseases / Q000134:cerebrospinal fluid* / Q000378:metabolism / Q000473:pathology*; D003430:Cross-Sectional Studies; D005260:Female; D006580:Genetic Carrier Screening; D006470:Hemorrhage / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000134:cerebrospinal fluid / Q000378:metabolism; D010766:Phosphorylation; D059409:Stroke, Lacunar / Q000097:blood / Q000134:cerebrospinal fluid / Q000473:pathology; D016875:tau Proteins / Q000134:cerebrospinal fluid / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D053327:Apolipoprotein E4; D015415:Biomarkers; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D016875:tau Proteins