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Original Investigation |

Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers

Maartje I. Kester, MD, PhD1; Jeroen D. C. Goos, MD, PhD1; Charlotte E. Teunissen, PhD2; Marije R. Benedictus, MSc1; Femke H. Bouwman, MD, PhD1; Mike P. Wattjes, MD, PhD3; Frederik Barkhof, MD, PhD3; Philip Scheltens, MD, PhD1; Wiesje M. van der Flier, PhD1,4
[+] Author Affiliations
1Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands
2Department of Clinical Chemistry, VU University Medical Center, Amsterdam, the Netherlands
3Department of Radiology, VU University Medical Center, Amsterdam, the Netherlands
4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
JAMA Neurol. 2014;71(7):855-862. doi:10.1001/jamaneurol.2014.754.
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Importance  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.

Design, Setting, and Participants  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.

Main Outcomes and Measures  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 and Relevance  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.

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Figure 1.
Effect of Magnetic Resonance Imaging (MRI) Measures on Cerebrospinal Fluid Biomarker Levels by Diagnosis

Linear regression analyses with dichotomous MRI measures (separate analyses for white matter hyperintensities, lacunes, and microbleeds) and cerebrospinal fluid biomarker levels of β-amyloid 42 (Aβ42) (A), tau (B), and tau phosphorylated at threonine 181 (P-tau181) (C) (dependent variables) were used, adjusted for age, sex, mediotemporal lobe atrophy, and diagnosis (as categories). Interaction terms for diagnosis MRI measure were included to estimate effect sizes per diagnosis group. Bars indicate standardized betas; error bars, 95% confidence intervals of the standardized betas.aP < .05.bP < .005.

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Figure 2.
Possible Model for the Upregulating Role of Apolipoprotein E (APOE) Genotype and Synergism Between Alzheimer Disease and Vascular Dementia Pathology
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