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Associations Between Cerebral Small-Vessel Disease and Alzheimer Disease Pathology as Measured by Cerebrospinal Fluid Biomarkers
Abstract
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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“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
From The overlap between vascular disease and Alzheimer’s disease - lessons from pathology (2014) · cites this paper as [195]
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A systemic view of Alzheimer disease — insights from amyloid-β metabolism beyond the brain
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The overlap between vascular disease and Alzheimer’s disease - lessons from pathology
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“Modern CSF biomarkers may support a direct relationship between SVD and AD pathology [195], although in the Alzheimer Disease Neuroimaging Initiative that is focused on AD, no interactions were noted between vascular risk factors and AD biomarkers [26].”
BackgroundAmsterdam Dementia Cohort: Performing Research to Optimize Care
van der Flier, W. M., & Scheltens, P. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170850 · Cited by 388
Self-citationCerebrovascular disease in ageing and Alzheimer’s disease
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“[83] analysed brain magnetic resonance imaging (MRI) findings and cerebrospinal fluid (CSF) tau and Aβ levels in 914 consecutive participants in the Amsterdam Dementia Cohort.”
BackgroundLewczuk, P., Riederer, P. F., O’Bryant, S. E., Verbeek, M. M., Dubois, B., Visser, P. J., Jellinger, K. A., Engelborghs, S., Ramírez, A., Parnetti, L., et al. (2017) · The World Journal of Biological Psychiatry · doi:10.1080/15622975.2017.1375556 · Cited by 318
“The associations between the occurrence of microbleeds in AD patients and CSF Ab42 and Tau, without differences in the CSF Ab40 levels, were confirmed in two other publications (Goos et al. 2012; Kester et al. 2014).”
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Metadata
- Authors
- Kester, M. I., Goos, J. D. C., Teunissen, C. E., Benedictus, M. R., Bouwman, F. H., Wattjes, M. P., Barkhof, F., Scheltens, P., & van der Flier, W. M.
- Affiliations
- Amsterdam UMC Location Vrije Universiteit Amsterdam (NL)
- Alzheimer Center, Department of Neurology, VU University Medical Center, Amsterdam, the Netherlands4Department of Epidemiology and Biostatistics, VU University Medical Center, Amsterdam, the Netherlands
- Corresponding author
- Kester, Maartje I.
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2014-07-01
- Volume
- 71
- Issue
- 7
- Pages
- 855
- ISSN
- 2168-6149 (ISSN-L)
- OpenAlex
- W1979218016
- Cited by
- 161
- References
- 40
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 4 · 2023: 15 · 2022: 16 · 2021: 8 · 2020: 17 · 2019: 18 · 2018: 16 · 2017: 11 · 2016: 22 · 2015: 23 · 2014: 3
- FWCI
- 15.00
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- JAMA Neurology (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Pure Amsterdam UMC (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Clinical Neurology › Cerebrovascular and genetic disorders
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- cerebral small vessel disease, Alzheimer disease pathology, cerebrospinal fluid biomarkers, white matter hyperintensities, lacunes, cerebral microbleeds, amyloid-beta 42, tau protein, phosphorylated tau, APOE ε4, vascular dementia, dementia, cognitive decline, subjective memory complaints, amyloid PET
- MeSH terms
- Aged, Alzheimer Disease, Cross-Sectional Studies, Female, Hemorrhage, Genetic Carrier Screening, Humans, Male, Middle Aged, Peptide Fragments, Phosphorylation, Biomarkers, Amyloid beta-Peptides, tau Proteins, Apolipoprotein E4, Cerebral Small Vessel Diseases, Stroke, Lacunar
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