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

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 beta-amyloid 42 (A beta 42), total tau, and tau phosphorylated at threonine 181 (P-tau(181)) as well as for a subset of apolipoprotein E (APOE) epsilon 4 carriers and noncarriers. RESULTS Microbleed presence was associated with lower CSF A beta 42 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-tau(181). The presence of WMH was associated with lower A beta 42 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-tau(181). The presence of lacunes was associated with higher A beta 42 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 A beta 42 or P-tau(181). Stratification for apolipoprotein E genotype revealed that these effects were mostly attributable to epsilon 4 carriers. CONCLUSIONS AND RELEVANCE Deposition of amyloid appears aggravated in patients with cerebral small-vessel disease, especially in apolipoprotein E epsilon 4 carriers, providing evidence for pathophysiological synergy between these 3 biological factors.