Cerebral small vessel disease and the risk of Alzheimer's disease: A systematic review

Background: Cerebral small vessel disease (CSVD) comprises a variety of disorders affecting small arteries and microvessels of the brain, manifesting as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and deep brain infarcts. In addition to its contribution to vascular dementia (VaD), it has also been suggested to contribute to the pathogenesis of Alzheimer's disease (AD). Method: A systematic review of the literature available on Medline, Embase and Pubmed was undertaken, whereby CSVD was divided into WMHs, CMBs and deep brain infarcts. Biomarkers of AD pathology in the cerebrospinal fluid or plasma, or positron emission tomographic imaging for amyloid and/or tau deposition were used for AD pathology. Results: A total of 4117 articles were identified and 41 articles met criteria for inclusion. These consisted of 17 articles on vascular risk factors for clinical AD, 21 articles on A beta pathology and 15 articles on tau pathology, permitting ten meta-analyses. CMBs or lobar CMBs were associated with pooled relative risk (RR) of AD at 1.546, (95%CI 0.842-2.838, z = 1.41 p = 0.160) and 1.526(95%CI 0.760-3.063, z = 1.19, p = 0.235) respectively, both non-significant. Microinfarcts were associated with significantly increased AD risk, with pooled odds ratio OR at 1.203(95%CI 1.014-1.428, 2.12 p = 0.034). A beta pathology was significantly associated with WMHs in AD patients but not in normal age-matched controls. The pooled beta (linear regression) for total WMHs with CSF A beta 42 in AD patients was -0.19(95%CI -0.26-0.11, z = 4.83 p = 0.000) and the pooled r (correlation coefficient) for WMHs and PiB in the normal population was -0.10 (95%CI -0.11-0.30, 0.93 p = 0.351). CMBs were significantly associated with A beta pathology in AD patients. The pooled standardized mean difference (SMD) was-0.453, 95%CI -0.697- -0.208, z = 3.63 p = 0.000. There was no significant relationship between the incidence of lacunes and levels of CSFA beta, with a pooled beta of 0.057 (95%CI-0.050-0.163, z = 1.05 p = 0.295). No significant relationship was found between CMBs and the levels of CSFt-tau/CSFp-tau in AD patients (-0.014, 95%CI -0.556-0.529, z = 0.05 p = 0.960;-0.058, 95%CI -0.630-0.515, z = 0.20 p = 0.844) and cortical CMBs and CSF p-tau in the normal population (0.000, 95%CI -0.706-0.706, z = 0.00 p = 0.999). Conclusions: Some CSVD markers were significantly associated with clinical AD pathology and may be associated with A beta/tau pathology. WMHs and microinfarcts were associated with increased risk of AD. It remains unclear whether they precede or follow AD pathology.