MRI Markers of Small Vessel Disease and the APOE Allele in Cognitive Impairment

Mana Shams; Sara Shams; Juha Martola; Lena Cavallin; Tobias Granberg; Magnus Kaijser; Max Wintermark; Eric Westman; Peter Aspelin; Maria Kristoffersen Wiberg; Lars-Olof Wahlund

doi:10.3389/fnagi.2022.897674

MRI Markers of Small Vessel Disease and the APOE Allele in Cognitive Impairment

Front Aging Neurosci. 2022 Jul 13:14:897674. doi: 10.3389/fnagi.2022.897674. eCollection 2022.

Authors

Mana Shams^{1

2}, Sara Shams^{1

2}, Juha Martola^{1

2}, Lena Cavallin^{1

2}, Tobias Granberg^{1

2}, Magnus Kaijser^{1

2}, Max Wintermark³, Eric Westman^{4

5}, Peter Aspelin^{1

2}, Maria Kristoffersen Wiberg^{1

2}, Lars-Olof Wahlund^{4

5}

Affiliations

¹ Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
² Department of Radiology, Karolinska University Hospital, Stockholm, Sweden.
³ Division of Neuroradiology, Department of Radiology, Stanford University Hospital, Stanford, CA, United States.
⁴ Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden.
⁵ Division of Clinical Geriatrics, Karolinska University Hospital, Stockholm, Sweden.

Abstract

Objective: The apolipoprotein E (APOE) ε4 allele is the main genetic risk factor for dementia and Alzheimer's disease (AD), but the underlying mechanism for the increased risk is not well understood. Cerebral small vessel disease (SVD) is prevalent among patients with cognitive impairment and is thought to play an important role in the pathophysiology of dementia. We aimed to investigate the association between the APOE ε genotype and magnetic resonance imaging (MRI) markers of SVD in a memory clinic population.

Material and methods: This is a cross-sectional study with a total of 520 patients undergoing dementia investigation, including an MRI brain scan and APOE genotyping in all patients enrolled, and cerebrospinal fluid (CSF) analysis for routine AD biomarkers in 399 patients. MR images were assessed for markers of SVD: cerebral microbleeds (CMBs), cortical superficial siderosis, intracerebral hemorrhage, white matter hyperintensities, lacunar infarcts, and enlarged perivascular spaces.

Results: Apolipoprotein E carriers with AD had a higher number of CMBs when looking at all brain regions and lobar brain regions (p < 0.001). A lower number of CMBs were seen in APOE ε2 (p < 0.05), ε3 and ε3/3 carriers (p < 0.001) when looking at all brain regions. A higher number of CMBs in deep and infratentorial regions were seen in APOE ε2 and ε3 (p < 0.05). In APOE ε4/4 carriers, CMBs, cortical superficial siderosis, white matter hyperintensities, and enlarged perivascular spaces were associated with lower levels of CSF amyloid β (Aβ) 42 in the whole cohort, and in individuals with AD and mild cognitive impairment (p < 0.05).

Conclusion: Apolipoprotein E ε4 is associated with MRI markers of SVD related to amyloid pathology, specifically CMBs and Aβ42 plaque formation in the brain, as reflected by decreased CSF Aβ42 levels, whereas APOE ε3 and ε2 are associated with the markers of hypertensive arteriopathy, as reflected by the association with CMBs in deep and infratentorial brain regions.

Keywords: Alzheimer's disease; apolipoprotein E; cerebral amyloid angiopathy; cerebral small vessel disease; dementia; hypertensive vasculopathy; magnetic resonance imaging.