IMPORTANCE: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels. OBJECTIVE: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024. MAIN OUTCOMES AND MEASURES: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating). RESULTS: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impairment (cognitive unimpairment [CU]), and 1107 had mild cognitive impairment (MCI) or AD dementia (ADD). One thousand five hundred and thirteen participants (37.1%) had amyloid pathology, 1368 of 3599 (38.0%) with data available were APOE ε4 carriers, and 648 (15.9%) had CMBs. In the CU group, amyloid pathology and APOE ε4 copy number were not associated with presence of any, no more than 4, or fewer than 2 CMBs but were associated with increased odds of lobar CMBs (odds ratio [OR] for amyloid, 1.42 [95% CI, 1.20-1.69], P < .001; OR for 2 vs 0 alleles, 1.81 [95% CI, 1.19-2.74], P = .006; OR for 1 vs 0 alleles, 1.10 [95% CI, 0.83-1.46], P = .49; and OR for 2 vs 1 allele, 1.64 [95% CI, 0.90-2.97], P = .11; overall P = .02). In the MCI-ADD group, amyloid pathology was associated with presence of any CMBs (OR, 1.51 [95% CI, 1.17-1.96], P = .002), no more than 4 CMBs (OR, 1.44 [95% CI, 1.18-1.82], P = .002), and fewer than 2 CMBs (OR 1.34 [95% CI, 1.03-1.74], P = .03) but not lobar CMBs. APOE ε4 copy number was associated with presence of any (OR for 2 vs 0 alleles, 1.72 [95% CI, 0.88-3.35], P = .11; OR for 1 vs 0 alleles, 0.78 [95% CI, 0.59-1.04], P = .09; and OR for 2 vs 1 allele, 2.20 [95% CI, 1.32-3.67], P = .002; overall P < .001) and no more than 4 CMBs (OR for 2 vs 0 alleles, 1.31 [95% CI, 0.64-2.68], P = .45; OR for 1 vs 0 alleles, 0.75 [95% CI, 0.54-1.04], P = .08; and OR for 2 vs 1 allele, 1.76 [95% CI, 0.97-3.19], P = .06; overall P = .03) but not with fewer than 2 or lobar CMBs. Prevalence estimates of CMBs ranged from 6% at 50 years of age in a non-APOE ε4 allele carrier with no amyloid pathology and no cognitive impairment to 52% at 90 years of age in an APOE ε4 homozygote carrier with amyloid pathology and cognitive impairment. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 4080 participants, prevalence estimates of CMBs were associated with amyloid status, APOE ε4 copy number, and age. CMB prevalence estimates may help inform safety evaluations for antiamyloid clinical trials.

1st Department of Neurology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

Ace Alzheimer Center Barcelona Universitat Internacional de Catalunya Barcelona Spain

Alzheimer Center Limburg Department of Psychiatry and Neuropsychology School for Mental Health and Neuroscience Maastricht University Maastricht the Netherlands

Alzheimer's Centre Reina Sofia Research Centre on Neurological Diseases Carlos 3 Health Institute Madrid Spain

Amsterdam Neuroscience Brain Imaging Amsterdam the Netherlands

Banner Alzheimer's Institute Phoenix Arizona

Center for Vital Longevity School of Behavioral and Brain Sciences University of Texas at Dallas

Cerebriu A S Copenhagen Denmark

Clinical Neurochemistry Laboratory Sahlgrenska University Hospital Mölndal Sweden

Department of Diagnostic Radiology Copenhagen University Hospital Rigshospitalet Copenhagen Denmark

Department of Medicine and Psychiatry University of Cantabria Santander Santander Spain

Department of Neurobiology Care Sciences and Society Karolinska Institutet Stockholm Sweden

Department of Neurodegenerative Disease University College London Queen Square Institute of Neurology London United Kingdom

Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Neurology Alzheimer Centre Amsterdam Amsterdam Neuroscience Amsterdam UMC Locatie VUmc Vrije Universiteit Amsterdam Amsterdam the Netherlands

Department of Neurology Columbia University New York New York

Department of Neurology Marqués de Valdecilla University Hospital and IDIVAL Santander Spain

Department of Neurology of Memory and Language Groupe Hospitalier Universitaire Paris Psychiatry and Neurosciences Hôpital Sainte Anne Paris France

Department of Neuroradiology Aiginition Hospital National and Kapodistrian University of Athens Medical School Athens Greece

Department of Nuclear Medicine Marqués de Valdecilla University Hospital and IDIVAL Santander Spain

Department of Psychiatry and Neurochemistry Institute of Neuroscience and Physiology Sahlgrenska Academy at the University of Gothenburg Mölndal Sweden

Department of Radiology and Nuclear Medicine Amsterdam UMC Vrije Universiteit Amsterdam Locatie VUmc Amsterdam the Netherlands

Department of Radiology Leiden University Medical Center Leiden the Netherlands

Department of Radiology Marqués de Valdecilla University Hospital and Instituto de Investigación Marqués de Valdecilla Santander Spain

Epidemiology and Data Science Vrije Universiteit Amsterdam Amsterdam UMC Locatie VUmc Amsterdam the Netherlands

Hong Kong Center for Neurodegenerative Diseases Hong Kong China

Memory Unit Neurology Department Hospital de la Santa Creu i Sant Pau Barcelona Spain

Network Center for Biomedical Research in Neurodegenerative Diseases National Institute of Health Carlos 3 Madrid Spain

Neurochemistry Laboratory Department of Laboratory Medicine Amsterdam Neuroscience Amsterdam UMC Locatie VUmc Vrije Universiteit Amsterdam Amsterdam the Netherlands

Paris Saclay University BioMaps French National Institute of Health and Medical Research Alternative Energies and Atomic Energy Commission Service Hospitalier Frederic Joliot Orsay France

Paris Saclay University Translational and Applicative Neuroimaging Research Unit Neurospin CEA Gif sur Yvette France

Queen Square Institute of Neurology and Centre for Medical Image Computing Department of Medical Physics and Biomedical Engineering UCL London United Kingdom

Research and Development Biogen Inc Cambridge Massachusetts

UK Dementia Research Institute London United Kingdom

Wisconsin Alzheimer's Disease Research Center School of Medicine and Public Health University of Wisconsin Madison

Wisconsin Alzheimer's Institute School of Medicine and Public Health University of Wisconsin Madison

Zobrazit více v PubMed

Sperling RA, Jack CR Jr, Black SE, et al. . Amyloid-related imaging abnormalities in amyloid-modifying therapeutic trials: recommendations from the Alzheimer’s Association Research Roundtable Workgroup. Alzheimers Dement. 2011;7(4):367-385. doi:10.1016/j.jalz.2011.05.2351 PubMed DOI PMC

Solopova E, Romero-Fernandez W, Harmsen H, et al. . Fatal iatrogenic cerebral β-amyloid-related arteritis in a woman treated with lecanemab for Alzheimer’s disease. Nat Commun. 2023;14(1):8220. doi:10.1038/s41467-023-43933-5 PubMed DOI PMC

Jansen WJ, Janssen O, Tijms BM, et al. ; Amyloid Biomarker Study Group . Prevalence estimates of amyloid abnormality across the Alzheimer disease clinical spectrum. JAMA Neurol. 2022;79(3):228-243. doi:10.1001/jamaneurol.2021.5216 PubMed DOI

Jansen WJ, Ossenkoppele R, Knol DL, et al. ; Amyloid Biomarker Study Group . Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis. JAMA. 2015;313(19):1924-1938. doi:10.1001/jama.2015.4668 PubMed DOI PMC

Ossenkoppele R, Jansen WJ, Rabinovici GD, et al. ; Amyloid PET Study Group . Prevalence of amyloid PET positivity in dementia syndromes: a meta-analysis. JAMA. 2015;313(19):1939-1949. doi:10.1001/jama.2015.4669 PubMed DOI PMC

Petersen RC. Mild cognitive impairment as a diagnostic entity. J Intern Med. 2004;256(3):183-194. doi:10.1111/j.1365-2796.2004.01388.x PubMed DOI

Winblad B, Palmer K, Kivipelto M, et al. . Mild cognitive impairment–beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment. J Intern Med. 2004;256(3):240-246. doi:10.1111/j.1365-2796.2004.01380.x PubMed DOI

Kim YJ, Kim HJ, Park JH, et al. . Synergistic effects of longitudinal amyloid and vascular changes on lobar microbleeds. Neurology. 2016;87(15):1575-1582. doi:10.1212/WNL.0000000000003220 PubMed DOI

Chiang GC, Cruz Hernandez JC, Kantarci K, Jack CR Jr, Weiner MW; Alzheimer’s Disease Neuroimaging Initiative . Cerebral microbleeds, CSF p-tau, and cognitive decline: significance of anatomic distribution. AJNR Am J Neuroradiol. 2015;36(9):1635-1641. doi:10.3174/ajnr.A4351 PubMed DOI PMC

Benedictus MR, Goos JD, Binnewijzend MA, et al. . Specific risk factors for microbleeds and white matter hyperintensities in Alzheimer’s disease. Neurobiol Aging. 2013;34(11):2488-2494. doi:10.1016/j.neurobiolaging.2013.04.023 PubMed DOI

Coomans EM, van Westen D, Binette AP, et al. . The role of cerebrovascular pathology in the association between amyloid-β and tau in cognitively unimpaired and impaired individuals. Alzheimers Dement. 2023;19(S14). doi:10.1002/alz.079060 DOI

Goos JD, Kester MI, Barkhof F, et al. . Patients with Alzheimer disease with multiple microbleeds: relation with cerebrospinal fluid biomarkers and cognition. Stroke. 2009;40(11):3455-3460. doi:10.1161/STROKEAHA.109.558197 PubMed DOI

Graff-Radford J, Botha H, Rabinstein AA, et al. . Cerebral microbleeds: prevalence and relationship to amyloid burden. Neurology. 2019;92(3):e253-e262. doi:10.1212/WNL.0000000000006780 PubMed DOI PMC

McCarter SJ, Lesnick TG, Lowe VJ, et al. . Association between plasma biomarkers of amyloid, tau, and neurodegeneration with cerebral microbleeds. J Alzheimers Dis. 2022;87(4):1537-1547. doi:10.3233/JAD-220158 PubMed DOI PMC

Noguchi-Shinohara M, Komatsu J, Samuraki M, et al. . Cerebral amyloid angiopathy-related microbleeds and cerebrospinal fluid biomarkers in Alzheimer’s disease. J Alzheimers Dis. 2017;55(3):905-913. doi:10.3233/JAD-160651 PubMed DOI

Sparacia G, Agnello F, La Tona G, Iaia A, Midiri F, Sparacia B. Assessment of cerebral microbleeds by susceptibility-weighted imaging in Alzheimer’s disease patients: a neuroimaging biomarker of the disease. Neuroradiol J. 2017;30(4):330-335. doi:10.1177/1971400916689483 PubMed DOI PMC

Poels MM, Vernooij MW, Ikram MA, et al. . Prevalence and risk factors of cerebral microbleeds: an update of the Rotterdam scan study. Stroke. 2010;41(10)(suppl):S103-S106. doi:10.1161/STROKEAHA.110.595181 PubMed DOI