Background: Co-occurrence of cerebral small vessel disease (CSVD) is common in aging and Alzheimer disease (AD) dementia, but, in symptomatic CSVD prevalence and role of AD and neurodegenerative co-pathologies have been less explored. Methods: In vivo determination of prevalence, predictors and relevance for cognition of AD and neurodegenerative co-pathologies in symptomatic CSVD, including deep perforator arteriopathy (DPA) and cerebral amyloid angiopathy (CAA), utilizing cerebrospinal fluid (CSF) biomarkers. Cross-sectional study from October 2010 to September 2021 of participants with magnetic resonance imaging (MRI) and CSF biomarkers (amyloid-beta 42/40 ratio, phosphorylated-tau, total-tau, neurofilament light). Biomarker levels were compared among groups; prevalence of ATN classification subtypes was estimated and related to clinical phenotype, CSVD MRI markers and global cognition. Results: The study comprised 229 individuals (median age 74 years; 47% females), 70 with AD dementia, 79 with probable CAA, 62 with DPA patients and 18 healthy controls. Participants were categorized based on the ATN classification: normal biomarkers (A-T-N-), AD pathology continuum (A+), and non-AD pathological changes, including primary age-related tauopathy (PART, A-T+N+) or isolated neurodegeneration (A-T-N+). Of 141 CSVD patients, 43 (30%) were A-T-N-, 39 (28%) A+, with lower prevalence in DPA than CAA (15% vs. 38%, p = .003), 18 (13%) A-T+N+, and 41 (29%) A-T-N+, with higher prevalence in DPA than CAA (42% vs. 19%, p = .002). A+ was associated with increasing age, female sex, lobar hemorrhages and low burden of deep white matter hyperintensities and lacunes. A-T-N+ was related to younger age, symptomatic stroke and lacunes. A-T+N+ had no specific predictors, except advanced age. Each pathological ATN profile was independently related to lower Mini Mental State Examination scores (A+: B = -2.7, p = .013; A-T+N+: B = -4.6, p = .002; A-T-N+: B = -2.3, p = .034), accounting for demographics, clinical phenotype and MRI CSVD severity. Conclusions: Using biomarkers, this study confirms in vivo that CSVD frequently co-occurs with AD or neurodegenerative pathologies, exerting independent effects on cognitive health. As disease-modifying therapies emerge, integrating interacting biomarkers will be crucial for the selection of patients with the greatest benefit.

The authors have declared no competing interest.

This work was funded by the Deutsche Alzheimer Gesellschaft e.V. (DAlzG) and the Foerderstiftung Dierichs (www.foerderstiftung-dierichs.de) (MD‑DARS project) and by the German Research Foundation (GRK SynAge 2413). PA received a research scholarship by the Medical Faculty of the Otto-von-Guericke University Magdeburg.

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