Alzheimer’s disease and neurodegeneration in symptomatic cerebral small vessel disease

Abstract

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.