Risk factors for dementia and cognitive impairment within 5 years after stroke: a prospective multicentre cohort study

Background: Stroke survivors frequently experience subsequent cognitive impairment or dementia. We aimed to identify risk factors for post-stroke dementia (PSD) and cognitive impairment (PSCI) within 5 years after stroke. Methods: The DEMDAS (German Center for Neurological Diseases (DZNE) mechanisms of dementia after stroke) study is a prospective cohort of stroke patients admitted to six German tertiary stroke centres between May 1, 2011 and January 31, 2019. Eligible dementia-free patients with ischaemic or haemorrhagic stroke underwent baseline examinations and regular clinical, neuropsychological, and neuroimaging follow-ups over 5 years, with the last follow-ups completed in January 2024. PSD was the primary outcome, determined by comprehensive cognitive testing, patient and informant interviews, and review of medical records. The secondary outcomes were early-onset PSD (3-6 months), delayed-onset PSD (>6 months), and PSCI. Associations between baseline risk factors and PSD were assessed using Cox regression models adjusted for age, sex, education, and stroke severity. Findings: Of 736 patients (245 33% female, mean age 68·0 years SD 11·2, median admission National Institutes of Health Stroke Scale (NIHSS) 3 IQR 1-5), 557 (76%) were followed up until death or the end of the study, and 706 (96%) contributed to the PSD analysis. During a median of 5·0 years IQR 3·3-5·1 of follow-up, 55 new dementia cases were diagnosed (6-month incidence: 3·1% 1·8-4·5, 5-year incidence: 8·8% 6·5-11·1), of which 21 (38%) were classified as early-onset PSD. The 5-year risk of PSD was associated with older age (HR 1·13 95% CI 1·08-1·18 per year), higher stroke severity (1·08 1·03-1·13 per point on NIHSS), lower educational attainment (1·16 1·05-1·28 per year), acute phase cognitive impairment (5·86 2·21-15·58), lower Barthel Index (1·10 1·05-1·16 per 5 points less), atrial fibrillation (1·91 1·10-3·30), metabolic syndrome (MetS, 2·05 1·15-3·64), particularly reduced high-density lipoprotein cholesterol (HDL-C, 2·61 1·50-4·52) and pre-/diabetes mellitus (2·13 1·13-4·00), imaging markers of small vessel disease, and stroke recurrence during follow-up (2·36 1·16-4·83). Patients who received acute reperfusion treatment had a 65% lower risk of PSD than those who did not (0·35 0·16-0·77). While factors related to the severity of the index stroke were more strongly associated with early-onset PSD, MetS showed a stronger association with delayed-onset PSD. The association between MetS and PSD was independent of stroke recurrence and consistent across age subgroups, with 5-year cumulative incidence ranging from 1·7% (0·0-4·0) in patients ≤65 years without MetS to 24·5% (14·3-33·4) in patients ≥74 years with MetS. Interpretation: The risk of dementia after stroke is multifactorial, with differing risk profiles for early-onset and delayed-onset PSD. Metabolic syndrome, including reduced HDL-C, emerged as a novel risk factor and potential target for PSD prevention. Funding: German Center for Neurodegenerative Diseases (DZNE).