Association of modified dementia risk score with cerebrospinal fluid biomarkers and cognition in adults without dementia.

Introduction: This study aimed to investigate the cognitive profile and prospective cognitive changes in non-demented adults with elevated Modified Dementia Risk Scores (MDRS), while also exploring the potential relationship between these associations and cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) pathology and neuroinflammation. Methods: Within the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, 994 participants without dementia were assessed on MDRS, CSF biomarkers and cognition. We examined the associations of the MDRS with CSF biomarkers and cognitive scores using linear regressions. Causal mediation analyses were conducted to analyze the associations among MDRS, brain pathologies, and cognition. The Alzheimer's Disease Neuroimaging Initiative (ADNI) study was used to validate the mediation effects and to investigate the longitudinal association between MDRS and cognitive decline. Results: The results revealed that higher MDRS were linked to poorer cognitive performance (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and increases in CSF levels of phosphorylated tau (P-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), total tau (T-tau, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001), P-tau/Aß42 ratio (Model 1: PFDR = 0.023; Model 2: PFDR = 0.028), T-tau/Aß42 ratio (Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) and soluble triggering receptor expressed on myeloid cells 2 (sTrem2, Model 1: PFDR < 0.001; Model 2: PFDR < 0.001) in the CABLE study. The impact of MDRS on cognition was partially mediated by neuroinflammation and tau pathology. These mediation effects were replicated in the ADNI study. Baseline MDRS were significantly associated with future cognitive decline, as indicated by lower scores on the Mini-Mental State Examination (MMSE, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), ADNI composite memory score (ADNI-MEM, Model 1: PFDR = 0.005; Model 2: PFDR < 0.001), ADNI composite executive function score (ADNI-EF, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001), and higher score on the Alzheimer's Disease Assessment Scale (ADAS13, Model 1: PFDR = 0.045; Model 2: PFDR < 0.001). Discussion: The findings of this study revealed significant associations between MDRS and cognitive decline, suggesting a potential role of tau pathology and neuroinflammation in the link between MDRS and poorer cognitive performance in individuals without dementia. Consequently, the MDRS holds promise as a tool for targeted preventive interventions in individuals at high risk of cognitive impairment.

Age-Related Association Between APOE ɛ4 and Cognitive Progression in de novo Parkinson's Disease.

BACKGROUND: APOE ɛ4 genotype was correlated with exacerbation of pathology and higher risk of dementia in Parkinson's disease (PD). Meanwhile, the differential influence of APOE ɛ4 on cognition in young and old individuals interpreted as antagonistic pleiotropy. OBJECTIVE: To examine whether the effect of APOE ɛ4 on cognitive progression in de novo PD is age dependent. METHODS: In this study, 613 de novo PD patients were recruited from Parkinson's Progression Markers Initiative (PPMI). To examine the age-dependent relationship between APOE ɛ4 and cognitive changes, we added 3-way interaction of APOE ɛ4*baseline age*time to the linear mixed-effect (LME) models and evaluated the specific roles of APOE ɛ4 in the middle age group and elderly group separately. Cox regression was utilized to examine the progression of cognition in age-stratified PD participants. RESULTS: Age significantly modified relationship between APOE ɛ4 and cognitive changes in most cognitive domains (pinteraction <0.05). In the elderly group, APOE ɛ4 carriers showed steeper decline in global cognition (p = 0.001) as well as in most cognitive domains, and they had a greater risk of cognitive progression (adjusted HR 1.625, 95% CI 1.143-2.310, p = 0.007), compared with non-carriers. However, in the middle age group, no significant relationships between APOE ɛ4 and cognitive decline can be detected. CONCLUSION: Our results indicated that the APOE ɛ4 allele has an age-dependent effect on cognitive decline in PD patients. The underlying mechanisms need to be investigated in the future.