Among the more than 90 identified genetic risk loci for late-onset Alzheimer's disease (AD) and related dementias, the apolipoprotein E (APOE) gene ɛ2/ɛ3/ɛ4 polymorphisms remain the longstanding benchmark for genetic disease risk with a consistently large effect across studies1-10. Despite this massive signal, the exact mechanisms by which ɛ4 increases and ɛ2 decreases dementia risk remain poorly understood. Notably, recent trials of anti-amyloid therapies suggest less efficacy and higher risks of severe side effects in ε4 carriers11-13, hampering the treatment of those with the highest unmet need. To improve our understanding of the genetic architecture of AD in the context of its main genetic driver, we performed genome-wide association studies (GWASs) stratified by ε4 and ε2 carrier status. HP1BP3, SLC50A1, PTPRC, NPAS3, DDHD1, CHST9, SMYD2, PRAMEF1 and GFRA1 emerged as new genomic signals for AD risk, appearing only when stratified by APOE carrier status. DDHD1 appeared especially promising, showing protective effects in ε4 carriers, being identified as an expression quantitative trait locus and being involved in rare neuronal diseases. Such APOE-stratified insights may help understand and overcome side effects, inform clinical trial enrollment strategies, and create the scientific basis for targeted, mechanism-driven therapies in neurodegenerative diseases.
J. Thomassen, H. Leonard, Brittany Ulms et al.· Nature Genetics· 0 citations
BackgroundThe choroid plexus (CP) is involved in cerebrospinal fluid production, immune surveillance, and brain fluid homeostasis. CP enlargement has been linked to neuroinflammation, glymphatic dysfunction, and white matter lesion (WML) burden, but the mechanisms underlying these associations remain uncertain.ObjectiveTo investigate the relationships among CP volume, glymphatic function estimated using diffusion tensor imaging along the perivascular space (DTI-ALPS), WML burden, and global cognitive performance in individuals with suspected neurodegenerative conditions, and to assess whether DTI-ALPS mediates the association between CP enlargement and white matter damage.MethodsWe retrospectively analyzed 104 participants, including 63 individuals with neurodegenerative conditions and 41 without neurodegeneration, who underwent multimodal MRI with 3D-T1-weighted, 3D-FLAIR, and diffusion-weighted sequences. CP volume was segmented using ASCHOPLEX and normalized to total intracranial volume. DTI-ALPS indices were derived from diffusion imaging, WML burden was quantified by automated segmentation, and global cognition was assessed using the Mini-Mental State Examination. Associations were tested using linear and quantile regression models. Mediation analysis evaluated indirect effects through DTI-ALPS.ResultsGreater CP volume was associated with lower DTI-ALPS values and higher WML burden. DTI-ALPS partially mediated the relationship between CP volume and WML burden, although the magnitude of mediation was modest. No significant mediation effect was observed for global cognitive performance. DTI-ALPS also showed strong associations with white matter integrity metrics, suggesting possible sensitivity to non-glymphatic microstructural changes.ConclusionsCP enlargement is associated with reduced DTI-ALPS and greater WML burden, but the contribution of glymphatic impairment remains uncertain. Alternative mechanisms, including neuroinflammation, blood-brain barrier dysfunction, and white matter microstructural damage, may contribute to these findings.
L. Sacchi, Valentina Veronesi, Giorgio Bocca et al.· Journal of Alzheimer's Disea...· 0 citations
Alzheimer's disease (AD) is increasingly recognized as a neurodegenerative disorder associated with chronic low-grade inflammation and age-related immune dysregulation. Microglial-derived extracellular vesicles (MDEVs) are emerging as important mediators of neuroimmune communication and potential biomarkers reflecting pathological processes occurring within the central nervous system (CNS). However, how EV-associated inflammatory signalling changes across different stages of AD remains poorly understood. In this study, we characterized the inflammatory molecular profile of serum-derived MDEVs in 22 AD patients, 19 prodromal AD subjects, and 23 healthy controls (HC). Cytokine concentrations were also evaluated in paired serum and cerebrospinal fluid (CSF) samples to compare vesicle-associated and soluble inflammatory signals across biological compartments. MDEVs were isolated by size exclusion chromatography followed by TMEM119-based immunoenrichment. Cytokine quantification was performed using the Ella Simple Plex automated immunoassay platform. MDEVs from AD patients showed a generalized reduction in both pro- and anti-inflammatory cytokines compared to HC, including IL-1β, TNF-α, IL-2, IFN-γ, IL-6, IL-12p70, IL-10, and IL-4. Notably, several alterations were already detectable at the prodromal stage. In contrast, soluble cytokines in serum and CSF displayed a predominantly pro-inflammatory profile in AD patients, with increased levels of IL-1β, TNF-α, and IL-12p70. No significant correlations were observed between cytokine levels measured in MDEVs and those detected in serum or CSF. Overall, these findings support the presence of a compartment-specific reorganization of inflammatory signalling during AD progression. Early alterations in MDEV inflammatory cargo may reflect disrupted EV-mediated neuroimmune communication and highlight the potential of MDEVs as accessible peripheral biomarkers of neuroinflammatory processes in AD.
Chiara Bianchessi, M. Serpente, E. Ferri et al.· GeroScience· 0 citations
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