AI Networking Cookbook: Practical recipes for AI-assisted network automation and development
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While most studies of Alzheimer's disease (AD) examine cross‐sectional relationships among biomarkers, longitudinal relationships are also highly relevant.
Staging amyloid beta (Aβ) burden along a continuous spectrum provides clinically relevant information. Conventional phosphorylated tau (p‐tau)217 reliably identifies amyloid positron emission tomography (PET) positivity, but its ability to capture the full Aβ continuum is limited. Recently developed brain‐derived (BD) p‐tau217 assays enrich for central nervous system tau species and may improve specificity.
Blood–brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown.
Lifestyle habits, cognitive reserve, and affective reserve (secure attachment, extraversion, psychological resilience) predict resilience in the oldest-old, though the underlying biological mechanisms remain unclear. This study explored relationships between these protective factors, 120 + NULISA CNS blood biomarkers, and multidimensional health outcomes (global cognition, mental health, walking speed) in 401 dementia-free participants (age 83-87) from the InveCe.Ab study. Using sparse partial least squares (sPLS) regression, eight biomarkers were stably associated with the protective factors: HBA1, DDC, IFNG, IL15, GOT1, ACHE, SNAP25, and SNCB. Structural equation modeling (SEM) showed that the three protective factors exerted an independent and domain-specific effect on health outcomes. Moreover, lifestyle habits were associated with ACHE (β = 0.26), IL15 (β = 0.22), and GOT1 (β = 0.28); affective reserve showed inverse associations with IFNG (β = -0.13) and IL15 (β = -0.31), and GOT1 (β = -0.18). Regarding health domains, SNAP25 was inversely related to global cognition (β = -0.10), while SNCB was associated with global cognition (β = 0.16) and walking speed (β = 0.13). Notably, no significant mediated effects were found, suggesting that the clinical benefits observed were not directly driven by the aforementioned biological pathways. The present study paves the way for further investigations on the biological mechanisms underlying resilient aging, while further demonstrating the key protective role of individual habits and psychosocial characteristics during the life course.
BACKGROUND Currently, no single biomarker can reliably identify preclinical Alzheimer's disease (AD), particularly at or before the mild cognitive impairment (MCI) stage. Given the heterogeneity of MCI, integrative approaches are needed to improve early risk stratification. OBJECTIVES (i) To derive robust latent cognitive components from a multicenter, clinically defined MCI cohort using principal component analysis (PCA); (ii) to investigate the associations between these components and plasma p-tau217 and p-tau181 levels. METHODS Data from 742 MCI participants in the AI-Mind cohort were analyzed. Cognitive domains were derived using PCA with varimax rotation and tested for associations with plasma p-tau biomarkers using site-specific linear regressions, adjusted for age, sex, and education. RESULTS A reproducible four-component cognitive structure emerged (memory, executive/processing speed, verbal fluency, visuospatial ability), with memory as the most p-tau-sensitive domain. The p-tau217 measure showed stronger associations with memory than p-tau181, though effects varied by site. CONCLUSION The findings indicate that a robust four-factor cognitive structure can be identified in clinically defined MCI cohorts without prior biological selection. The association between latent memory factors and plasma p-tau217, observed primarily in cohorts with higher biomarker burden or clearer amnestic profiles, highlights the potential for blood-based biomarkers to refine risk assessment in routine clinical practice.
BACKGROUND There is increasing evidence for the role of central and peripheral inflammation across neurodegenerative disorders, with animal models and post-mortem studies identifying T-cell infiltration in the brain associated with pathology and neurodegeneration. Peripheral T-cell changes have been measured in Alzheimer's disease (AD), dementia with Lewy bodies (DLB), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP). This study examines a unique cohort of blood-based T-cell profiles across a range of neurodegenerative dementias including AD, DLB, FTD, corticobasal syndrome (CBS), PSP, and aged-matched healthy controls. Then it also explores their associations with dementia-relevant plasma biomarkers and clinical outcomes. METHODS Freshly prepared peripheral blood mononuclear cells (PBMCs) from 174 participants (AD = 20, DLB = 24, FTD = 19, CBS = 18, PSP = 58, controls = 35) were studied using a flow-cytometry panel designed to analyse major T-cell subpopulations, including memory and T-helper subtypes. Neurodegeneration-relevant biomarkers (p-tau217, p-tau231, GFAP, NfL, and A-beta42/40) were measured in plasma samples. T-cell populations were compared between groups and in association with biomarkers, and principal components analysis (PCA) was used to identify T-cell profiles and their association with dementia-relevant biomarkers in diagnostic classification and survival prediction. RESULTS There was a significant reduction in the fraction of CD3+ cells in patients with DLB compared to other diagnostic groups, and an increase in relative Th1/17-like cell levels in patients with FTD compared to controls. This increase in Th1/17-like cells correlated with NfL and GFAP plasma levels in patients with FTD. PCA identified five components primarily representing CD4+ memory cell population subsets. After sex and age adjustments, component 4 marked by effector memory types including Th2-like, Th-like1 and Th1/17-like cells was a significant predictor of FTD, however was not as accurate as plasma NfL. Higher scores in specific T-cell components (1 and 3) were associated with reduced mortality across all diseases, with component 3 remaining a significant predictor even when controlling for traditional neurodegenerative biomarkers like NfL and p-tau217. CONCLUSIONS This study provides evidence that T-cell dysregulation is not unified in patients with neurodegenerative diseases. We observe different involvement across different dementia types establishing adaptive immunity as a key contributor to disease heterogeneity. However, although plasma biomarkers such as NfL and p-tau217 exhibit superior diagnostic accuracy for clinical classification, peripheral T-cell signature were associated with survival outcomes across diagnostic groups, highlighting their promise for prognostic applications and disease monitoring. The characterisation of T-cell populations across neurodegenerative conditions may inform target development and patient stratification for new interventional trials.
Abstract Individuals with autosomal dominant frontotemporal dementia (FTD) exhibit considerable variability in disease onset and progression. Both modifiable and non-modifiable factors—such as sex, educational attainment or geographic region of residence—may contribute to this heterogeneity, potentially through their influence on cognitive reserve. The aim of the present study was to investigate the role of cognitive reserve modulators within the Genetic Frontotemporal dementia Initiative (GENFI) cohort. To this end, we used functional MRI (i.e. spatial chronnectome measures) and neurodegenerative markers (i.e. plasma neurofilament light chains levels) to determine disease stage using a Discriminative Event-Based Model (DEBM). We then examined how potential modulators influence the relationship between disease stage and cognitive performance. We analysed a total of 711 participants, including 106 patients with genetic FTD, 325 presymptomatic mutation carriers and 280 non-carriers healthy controls. Female participants showed a weaker association between disease stage and cognitive performance compared to males (P < 0.001), with difference becoming progressively more pronounced across symptomatic stages. Educational attainment exhibited a similar effect: individuals with higher education demonstrated an attenuated association compared to those with secondary or primary schooling (P < 0.001), with differences already detectable at prodromal disease stages. The effect of geographical region of residence was associated with education levels, but appeared to have an indirect and less strong influence. In summary, sex and educational attainment significantly affect the development and maintenance of cognitive reserve in individuals with genetic FTD. These findings underscore the importance of identifying disease-modifying interventions since the presymptomatic stages of the disease.
In this large longitudinal sample of asymptomatic individuals, the Aβ-dominant biomarker component showed the strongest association with longitudinal GM atrophy and cognitive decline, beyond the effects of tau pathophysiology and neuroaxonal injury.
Plasma p-tau217 and p-tau181 are effective biomarkers for distinguishing biologically defined EOAD from EOFTD and adding NfL, GFAP, and APOE ε4 status further improves the discriminative accuracy for differentiating EOAD from EOFTD.
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