👤 Aravindakshan Jagadeesan

Alzheimer’s disease (AD) is increasingly recognized as a disorder of dysregulated neuroimmune connectivity rather than isolated proteinopathy. The immuno-glial connectome, the dynamic interplay between microglia, astrocytes, and peripheral immune systems, constitutes a central driver of disease initiation and progression. Emerging single-cell and spatial transcriptomic studies reveal heterogeneous glial subpopulations with context-dependent transcriptional programs governed by TREM2–APOE, NF-κB, JAK/STAT, and NLRP3 inflammasome signaling. These networks converge to sustain chronic inflammation, impair amyloid-β clearance, and accelerate tau pathology. Complement dysregulation (C1q–C3 axis) further promotes aberrant synaptic pruning, while cytokine feedback loops involving IL-1β, TNF-α, and IFN-γ amplify neurotoxicity. Beyond the brain, peripheral immune cells, monocytes, macrophages, T and B lymphocytes, and neutrophils breach the compromised blood–brain barrier (BBB), perpetuating inflammatory cascades. Parallelly, gut dysbiosis and microbial metabolites modulate microglial reactivity via the gut–brain axis (GBA), linking systemic inflammation to central immune activation. Recent advances in plasma and cerebrospinal biomarkers (GFAP, sTREM2, YKL-40, and neurofilament light chain) enable in vivo tracking of neuroinflammatory dynamics, bridging mechanistic research with clinical translation. Therapeutic strategies targeting the immuno-glial interface, including selective NLRP3 inhibitors, TREM2 agonists, anti-cytokine biologics, and microbiome modulation, are reshaping the therapeutic landscape. Framed through the concept of an immune–glial connectome, this review synthesizes how coordinated interactions among microglia, astrocytes, and peripheral immune cells converge to drive synaptic dysfunction, circuit-level disintegration, and cognitive decline in neurodegenerative disease, particularly in AD. An immuno-glial network in AD, where central glia, peripheral immune cells, and the gut–brain axis interact through cytokines, oxidative stress, and barrier dysfunction. These interrelated pathways amplify inflammation via NF-κB, JAK/STAT, and NLRP3 signaling, linking immune dysregulation to neurodegeneration. [Image: see text] Show less

Despite decades of research, Alzheimer's disease (AD) remains without a curative therapy. While amyloid- and tau-centered approaches have dominated the field, failures of monotherapeutic strategies underscore the need for a broader system-level understanding. Here, this review critically revisits the principal hypotheses of AD pathogenesis, including the amyloid cascade, tauopathy, neuroinflammation, cholinergic dysfunction, oxidative and mitochondrial stress, metal dyshomeostasis, autophagy-lysosomal failure, genetic susceptibility, and infectious triggers. This review synthesizes molecular and cellular evidence from human genetics, neuropathology, and experimental models, correcting common misconceptions and emphasizing interactions between pathways. Neuroinflammation is increasingly recognized as a central hub linking amyloid, tau, and vascular factors, while mitochondrial and lysosomal dysfunctions emerge as amplifiers of proteotoxic stress. Genetic studies highlight apolipoprotein-E ε4 (APOE ε4) as the strongest common risk allele, but also implicate genes involved in endosomal trafficking, lipid metabolism, and immune regulation. Taken together, AD is best understood as a multi-hit disorder in which converging processes, rather than a single driver, dictate disease initiation and progression. This narrative review proposes a systems neurobiology framework that integrates these mechanisms and identifies key points of convergence amenable to therapeutic targeting and biomarker development. Finally, this reappraisal aims to inform future research directions and guide the rational design of multi-target interventions. Show less

The genetic variant MYBPC3Δ25bp occurs in 4% of South Asian descendants, with an estimated 100 million carriers worldwide. MYBPC3 Δ25bp has been linked to cardiomyopathy and heart failure. However, the high prevalence of MYBPC3Δ25bp suggests that other stressors act in concert with MYBPC3Δ25bp. To determine whether there are additional genetic factors that contribute to the cardiomyopathic expression of MYBPC3Δ25bp. South Asian individuals living in the United States were screened for MYBPC3Δ25bp, and a subgroup was clinically evaluated using electrocardiograms and echocardiograms at Loyola University, Chicago, Illinois, between January 2015 and July 2016. Next-generation sequencing of 174 cardiovascular disease genes was applied to identify additional modifying gene mutations and correlate genotype-phenotype parameters. Cardiomyocytes derived from human-induced pluripotent stem cells were established and examined to assess the role of MYBPC3Δ25bp. In this genotype-phenotype study, individuals of South Asian descent living in the United States from both sexes (36.23% female) with a mean population age of 48.92 years (range, 18-84 years) were recruited. Genetic screening of 2401 US South Asian individuals found an MYBPC3Δ25bpcarrier frequency of 6%. A higher frequency of missense TTN variation was found in MYBPC3Δ25bp carriers compared with noncarriers, identifying distinct genetic backgrounds within the MYBPC3Δ25bp carrier group. Strikingly, 9.6% of MYBPC3Δ25bp carriers also had a novel MYBPC3 variant, D389V. Family studies documented D389V was in tandem on the same allele as MYBPC3Δ25bp, and D389V was only seen in the presence of MYBPC3Δ25bp. In contrast to MYBPC3Δ25bp, MYBPC3Δ25bp/D389V was associated with hyperdynamic left ventricular performance (mean [SEM] left ventricular ejection fraction, 66.7 [0.7%]; left ventricular fractional shortening, 36.6 [0.6%]; P < .03) and stem cell-derived cardiomyocytes exhibited cellular hypertrophy with abnormal Ca2+ transients. MYBPC3Δ25bp/D389V is associated with hyperdynamic features, which are an early finding in hypertrophic cardiomyopathy and thought to reflect an unfavorable energetic state. These findings support that a subset of MYBPC3Δ25bp carriers, those with D389V, account for the increased risk attributed to MYBPC3Δ25bp. Show less

Over 1,500 gene mutations are known to cause hypertrophic cardiomyopathy (HCM). Previous studies suggest that cardiac β-myosin heavy chain (MYH7) gene mutations are commonly associated with a more severe phenotype, compared to cardiac myosin binding protein-C (MYBPC3) gene mutations with milder phenotype, incomplete penetrance and later age of onset. Compound mutations can worsen the phenotype. This study aimed to validate these comparative differences in a large cohort of individuals and families with HCM. We performed genome-phenome correlation among 80 symptomatic HCM patients, 35 asymptomatic carriers and 35 non-carriers, using an 18-gene clinical diagnostic HCM panel. A total of 125 mutations were identified in 14 genes. MYBPC3 and MYH7 mutations contributed to 50.0% and 24.4% of the HCM patients, respectively, suggesting that MYBPC3 mutations were the most frequent cause of HCM in our cohort. Double mutations were found in only nine HCM patients (7.8%) who were phenotypically indistinguishable from single-mutation carriers. Comparisons of clinical parameters of MYBPC3 and MYH7 mutants were not statistically significant, but asymptomatic carriers had high left ventricular ejection fraction and diastolic dysfunction when compared to non-carriers. The presence of double mutations increases the risk for symptomatic HCM with no change in severity, as determined in this study subset. The pathologic effects of MYBPC3 and MYH7 were found to be independent of gene mutation location. Furthermore, HCM pathology is independent of protein domain disruption in both MYBPC3 and MYH7. These data provide evidence that MYBPC3 mutations constitute the preeminent cause of HCM and that they are phenotypically indistinguishable from HCM caused by MYH7 mutations. Show less