Search

Large-scale genetic studies have identified numerous genetic risk factors that suggest a central role for innate immune cells in susceptibility to Alzheimer's disease (AD). CD33, an immunomodulatory transmembrane sialic acid binding protein expressed on myeloid cells, was identified as one such genetic risk factor associated with Alzheimer's disease. Several studies explored the molecular outcomes of genetic variation at the CD33 locus. It has been determined that the risk variant associated with AD increases the expression of the large isoform of CD33 (CD33M) in innate immune cells and alters its biological functions. CD33 is thought to signal via the interaction of its ITIM motif and the protein tyrosine phosphatase, SHP-1. Here, we utilize different molecular and computational approaches to investigate how AD-associated genetic variation in CD33 affects its interaction with SHP-1 in human microglia and microglia-like cells. Our findings demonstrate a genotype-dependent interaction between CD33 and SHP-1, which may functionally contribute to the AD risk associated with this CD33 variant. We also found that CD33-PTPN6 (SHP-1) gene–gene interactions impact AD-related traits, while CD33-PTPN11 (SHP-2) interactions do not. [ABSTRACT FROM AUTHOR]

ZCCHC17 is a putativemaster regulator of synaptic gene dysfunction in Alzheimer's disease (AD), and ZCCHC17 protein declines early in AD brain tissue, before significant gliosis or neuronal loss. Here, we investigate the function of ZCCHC17 and its role in AD pathogenesis using data fromhuman autopsy tissue (consisting of males and females) and female human cell lines. Co-immunoprecipitation (co-IP) of ZCCHC17 followed by mass spectrometry analysis in human iPSC-derived neurons reveals that ZCCHC17's binding partners are enriched for RNA-splicing proteins. ZCCHC17 knockdown results in widespread RNA-splicing changes that significantly overlap with splicing changes found in AD brain tissue, with synaptic genes commonly affected. ZCCHC17 expression correlates with cognitive resilience in AD patients, and we uncover an APOE4-dependent negative correlation of ZCCHC17 expression with tangle burden. Furthermore, amajority of ZCCHC17 interactors also co-IP with known tau interactors, and we find a significant overlap between alternatively spliced genes in ZCCHC17 knockdown and tau overexpression neurons. These results demonstrate ZCCHC17's role in neuronal RNA processing and its interaction with pathology and cognitive resilience in AD, and suggest that the maintenance of ZCCHC17 function may be a therapeutic strategy for preserving cognitive function in the setting of AD pathology. [ABSTRACT FROM AUTHOR]

Immunosenescence (ISC), the aging of the immune system, has largely been studied in populations of European descent. Here, circulating immune cell cytometric data from African-American, Hispanic, and non-Hispanic White participants were generated. Known and novel age effects were identified using either a meta-analysis approach or a parallel genetic approach. Most results are consistent across the three populations, but some cell populations display evidence of heterogeneity, such as a PD-L1 + CD56 + NK cell subset. The study estimated "Immunological Age" (IA) during physiologic aging. While we found no relation of IA to Multiple Sclerosis, IA is associated with entorhinal cortex atrophy, a presymptomatic feature of Alzheimer's disease, linking neurodegeneration and peripheral immunity. ISC trajectories were also inferred, highlighting age, CMV status, and genetic ancestry as key influences. Our assessment offers reference ISC trajectories for personalization of assessments of immune function over the life course in diverse populations.

In recent years, multiple groups have shown that what is currently thought of as "Alzheimer's Disease" (AD) may be usefully viewed as several related disease subtypes. As these efforts have continued, a related issue is how common co-pathologies and ethnicity intersect with AD subtypes. The goal of this study was to use a dataset constituting 153 pathologic variables recorded on 666 AD brain autopsies to better define how co-pathologies and ethnicity relate to established AD subtypes. Pathologic clustering suggests 8 subtypes within this cohort, and further analysis reveals that the previously described continuum from hippocampal predominant to hippocampal sparing is well represented in our data. Small vessel disease is overall highest in a cluster with a low hippocampal/cortical tau ratio, and across all clusters small vessel disease segregates separately from Lewy body disease. Two AD clusters are identified with extensive Lewy bodies outside amygdala (one with a high hippocampal/cortical tau ratio and one with a low ratio), and we find an inverse relationship between cortical tau and Lewy body pathology across these two clusters. Finally, we find that brains from persons of Hispanic descent have significantly more AD pathology in multiple neuroanatomic areas. We find that Hispanic ethnicity is not uniformly distributed across clusters, and this is particularly pronounced in clusters with significant Lewy body pathology, where Hispanic donors are only found in a cluster with a low hippocampal/cortical tau ratio. In summary, our analysis of recorded pathologic data across two decades of banked brains reveals new relationships in the patterns of AD-related proteinopathy, co-pathology, and ethnicity, and highlights the utility of pathologic subtyping to classify AD pathology., Competing Interests: Competing Interests: The authors declare no conflicts of interest

Background: Genetic research on Alzheimer's disease (AD) has primarily focused on amyloid-β (Aβ) pathogenesis, with fewer studies exploring tau pathology. Elucidating the genetic basis of tau pathology could identify novel pathways in AD., Methods: We conducted a genome-wide association study of tau standard uptake value ratios (SUVRs) from [18] F-flortaucipir positron emission tomography (PET) images to identify genetic variants underlying Tau pathology. Genetic data and tau-SUVRs from [18] F-flortaucipir PET images were acquired from the A4 (311 with preclinical AD) and ADNI (280 cognitively normal, 76 with mild cognitive impairment, and 19 AD patients) studies. Circulating plasma proteins in UK Biobank Pharma Proteomics Project (UKBPPP, N=54,129) were used to validate genetic findings. SNP genotypes were tested for association with Tau-SUVR levels adjusting for age, sex and population substructure variables. AD association of polygenic risk scores (PRS) of tau and amyloid-SUVRs were assessed. Causal effect of plasma protein levels on Tau pathology were tested using Mendelian randomization analyses., Results: GWAS of tau-SUVR revealed two significant loci: rs78636169 ( P =5.76×10 -10 ) in JARID2 and rs7292124 ( P =2.20×10 -8 ) near ISX . Gene-based analysis of tau deposition highlighted APOE ( P =2.55×10 -6 ), CTNNA3 ( P =2.86×10 -6 ) and JARID2 ( P =1.23×10 -4 ), a component of the PRC2 multi-protein complex which regulates gene expression. Mendelian randomization analysis of available circulating plasma proteins in the UK Biobank Pharma Proteomics Project (UKBPPP) identified LRRFIP1, a protein that binds with PRC2 multi-protein complex, as potentially causally linked to tau pathology. Genes associated with both amyloid and tau pathologies were enriched in endocytosis and signal transduction pathways. AD polygenic risk score (PRS) was associated with amyloid-SUVR but not with tau-SUVR. Amyloid-SUVR PRS had a notable association with AD clinical status, particularly in younger APOE -ε4 carriers, whereas tau-SUVR PRS showed a stronger association in older carriers., Conclusion: We identified a novel potential therapeutic target, JARID2 in the PRC2 multi-protein complex, for tau pathology. Furthermore, gene pathway analysis clarified the distinct roles of Aβ and tau in AD progression, underscoring the complexity of genetic influences across different stages of the disease.