One goal of the Longitudinal Early-onset Alzheimer\'s Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants.
LEADS amyloid-positive early-onset Alzheimer\'s disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson\'s Progression Markers Initiative (PPMI) study.
Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases.
Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases.
Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer\'s Disease Study (LEADS) is a key resource for early-onset Alzheimer\'s genetic research.

Alzheimer\'s disease (AD), the most common neurodegenerative disease and the first cause of dementia worldwide, has no effective treatment, and its pathological mechanisms are not yet fully understood. We conducted this study to explore the proteomic differences associated with Familial Alzheimer\'s Disease (FAD) in olfactory ecto-mesenchymal stem cells (MSCs) derived from PSEN1 (A431E) mutation carriers compared with healthy donors paired by age and gender through two label-free liquid chromatography-mass spectrometry approaches. The first analysis compared carrier 1 (patient with symptoms, P1) and its control (healthy donor, C1), and the second compared carrier 2 (patient with pre-symptoms, P2) with its respective control cells (C2) to evaluate whether the protein alterations presented in the symptomatic carrier were also present in the pre-symptom stages. Finally, we analyzed the differentially expressed proteins (DEPs) for biological and functional enrichment. These proteins showed impaired expression in a stage-dependent manner and are involved in energy metabolism, vesicle transport, actin cytoskeleton, cell proliferation, and proteostasis pathways, in line with previous AD reports. Our study is the first to conduct a proteomic analysis of MSCs from the Jalisco FAD patients in two stages of the disease (symptomatic and presymptomatic), showing these cells as a new and excellent in vitro model for future AD studies.

UNASSIGNED: Our limited understanding of the mechanisms that trigger the emergence of Alzheimer\'s disease (AD) has contributed to the lack of interventions that stop, prevent, or fully treat this disease. We believe that the development of a non-human primate model of AD will be an essential step toward overcoming limitations of other model systems and is crucial for investigating primate-specific mechanisms underlying the cellular and molecular root causes of the pathogenesis and progression of AD.
UNASSIGNED: A new consortium has been established with funding support from the National Institute on Aging aimed at the generation, characterization, and validation of Marmosets As Research Models of AD (MARMO-AD). This consortium will study gene-edited marmoset models carrying genetic risk for AD and wild-type genetically diverse aging marmosets from birth throughout their lifespan, using non-invasive longitudinal assessments. These include characterizing the genetic, molecular, functional, behavioral, cognitive, and pathological features of aging and AD.
UNASSIGNED: The consortium successfully generated viable founders carrying PSEN1 mutations in C410Y and A426P using CRISPR/Cas9 approaches, with germline transmission demonstrated in the C410Y line. Longitudinal characterization of these models, their germline offspring, and normal aging outbred marmosets is ongoing. All data and resources from this consortium will be shared with the greater AD research community.
UNASSIGNED: By establishing marmoset models of AD, we will be able to investigate primate-specific cellular and molecular root causes that underlie the pathogenesis and progression of AD, overcome limitations of other model organisms, and support future translational studies to accelerate the pace of bringing therapies to patients.

The associations of non-pathogenic variants of APP, PSEN1, and PSEN2 with Alzheimer\'s disease (AD) remain unclear. This study is aimed at determining the role of these variants in AD.
Our study recruited 1154 AD patients and 2403 controls. APP, PSEN1, PSEN2, and APOE were sequenced using a targeted panel. Variants were classified into common or rare variants with the minor allele frequencies (MAF) cutoff of 0.01. Common variant (MAF≥0.01)-based association test was performed by PLINK 1.9, and gene-based (MAF <0.01) association analysis was conducted using Sequence Kernel Association Test-Optimal (SKAT-O test). Additionally, using PLINK 1.9, we performed AD endophenotypes association studies.
A common variant, PSEN2 rs11405, was suggestively associated with AD risk (p = 1.08 × 10-2 ). The gene-based association analysis revealed that the APP gene exhibited a significant association with AD (p = 1.43 × 10-2 ). In the AD endophenotypes association studies, APP rs459543 was nominally correlated with CSF Aβ42 level (p = 7.91 × 10-3 ).
Our study indicated that non-pathogenic variants in PSEN2 and APP may be involved in AD pathogenesis in the Chinese population.

UNASSIGNED: Psoriasis is a chronic autoimmune inflammatory disease, the prevalence of which is 1-3% in the Polish population. Genome testing using single nucleotide polymorphisms revealed more than 50 regions associated with the risk of psoriasis, and most of these genes are associated with the immune system.
UNASSIGNED: To assess the presence of PSEN1 subunits of the γ-secretase gene polymorphisms in patients with psoriasis and comparison of results with a healthy control group.
UNASSIGNED: We used polymerase chain reaction - restriction fragment length polymorphism (PCR RFLP) method to assess polymorphisms. The starting material for analysis was peripheral blood obtained from the patient.
UNASSIGNED: PSEN1a-positivity was found in 2/52 (2.78%) of patients with psoriasis and 1/36 (3.85%) of healthy controls. PSEN1b positivity was seen in 3/52 (5.77%) of patients with psoriasis and 1/36 (3.85%) of control individuals. Only 3 patients with psoriasis but none of healthy volunteers had a presence of PSEN1c. Four patients were excluded from further statistical analysis.
UNASSIGNED: We have not shown a relationship between PSEN1 polymorphism and the clinical occurrence of psoriasis but now we start the assessment of other subunits of the γ-secretase gene - PSENEN and NCSTN.

Alzheimer\'s disease (AD) is the most common form of dementia. This neurodegenerative disorder is associated with neuronal death and gliosis heavily impacting the cerebral cortex. AD has a substantial but heterogeneous genetic component, presenting both Mendelian and complex genetic architectures. Using bulk RNA-seq from the parietal lobes and deconvolution methods, we previously reported that brains exhibiting different AD genetic architecture exhibit different cellular proportions. Here, we sought to directly investigate AD brain changes in cell proportion and gene expression using single-cell resolution.
We generated unsorted single-nuclei RNA sequencing data from brain tissue. We leveraged the tissue donated from a carrier of a Mendelian genetic mutation, PSEN1 p.A79V, and two family members who suffer from sporadic AD, but do not carry any autosomal mutations. We evaluated alternative alignment approaches to maximize the titer of reads, genes, and cells with high quality. In addition, we employed distinct clustering strategies to determine the best approach to identify cell clusters that reveal neuronal and glial cell types and avoid artifacts such as sample and batch effects. We propose an approach to cluster cells that reduces biases and enable further analyses.
We identified distinct types of neurons, both excitatory and inhibitory, and glial cells, including astrocytes, oligodendrocytes, and microglia, among others. In particular, we identified a reduced proportion of excitatory neurons in the Mendelian mutation carrier, but a similar distribution of inhibitory neurons. Furthermore, we investigated whether single-nuclei RNA-seq from the human brains recapitulate the expression profile of disease-associated microglia (DAM) discovered in mouse models. We also determined that when analyzing human single-nuclei data, it is critical to control for biases introduced by donor-specific expression profiles.
We propose a collection of best practices to generate a highly detailed molecular cell atlas of highly informative frozen tissue stored in brain banks. Importantly, we have developed a new web application to make this unique single-nuclei molecular atlas publicly available.