Basic Science and Pathogenesis.

Background: Microglia are the major innate immune cells of the brain and play diverse roles in brain development and homeostasis. In the context of Alzheimer's disease, microglia acquire new phenotypes that can exert protective or pathogenic roles. Single cell and single nuclei RNA sequencing experiments have defined molecular signatures of different disease-associated microglia states associated with protective or pathogenic functions, but the mechanisms driving these transitions are not known.

Basic Science and Pathogenesis.

Motor proteins play a key role in neuronal functions and morphology that are important for learning and memory. We have previously reported that increased expression KIF11/Kinesin-5 overrides Aß-mediated effects on dendritic spine density and long-term potentiation in a mouse model of Alzheimer's disease (AD), effectively maintaining cognitive function in the face of Aß pathology. Here, we evaluated the association of key AD phenotypes with mRNA expression levels of a select set of Dynein motor proteins METHOD: We utilized measurements of gene expression, AD neuropathology burden, and cognition provided by the ROS/MAP study to determine whether an association exists between AD phenotypes and expression of genes for cytoplasmic and axonemal dynein heavy chains.

Basic Science and Pathogenesis.

Background: Several viruses have been linked to Alzheimer disease (AD) by independent lines of evidence.

Method: Whole genome and whole exome sequences (WGS/WES) derived from brain (3,404 AD cases, 894 controls) and blood (15,612 AD cases, 24,544 controls) obtained from European ancestry (EU), African American (AA), Mexican (HMX), South Asian Indian (IND), and Caribbean Hispanic (CH) participants of the Alzheimer's Disease Sequencing Project (ADSP) and 276 AD cases 3,584 controls (all EU) from the Framingham Heart Study (FHS) that did not align to the human reference genome were aligned to viral reference genomes. A genome-wide association study (GWAS) for viral DNA load was conducted using PLINK software and regression models with covariates for sex, age, ancestry principal components, and tissue source.

Basic Science and Pathogenesis.

Background: Single-nucleus RNA sequencing (snRNAseq) allows for the dissection of the cell type-specific transcriptional profiles of tissue specimens. In this study, we compared gene expression in multiple brain cell types in brain tissue from Alzheimer disease (AD) cases with no or other co-existing pathologies including Lewy body disease (LBD) and vascular disease (VaD).

Method: We evaluated differential gene expression measured from single nucleus RNA sequencing (snRNAseq) data generated from the hippocampus region tissue donated by 11 BU ADRC participants with neuropathologically confirmed AD with or without a co-existing pathology (AD-only = 3, AD+VaD = 6, AD+LBD = 2).

Basic Science and Pathogenesis.

Background: Excessive daytime sleepiness is a common and early symptom of Alzheimer's disease (AD). The subcortical wake-promoting neurons in the lateral hypothalamic area, tuberomammillary nucleus (TMN), and locus coeruleus synchronize to maintain wakefulness/arousal. Although significant neuronal decline occurs in wake-promoting regions, the TMN histaminergic neurons remain relatively more intact than orexinergic and nor-adrenergic neurons.

Basic Science and Pathogenesis.

Background: Genome-wide association studies (GWAS) in Alzheimer's disease (AD) leveraging endophenotypes beyond case/control diagnosis, such as brain amyloid β pathology, have shown promise in identifying novel variants and understanding their potential functional impact. In this study, we leverage two brain amyloid β pathology measurement modalities, PET imaging and neuropathology, to address sample size limitations and to discover novel genetic drivers of disease.

Method: We conducted a meta-analysis on an amyloid PET imaging GWAS (N = 7,036, 35% amyloid positive, 53.

Basic Science and Pathogenesis.

Background: The limited treatment options for Alzheimer's emphasizes the need to explore novel drug targets and bring new therapeutics to market. Drug repurposing is an efficient route to bring a safe and effective treatment to the clinic. Agomelatine (AGO) was identified by a high-throughput drug screening algorithm as having mechanistic potential to treat Alzheimer's.

Basic Science and Pathogenesis.

Background: Microglia undergo varying regional dependent functional changes, which can exacerbate cognitive decline in Alzheimer's disease, but the full clinical relevance remains unclear. Ramified microglia survey the micro-environment and inert/amoeboid microglia engulf debris. A third morphological type; rod microglia, have been observed in a number of pathological conditions, but are relatively understudied.

Basic Science and Pathogenesis.

Background: The misfolding and aggregation of the tau protein into neurofibrillary tangles constitute a central feature of tauopathies. Traumatic brain injury (TBI) has emerged as a potential risk factor, triggering the onset and progression of tauopathies. Our previous research revealed distinct polymorphisms in soluble tau oligomers originating from single versus repetitive mild TBIs.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has both genetic and environmental risk factors. Gene-environment interaction may help explain some missing heritability. There is strong evidence for cigarette smoking as a risk factor for AD.

Basic Science and Pathogenesis.

Background: Levels of inflammatory components gradually rise in tissues and blood as we age. This "inflammageing" process is often debilitating and even fatal. Cognitive impairment is one example of inflammageing's incapacitating nature.

Basic Science and Pathogenesis.

Background: Leveraging non-invasive ultra-high field, 7 Tesla (7T) MRI, with increased signal-to-noise ratio and improved soft tissue contrast afforded by 7T allows us to accurately map tissue microstructure. We aim to use 7T MR Elastography (MRE), 7T Diffusion Tensor Imaging (DTI), 3T amyloid-PET, and Preclinical Alzheimer Cognitive Composite (PACC) score to determine the relationships between these metrics in a cohort of older individuals with either normal cognition (CN), mild cognitive impairment (MCI), or Alzheimer's Disease (AD).

Methods: 7T MRE, 7T DTI, 3T PET (Fig.

Basic Science and Pathogenesis.

Background: The Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) is a public-private partnership linking NIH, the FDA, pharmaceutical companies, and nonprofit organizations in an interactive, collaborative program utilizing transcriptomics, genomics, metagenomics, proteomics, and metabolomics to provide data for computational analysis, that, in turn, enables promising targets to be ranked by a combination of omic scores and druggability. This ranking informs the selection of targets for validation.

Method: Human postmortem samples were obtained from Mount Sinai, ROSMAP (Religious Orders Study and Rush Memory and Aging Project), Mayo Clinic (Florida), and Columbia University.

Basic Science and Pathogenesis.

Background: Cerebral amyloid angiopathy (CAA) co-occurs with neurodegeneration in Alzheimer's disease (AD). CAA is absent in many AD mouse models, rendering CAA difficult to study. Previous work has shown wild-derived WSB/EiJ (WSB) mice over-expressing APP/PS1 had increased CAA, and thus may be useful in investigating CAA-causing mechanisms.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a devastating neurodegenerative disorder with few therapies to treat, mitigate or prevent its onset. Understanding of this disease is predominantly based on research in non-Hispanic Whites (NHW) although AD disproportionately affects African Americans (AA) and Latin Americans (LA), underrepresented in AD research. To address this knowledge gap, the Accelerating Medicine Partnership for Alzheimer's Disease (AMP-AD) Diversity Working Group was launched to generate multi-omics data from post-mortem brain tissue from donors of predominantly AA and LA descent.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is highly comorbid with Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC), and the combined AD+LATE-NC is more common than either pathology alone. However, the topographic relationship between tau and TDP-43 in AD+LATE-NC remains unclear.

Method: We analyzed the data from the Religious Orders Study (ROS) and the Rush Memory and Aging Project (MAP) participants.

Basic Science and Pathogenesis.

Background: Recent research reported that cancer patients had lower risk of Alzheimer's disease (AD). Common signaling pathways, hormonal systems, and genetic predispositions have been hypothesized as important factors contributing to this inverse association. However, the exact mechanisms are still unknown.

Basic Science and Pathogenesis.

Background: Non-coding RNA species, such as microRNA (miRNA), regulate multiple biological and pathological processes by binding to target mRNAs and facilitating alteration of translation levels via complexes such as RNA-induced silencing complex (RISC). Disrupting this process could contribute to AD pathogenesis by fostering aggregation of hyperphosphorylated microtubule-associated protein tau and amyloid-β (Aβ) peptides, and neuroinflammation. Understanding how these pathological changes are regulated remains our research focus.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) has a complex etiology where insults in multiple pathways conspire to disrupt neuronal function, yet molecular changes underlying AD remain poorly understood. Previously, we performed mass-spectrometry on post-mortem human brain tissue to identify >40 protein co-expression modules correlated to AD pathological and clinical traits. Module 42 has the strongest correlation to AD pathology and consists of 32 proteins including SMOC1, a predicted driver of network behavior and potential biomarker for AD.

Basic Science and Pathogenesis.

Background: Possession of the APOE4 allele is the strongest genetic risk factor for developing the sporadic form of Alzheimer's disease (AD). Studies investigating APOE4's associated AD risk have largely centered on APOE4's propensity to regulate the deposition of extracellular amyloid beta plaques. More recent attempts to characterize APOE4's role in AD have brought into question the role APOE4 may possess in modulating the pathogenesis of intracellular tau tangles.

Basic Science and Pathogenesis.

Background: The common APOE2/E3/E4 polymorphism, the strongest risk factor for Alzheimer's disease (AD), is determined by two-site haplotypes at codons 112 (Cys>Arg) and 158 (Arg>Cys), resulting into six genotypes. Due to strong linkage disequilibrium between the two sites, 3 of the 4 expected haplotypes (E2, E3, E4) have been observed and extensively studied in relation to AD risk. Compared to the most common haplotype of E3 (Cys112 - Arg158), E4 (Arg112 - Arg 158) and E2 (Cys112 - Cys158) haplotypes are determined by a single-point mutation at codons 112 and 158, respectively.

Basic Science and Pathogenesis.

Background: In tauopathies, the protein tau misfolds into a b-sheet conformation that self-templates and spreads throughout the brain causing progressive degeneration. Biological and structural data have shown that the shape, or strain, that tau adopts when it misfolds determines which disease a patient will develop. We previously used HEK293T cells expressing TauRD-YFP to show that tau strain formation is isoform-specific.

Basic Science and Pathogenesis.

Background: Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer's disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood-brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma.

Basic Science and Pathogenesis.

Background: The Apolipoprotein E ε4 (APOE-ε4) allele is common in the population, but acts as the strongest genetic risk factor for late-onset Alzheimer's disease (AD). Despite the strength of the association, there is notable heterogeneity in the population including a strong modifying effect of genetic ancestry, with the APOE-ε4 allele showing a stronger association among individuals of European ancestry (EUR) compared to individuals of African ancestry (AFR). Given this heterogeneity, we sought to identify genetic modifiers of APOE-ε4 related to cognitive decline leveraging APOE-ε4 stratified and interaction genome-wide association analyses (GWAS).