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: Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TDP-43 pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN levels in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution.

Basic Science and Pathogenesis.

Background: Memory consolidation is an essential process for our everyday lives that is severely disrupted in Alzheimer's Disease (AD). Memories are initially encoded in the hippocampus before being consolidated in the neocortex by synaptic plasticity processes that depend on protein synthesis. However, how molecular pathways affect synaptic signalling during memory consolidation in health and disease is unclear.

Basic Science and Pathogenesis.

Background: Peripheral metabolic health status can reflect and/or contribute to the risk of Alzheimer's disease (AD). Peripheral metabolic health status can be indicated by metabolic health markers, such as inflammatory biomarker glycoprotein acetyls (GlycA) and specific components of lipoproteins (e.g.

Basic Science and Pathogenesis.

Background: Lewy body pathology (LBP) is common in autosomal dominant (ADAD) or sporadic Alzheimer disease (sAD). LBP seems to be the most frequent co-pathology in sAD and even in the relatively young ADAD population, where other co-pathologies are rare. Knowledge of neuropathological distribution patterns of LBP and associated survival and genetic characteristics in both AD variants is incomplete.

Basic Science and Pathogenesis.

Background: Argonaute2 (Ago2) plays an essential role in RISC-mediated silencing of target mRNAs, which are critical for cellular functions. Argonaute2 Syndrome, also known as Ago2 Syndrome, is a rare neurological disorder recently discovered in humans. It has significant implications for brain development, yet it remains unstudied to date METHOD: To study this effect, we deleted the Ago2 gene in GABAergic (Slc32a1 cre) and Glutamatergic (Slc17a6 cre) mice.

Basic Science and Pathogenesis.

Background: A significant proportion of individuals preserve cognitive function despite meeting neuropathological criteria for Alzheimer's disease (AD) at autopsy, known as cognitive resilience. We aimed to define the molecular and cellular signatures of cognitive resilience against AD.

Method: We integrated multi-modal data from the Religious Order Study and Memory and Aging Project (ROSMAP), including bulk (n = 631) and multi-regional single nucleus (n = 48) RNA sequencing.

Basic Science and Pathogenesis.

Background: Despite recent breakthroughs, Alzheimer's disease (AD) remains untreatable. In addition, we are still lacking robust biomarkers for early diagnosis and promising novel targets for therapeutic intervention. To enable utilizing the entirety of molecular evidence in the discovery and prioritization of potential novel biomarkers and targets, we have developed the AD Atlas, a network-based multi-omics data integration platform.

Basic Science and Pathogenesis.

Background: Anti-amyloid antibodies have been associated with amyloid-related-imaging-abnormalities (ARIA) in AD patients, causing vasogenic edema and microhemorrhages, especially in ApoE4 carriers. Here, we compared recombinant 3D6-L, a murine version of bapineuzumab, and an isotype control IgG2a monoclonal antibody (mAb) to investigate potential mechanisms, including complement activation, involved in these side effects (ARIA-H or microhemorrhages) following passive immunization.

Method: Plaque-rich 16.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) related pathologies (i.e., neurofibrillary tangles [NFTs], amyloid-β plaques, and phosphorylated-TAR-DNA-binding-protein-43 [pTDP-43]) differ across sexes.

Basic Science and Pathogenesis.

Background: The microtubule-associated protein tau is the most commonly misfolded protein in neurodegenerative disorders including Alzheimer's disease and other related tauopathies. These neurological illnesses are hypothesized to share a common mechanism of disease progression, where pathogenic aggregates or 'seeds' of the tau protein function as templates promoting misfolding of functional, soluble tau protein. Under this premise, therapeutic strategies that modulate the seeding cascade, have high potential to interfere with the disease process.

Basic Science and Pathogenesis.

Background: Genetic variations have emerged as crucial players in the etiology of Alzheimer's disease (AD), and they serve for a better understanding of the disease mechanisms; yet the specific roles of these genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Therefore, we generated zebrafish models for AD variants to analyze the in depth molecular and biological functions of these variants.

Basic Science and Pathogenesis.

Background: Western-diet (WD) can induce sterile inflammation and epigenetic reprogramming of myeloid cells, affecting their immune response (Christ et al., 2018). However, the molecular signaling mediating these changes was unknown.

Basic Science and Pathogenesis.

Background: As neurodegenerative diseases advance, postmitotic neurons are affected by disturbed proteostasis and the accumulation of misfolded proteins. This renders neurons sensitive to cell death, ultimately leading to progressive neuron loss. Multiple studies show the involvement of distinct pathways of regulated cell death (RCD) in neurodegenerative diseases, such as necroptosis.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), an untreatable synaptic disorder, is the most frequent cause of dementia. It is still unclear which mechanisms drive the early synapse dysfunction in the most common late-onset AD (LOAD). The second most important LOAD risk gene identified, BIN1, is an endocytic regulator.

dEREGulated pathways: Unraveling the role of epiregulin in skin, kidney and lung fibrosis.

The epidermal growth factor receptor (EGFR) signaling pathway is an evolutionary conserved mechanism to control cell behavior during tissue development and homeostasis. Deregulation of this pathway has been associated with abnormal cell behavior, including hyperproliferation, senescence, and an inflammatory cell phenotype, thereby contributing to pathologies across a variety of organs, including kidney, skin, and lung. To date, there are seven distinct EGFR ligands described.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) brains commonly exhibit various co-morbid pathologies, with cerebral amyloid angiopathy (CAA) being the most prevalent, affecting 70-90% of patients. CAA can be restricted to medium and large vessels or extend to capillaries. Additionally, AD patients often show pathologies involving phosphorylated-TDP-43 (pTDP-43) and alpha-synuclein (αSyn), typically demonstrating an amygdala-predominant subtype.

Basic Science and Pathogenesis.

Background: Worldwide, the actual number of 55 million people diagnosed with dementia is estimated to increase to 139 million people affected by dementia in 2050. 61% of these individuals resided in low and middle-income countries (LMIC). Genetic risk factors account for up to 80% of the attributable risk of Alzheimer's disease (AD), the leading cause of dementia.

Basic Science and Pathogenesis.

Background: Individuals with early stages of cognitive decline face a significant stagnation in their financial capacity, leading to a decrease in quality of life. However, whether changes in brain function are associated with financial capacity remains unclear. Here, we evaluate the association between financial capacity and brain glucose metabolism.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a heterogenous disease with a strong heritability. Genetic studies are of irreplaceable value in elucidating the mechanisms that underly this disease. The classical genome-wide association studies (GWAS) rely on ever-increasing sample sizes and utilize clinical AD diagnosis to investigate genetic risk.

Basic Science and Pathogenesis.

Background: Neuroimaging studies have revealed age and sex-specific differences in Alzheimer's disease (AD) trajectories. However, how age and sex modulate tau spreading remains unclear. Thus, we investigated how age and sex modulate the amyloid-beta (Aβ)-induced accumulation and spreading of tau pathology from local epicenters across connected brain regions.

Clinical Manifestations.

Future clinical trials targeting Alzheimer's disease (AD) on new disease modifying drugs necessitate a paradigm shift towards early identification of individuals at risk. Emerging evidence indicates that subtle alterations in language and speech characteristics may manifest concurrently with the progression of neurodegenerative disorders like AD. These changes manifest as discernible variations, assessable through semantic nuances, word choices, sentiment, grammar usage (linguistic features), and phonetic/acoustic traits (paralinguistic features).

Clinical Manifestations.

Background: Subjective cognitive decline (SCD) is a condition, where individuals report persistent decline of cognitive abilities, even though this decline is not detectable by neuropsychological screenings. Individuals with SCD are at a higher risk of suffering from mild cognitive impairment (MCI) and Alzheimer's disease (AD) in the future. It is important to better understand SCD to develop prevention measures, before a transition from a possible preclinical stage to MCI and AD.

Clinical Manifestations.

Background: Changes in speech and language functions have shown to be early symptoms of AD pathology. Recent developments in automatic speech and language processing have opened avenues for objective assessments of these changes. The primary objective of this study is to explore whether speech and language markers extracted from cognitive testing conducted during an automated phone call differ according to underlying AD pathology as measured in cerebrospinal fluid (CSF) in preclinical or early stage individuals.

Clinical Manifestations.

Background: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a neuropathologically-defined disease, and it is frequently comorbid with Alzheimer's disease neuropathological change (ADNC). However, the neurological syndrome associated with LATE neuropathological change (LATE-NC) is not defined. We propose a set of clinical criteria for a limbic-predominant amnestic neurodegenerative syndrome (LANS) that is highly associated with LATE-NC.