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).

Basic Science and Pathogenesis.

Background: Spatial disorientation is an early symptom of Alzheimer's disease (AD). The hippocampus creates a cognitive map, wherein cells form firing fields in specific locations within an environment, termed place cells. Critically, place cells remain stable across visits to an environment, but change their firing rate or field location in a different environment.

Basic Science and Pathogenesis.

Background: Heparan sulfate (HS) interacts with many important proteins. These interactions are primarily driven by electrostatics, with specificity determined by sulfation patterns. Although 3-O-sulfation is a rare modification in HS, several genome-wide association studies (GWAS) revealed that the Hs3st1 gene, encoding HS-3-O-sulfotransferase-1, is significantly linked to late onset AD risk.

Basic Science and Pathogenesis.

Background: Vascular dysfunction, blood-brain barrier (BBB) dysregulation, and neuroinflammation are thought to participate in Alzheimer`s disease (AD) pathogenesis, though the mechanism is poorly understood. Among pathways of interest, AD pathology appears to affect vascular endothelial growth factor-A (VEGFA) signaling in a bidirectional manner. Higher VEGF levels are thought to have a protective role and slow cognitive decline.

Basic Science and Pathogenesis.

Background: Stress is a common modifiable risk factor for AD, which increases dementia risk 2-fold. During the stress response, the hypothalamic-pituitary adrenal (HPA) axis is activated which stimulates the release of stress hormones called glucocorticoids into the blood stream. Studies on early-life stress have shown a glucocorticoid dependent vulnerability towards late-life inflammation.

Basic Science and Pathogenesis.

Background: To identify discrete and continuous cell type signatures in brain tissue from donors with minimal cognitive decline despite harboring substantial proteinopathies associated with Alzheimer's Disease and Alzheimer's Disease-related dementias.

Method: Three large-scale single-nucleus RNA-seq studies on Alzheimer's Disease post-mortem human tissue were re-annotated and integrated to identify cell type composition associations with cognitive resilience to various neuropathologies. Cell type signatures were defined in two ways: using an integrated clustering approach and using a continuous factor-based analysis.

Basic Science and Pathogenesis.

Background: Emerging studies have identified changes in lipid processing in Alzheimer's disease patients. However, how the various brain cell types respond to these changes is unclear. Multiple Alzheimer's disease risk genes are expressed in microglia and involved in lipid sensing and processing.

Basic Science and Pathogenesis.

Background: Women are disproportionately affected by Alzheimer's disease (AD) and exhibit greater AD neuropathology than men. Women possess two X chromosomes, with one randomly silenced across each cell for dosage compensation. X chromosome inactivation (XCI) is not complete, and XCI-escaping genes provide a promising avenue of discovery for biological pathways driving sex-specific AD risk.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disease that inflicts the elderly worldwide. Recent studies revealed the association of abnormal methylomic alterations in AD. However, a systematic and comprehensive study is needed to investigate the effects of methylomic changes on the molecular networks underpinning AD, in particular, in brain regions most vulnerable to AD neuropathology.

Basic Science and Pathogenesis.

Background: As high as 50% of Alzheimer's disease (AD) patients experience "sundowning", which refers to an increased severity of neuropsychiatric symptoms (NPS), including agitation, confusion, and anxiety, selectively in the evening. Although sundowning significantly influences the decision to institutionalize patients, few preclinical models of this phenomenon exist and the underlying neural mechanisms are unknown. Here, we establish a model of sundowning by phenotyping the sleep-wake cycle and anxiety and exploratory behavior at different times of day in an AD mouse model.

Basic Science and Pathogenesis.

Background: Common and rare variants in SORL1 have been associated with increased risk of Alzheimer's disease (AD). Since 2019, we have run an international collaborative research initiative to ascertain a Peruvian cohort for Alzheimer's disease and other related dementias for genetic studies (PeADI).

Method: A Peruvian family (4 AD cases and two mild cognitive impairment (MCI) cases) was recruited through the PeADI study.

Basic Science and Pathogenesis.

Background: SMOC1 has recently emerged as one of the most significant and consistent new biomarkers of early Alzheimer's disease (AD). SMOC1 is one of the earliest changing proteins in AD, with SMOC1 cerebrospinal fluid levels increasing 29 years before symptom onset in autosomal dominant AD. Despite this clear association with disease, very little is known about the role of SMOC1 in AD or its function in the brain.

Basic Science and Pathogenesis.

Background: The molecular etiology of tau-derived neurodegeneration remains poorly understood, reflected in the low success rate of clinical trials. Hence, aquiring a better understanding the molecular basis of tauopathies is a critical need.

Objective: To develop a versatile and reproducible system to study tau aggregation with high spatiotemporal control through optogenetics that will aid in investigating the differences in tau aggregation kinetics, the burden the burden of tau isoforms, and mutations and that will be suitable for high-throughput analysis of tauopathy-related mechanisms.

Basic Science and Pathogenesis.

Background: Microglia have been implicated as a key aspect of the pathology of Alzheimer's disease (AD). However, high microglial heterogeneities, including disease-associated microglia (DAM), tau microglia (tau-pathology related), and neuroinflammation-like microglia (NIM), hinder the development of microglia-targeted treatment.

Method: In this study, we integrated ∼0.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a severe neurodegenerative condition that affects millions of people worldwide. The TgF344 AD rat model, which exhibits early depression-like behavior followed by later cognitive impairment, is widely used to evaluate putative biomarkers and potential treatments for AD. The P7C3 neuroprotective compounds have shown protective efficacy for both brain pathology and neuropsychiatric impairment in this model.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) manifests with early spatial memory impairment and is linked to the degeneration of hippocampal circuits. Hippocampal sharp wave ripples (SWRs) are high-frequency population-burst events that coordinate the reactivation of neural assemblies (groups of neurons that become correlated in their firing patterns during learning) in post-learning sleep, which is the neural basis of memory consolidation. SWRs are reduced in the APP/PS1 mouse model of AD-like pathology.

Basic Science and Pathogenesis.

Background: Protective brain barriers, such as blood-brain barrier, become dysfunctional with age. The BBB is a dynamic and selective barrier, gating the passage of molecules and cells to and from the brain. The function of this barrier is critical for the maintenance of brain homeostasis.

Basic Science and Pathogenesis.

Background: Down syndrome (DS) is strongly associated with Alzheimer's disease (AD), attributable to APP overexpression, displaying common features with early-onset AD (EOAD) and late-onset AD (LOAD) like Amyloid-β (Aβ) and tau pathology. Here, we evaluated the Aβ plaques proteome of DS, EOAD and LOAD.

Method: We used unbiased localized proteomics to analyze amyloid plaques and the adjacent plaque-devoid tissue ('AD non-plaque') from post-mortem paraffin-embedded tissues in three subtypes of AD (n = 20/group): DS (59.

Basic Science and Pathogenesis.

Background: Activation of the mTOR pathway is pivotal for microglia to induce and sustain neuroprotective functions (Ulland et al., 2017; Wang et al., 2022).

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a degenerative condition characterized by a progressive decline in cognitive function, predominantly affecting older individuals. AD is associated with a range of histopathological alterations, including the gradual demise of neuronal cells, the accumulation of amyloid plaques, and the formation of neurofibrillary tangles. Furthermore, research suggests that the brain tissue of AD patients is subject to oxidative stress, which manifests as the oxidation of proteins, lipids, DNA, and the process of glycoxidation, throughout the disease progression.

Basic Science and Pathogenesis.

Background: APOEε4 significantly increases the risk of developing Alzheimer's disease (AD). Cognitively healthy APOEε4-carriers exist, suggesting potential protective mechanisms against APOEε4. We hypothesized that some APOEε4-carriers may have genetic variations protecting them from developing APOEε4-mediated AD pathology.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by progressive, irreversible neurodegeneration, leading to memory loss and cognitive decline. In mouse models of AD, global decreases in cerebral blood flow (CBF) are brought on by the plugging of capillaries by arrested neutrophils, and the administration of the neutrophil-specific antibody against Ly6G (anti-Ly6G) reduces these capillary stalls in minutes and improves cognitive function within hours. This suggests that at least some aspects of neural activity impairment are reversible, but the mechanism of this recovery - and what specific neural activity is normalized - is not yet known.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD), an age-associated neurodegenerative disorder, is characterized by progressive neuronal loss and the accumulation of misfolded proteins such as amyloid-β and tau. While neuroinflammation, mediated by microglia and brain-resident macrophages, plays a pivotal role in AD pathogenesis, the intricate interactions among age, genes, and other risk factors remain elusive. Somatic mutations, known to accumulate with age, instigate clonal expansion across diverse cell types, impacting both cancer and non-cancerous conditions.

Basic Science and Pathogenesis.

Emotional well-being (EWB) is considered to play an important role in the health of individuals over their lifespan. Clinical studies suggest an association between EWB and the risk or progression of AD. However, the mechanistic link and causal relationship between EWB and AD remain unknown, due to limited experimental access and control of the underlying brain processes in human.