Basic Science and Pathogenesis.

Background: Accumulation of the amyloid-β (Aβ) peptide into amyloid plaque is one of the key pathological markers of Alzheimer's disease (AD). Apolipoprotein E (APOE) is known to modify AD risk and has been reported to influence Aβ accumulation in the brain in an isoform-dependent manner. ApoE can be produced by various cell types in the brain, with astrocytes being the main producer.

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: It is increasingly apparent that tau pathology in Alzheimer's disease (AD) begins in the brainstems of middle-aged patients, decades before the onset of symptoms. Most studies are, however, based on brain-bank cohorts and focus on patients dying of natural causes. The true incidence of tau pathology in the brainstem thus remains unclear.

Basic Science and Pathogenesis.

Background: Progressive supranuclear palsy (PSP) is a devastating primary tauopathy with rapid progression to death. Although several therapies currently in the development pipeline show promising safety profiles and robust target engagement, few demonstrated significant efficacy in patients, underscoring the need to interrogate additional targets with novel therapeutic modalities to expand the potential therapeutic arsenal. To diversify the therapeutic avenues for PSP and related tauopathies (e.

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: The extracellular amyloid plaques, one of the pathological hallmarks of Alzheimers Disease (AD), are frequently also observed in the cortex of cognitively unimpaired subjects or as co-pathology in other neurodegenerative diseases. Progressive deposition of fibrillar amyloid-β (Aβ) as amyloid plaques for two decades prior disease onset leads to extensive isomerization of Aβ N-terminus. Quantifying the extent of isomerized Aβ can be provide insight into the different stages of amyloidosis in the brain.

Basic Science and Pathogenesis.

Background: The microvasculature of the central nervous system (CNS), which delivers oxygen and nutrients and forms a critical barrier protecting the CNS, is deleteriously affected by both Alzheimer's Disease (AD) and Type 2 Diabetes (T2D). Previous studies have shown pericyte dropout and vessel constriction in brain capillaries in AD, while other studies have shown pericyte bridging and dropout in retinal capillaries in T2D. T2D patients have increased risk of AD, suggesting potentially related microvascular pathological mechanisms.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is a neurological disorder marked by progressive cognitive decline, memory deficits, and neuronal cell loss (Knopman, 2021). A brain region significantly impacted by the progression of AD is the subiculum, a structure responsible for spatial navigation, cognitive processes, and the modulation of emotional and affective behaviors within the hippocampus (Fanselow and Dong, 2010). Although subiculum cell loss has been well-established as an early indicator of AD (Carlesimo et al.

Basic Science and Pathogenesis.

Background: Preclinical animal models are essential for the development of effective treatments. For instance, the 5xFAD mouse model successfully represents the pathophysiology of Alzheimer's disease (AD). Expression of humanized APP (K670N/M671L - Swedish, I716V - Florida, V717I - London) and PSEN1 (M146L and L286V), found in early onset AD patients, induces the production of amyloid-β 42 (Aβ42) and amyloid deposition, gliosis, and progressive neuronal loss.

Basic Science and Pathogenesis.

Background: Mitochondrial dysfunction and Aβ accumulation are hallmarks of Alzheimer's disease (AD). However, the role of these pathologies in Down Syndrome associated Alzheimer's Disease (DSAD) is unknown. Decades of research describe a relationship between mitochondrial function and Aβ production.

Basic Science and Pathogenesis.

Background: Dementia exhibits abnormal network activity, including altered gamma frequency (30-100 Hz) in Alzheimer's disease (AD). A non-pharmacological, non-invasive approach to AD treatment involves stimulating sensory inputs using gamma band, with 40 Hz as the most effective in eliciting a robust EEG response. Light and sound stimulation at 40 Hz reduces AD pathology in mouse models and improves cognition in humans with AD.

Basic Science and Pathogenesis.

Background: Subjective Memory Complaints (SMC) are defined as the perception of one's own memory. In several studies SMC are associated with Alzheimer's disease (AD) neuropathologic changes, and only one study has analyzed and found an association of SMC with other neurodegenerative, but not vascular, neuropathologic changes. Yet, the evidence on the association of SMC with non-AD neuropathologic changes is insufficient.

Basic Science and Pathogenesis.

Background: Hemoglobin A1C (A1C) is a measure of long-term glycemic control. In a previous study using a single measure of A1C, we showed that it is related to postmortem cerebrovascular pathology. Here, we use annually collected A1C data to study the relationship of A1C average and variability over time with neuropathology in a large number of older adults with and without diabetes.

Basic Science and Pathogenesis.

Background: Recent studies suggest genome-wide-association-studies (GWAS) loci confer their effects on microglia in late-onset Alzheimer's disease (LOAD) brains. Relatively fewer studies have investigated the effects of other genome-wide significant loci (p<5e) using human neurons.

Method: GWAS itself cannot directly identify causal variant-(effector)gene-pairs as GWAS only reports the sentinel variant at a given locus.

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: 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: Dementia with Lewy Bodies (DLB) is one of the most common Alzheimer's Disease (AD)-related dementias and it is defined by the presence of abnormal cytoplasmic inclusions composed of aggregated α-synuclein (αsyn) in neuronal soma, known as Lewy bodies (LB). LB often coexists with AD type pathology such as amyloid-β (Aβ) plaques and neurofibrillary tangles containing hyperphosphorylated tau in several LB dementias, including Parkinson's Disease Dementia and Lewy Body variant AD. These co-pathologies likely represent a spectrum of various contributions of shared mechanisms that underlie these diseases.

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: An important hallmark of Alzheimer's Disease (AD) is the presence of neurofibrillary tangles (NFTs) composed of phosphorylated tau, which are commonly assessed using AT8 immunostains. Identifying additional markers to characterize the spectrum of NFT pathology is crucial for advancing our understanding and diagnosis of AD. This study introduces new potential markers to differentiate between tangles and healthy neurons.

Basic Science and Pathogenesis.

Background: SNX19 is a key player in endolysosomal and autophagy pathways, which have been extensively reported in neuronal dysfunction and neurodegenerative diseases. Although genetic and cellular evidence suggests SNX19 contributes to neuropathology, the underlying mechanisms remain unknown. Here, we propose to study the mechanism in aging postmortem brain tissue at single cell level and model SNX19 in human induced pluripotent stem cell (hiPSCs) derived brain organoids.

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: Abnormal tau protein accumulation selectively affects distinct brain regions and specific neuron and glia populations in tau-related dementias like Alzheimer's disease (AD), frontotemporal dementia (FTD, Pick's disease type), and Progressive supranuclear palsy (PSP). The regulatory mechanisms governing cell-type vulnerability remain unclear.

Method: In a cross-disorder single-nucleus analysis, we examined 663,896 nuclei, assessing chromatin accessibility in three brain regions (motor cortex, visual cortex and insular cortex) across PSP, AD, and FTD in 40 individuals.

Basic Science and Pathogenesis.

Background: Compared with the E3 allele of Apolipoprotein E (APOE), E4 increases late-onset Alzheimer's Disease (AD) risk up to 15-fold, while the E2 allele substantially decreases risk. In the CNS, ApoE is predominantly synthesized by astrocytes and microglia, making these two cell types promising targets for ApoE-directed therapeutic approaches. Our lab has generated an inducible "switch" mouse model (APOE4s2) in which we can conditionally replace E4 with the protective E2 in a cell-specific manner.

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.