Basic Science and Pathogenesis.

Background: Brain arteriolosclerosis (B-ASC) is a pathologic hallmark characterized by dysmorphic brain arteriolar wall thickening. B-ASC is a common finding at autopsy in aged persons - some degree of B-ASC is seen in >80% of brains beyond age 80 years - and is associated with cognitive impairment. Hypertension and diabetes are widely recognized as risk factors for B-ASC.

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: Apolipoprotein E (ApoE) exists in three protein isoforms: E2, E3, and E4, which differ by only one or two amino acids. These slight differences profoundly effect protein structure and function, allowing each isoform to differentially impact Alzheimer's Disease (AD) risk. Relative to the most common E3 isoform, E4 dramatically increases risk, while E2 confers a substantial decrease in risk.

Basic Science and Pathogenesis.

Background: Limbic-predominant age-related TDP-43 encephalopathy (LATE) has been recently recognized as a cause of dementia in the elderly. LATE and Alzheimer's disease (AD) share similar clinical presentations, and their neuropathological changes-LATE-NC and ADNC-commonly co-occur in the brains of individuals with dementia. Frontotemporal degeneration (FTLD-TDP) represents another group of TDP-43-associated neurodegenerative diseases.

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: Diagnosis of Alzheimer's disease (AD) via MRI is costly and can be limited by regional availability. With the recent advancements and discovery of amyloid in the retina, diagnosis of AD and the effect of AD pathology on the retina is becoming well characterized. However, the prevalence of vascular contributions to cognitive impairment and dementia (VCID) and its effects on the retina are less well known.

Basic Science and Pathogenesis.

Background: Cerebral Amyloid Angiopathy (CAA) occurs at the intersection of Alzheimer's disease and vascular contributions to cognitive impairment and dementia (VCID). In the human brain it occurs when amyloid beta (Aβ) aggregates in small/medium-sized cerebral blood vessels, which contribute to hypoperfusion and cognitive decline by altering vascular function and integrity. The current study seeks to track the progression of CAA and associated neuroinflammation and glial cell changes in Tg2576 mice.

Basic Science and Pathogenesis.

Background: This study identifies and quantifies diverse pathological tau forms in the retina at both early and advanced stages of Alzheimer's disease (AD) and assesses their correlation with disease status. In the pathogenesis of AD, the tau protein undergoes post-translational modifications, including hyperphosphorylation (p-tau). As the disease progresses, pathological tau can propagate as oligomers, aggregate into fibrils, and paired helical filaments (PHF), and ultimately form intraneuronal neurofibrillary tangles (NFTs).

Basic Science and Pathogenesis.

Background: We recently reported genetic associations with dementia-related proteinopathies. Using multidimensional generalized partial credit modeling, we constructed three continuous latent variables, corresponding to TDP-43, Aβ/Tau, and a-synuclein related neuropathology endophenotype scores.

Method: Participant data were drawn from the National Alzheimer's Coordinating Center (NACC) neuropathology (NP) data (from the September 2023 data freeze) linked to Alzheimer's Disease Genetics Consortium (ADGC) genotype data.

Basic Science and Pathogenesis.

Background: Aging microglia accumulate lipid droplets (LDs), secrete pro-inflammatory cytokines, and are defective in phagocytosis. The E4 allele of Apolipoprotein E (APOE) is the strongest genetic risk factor for late-onset Alzheimer's disease (LOAD) and is associated with increased neuroinflammation and LD accumulation. Here, we aimed to determine if the effects of aging and the E4 allele are synergistic in causing the accumulation of LDs seen in LOAD.

Basic Science and Pathogenesis.

Background: Compared to the 'neutral' E3, the E4 allele of Apolipoprotein E (APOE) confers up to a 15-fold increase in Alzheimer's Disease (AD) risk. Conversely, the neuroprotective E2 allele decreases AD risk by a similar degree. Here, we aimed to assess the therapeutic potential of cell-type specific allelic 'switching' by investigating the physiological and neuropathological changes associated with an inducible, in vivo APOE4 to APOE2 transition in astrocytes using a novel transgenic mouse model METHOD: The APOE "switch mouse" (APOE4s2) uses the Cre-loxP system to allow for inducible APOE allele switching from E4 to E2.

Basic Science and Pathogenesis.

Background: The characterization of intercellular communication between peripheral immune cells and the central nervous system (CNS) are essential for understanding the brain's response to aging and disease states, such as Alzheimer's disease. MicroRNAs (miRNAs) constitute a class of small non-coding RNAs that play a crucial role in regulating various biological and pathological processes, including those related to immunity and inflammation. MiR-223-3p, residing on the X chromosome, is a pivotal miRNA involved in the inflammatory response, with its expression being enriched in macrophages/microglia.

Clinical Manifestations.

Background: Disruption of sleep and circadian rhythms are associated with cognitive decline, preclinical Alzheimer's Disease (AD) pathology, and increased risk of dementia. Alleviating circadian rhythm and sleep disruption may improve cognition and reduce the progression of AD and related dementias (ADRD). Time-restricted eating (TRE), a circadian behavioral intervention that corrects disrupted eating rhythms by aligning food intake to the daytime, has demonstrated improvements in metabolic dysfunction and sleep quality.

Understanding recent advances in non-amyloid/non-tau (NANT) biomarkers and therapeutic targets in Alzheimer's disease.

Unlabelled: The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta-amyloid and tau. Recent clinical trial readouts implicate a variety of non-amyloid/non-tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13-14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs.

Acute communication between microglia and non-parenchymal immune cells in the anti-Aβ antibody injected cortex.

Anti-Aβ immunotherapy use to treat Alzheimer's disease is on the rise. While anti-Aβ antibodies provide hope in targeting Aβ plaques in the brain there still remains a lack of understanding regarding the cellular responses to these antibodies in the brain. In this study we sought to identify acute effects of anti-Aβ antibody on immune responses.

Behavioral and genetic markers of susceptibility to escalate fentanyl intake.

Background: The "loss of control" over drug consumption, present in opioid use disorder (OUD) and known as escalation of intake, is well-established in preclinical rodent models. However, little is known about how antecedent behavioral characteristics, such as valuation of hedonic reinforcers prior to drug use, may impact the trajectory of fentanyl intake over time. Moreover, it is unclear if distinct escalation phenotypes may be driven by genetic markers predictive of OUD susceptibility.

Targeted long-read sequencing to quantify methylation of the C9orf72 repeat expansion.

Background: The gene C9orf72 harbors a non-coding hexanucleotide repeat expansion known to cause amyotrophic lateral sclerosis and frontotemporal dementia. While previous studies have estimated the length of this repeat expansion in multiple tissues, technological limitations have impeded researchers from exploring additional features, such as methylation levels.

Methods: We aimed to characterize C9orf72 repeat expansions using a targeted, amplification-free long-read sequencing method.

The double life of glucose metabolism: brain health, glycemic homeostasis, and your patients with type 2 diabetes.

The maintenance of cognitive function is essential for quality of life and health outcomes in later years. Cognitive impairment, however, remains an undervalued long-term complication of type 2 diabetes by patients and providers alike. The burden of sustained hyperglycemia includes not only cognitive deficits but also the onset and progression of dementia-related conditions, including Alzheimer's disease (AD).

White matter free water mediates the associations between placental growth factor, white matter hyperintensities, and cognitive status.

Introduction: Placental growth factor (PlGF) may regulate cerebrovascular permeability. We hypothesized that white matter interstitial fluid accumulation, estimated via magnetic resonance imaging (MRI) free water (FW), would explain the associations between elevated PlGF, white matter hyperintensities (WMH), and cognitive impairment.

Methods: MarkVCID consortium participants ≥55 years old with plasma PlGF and brain MRI were included.

A Review of the Association Between Dietary Intake and Brain Iron Levels in Older Adults: Preliminary Findings and Future Directions.

Non-heme iron is essential for critical neuronal functions such as ATP generation, synaptogenesis, neurotransmitter synthesis, and myelin formation. However, as non-heme iron accumulates with age, excessive levels can contribute to oxidative stress, potentially disrupting neuronal integrity and contributing to cognitive decline. Despite growing evidence linking high brain iron with poorer cognitive performance, there are currently no proven methods to reduce brain iron accumulation in aging or to protect cognitive function from iron's negative effects.

RNApysoforms: Fast rendering interactive visualization of RNA isoform structure and expression in Python.

Motivation: Alternative splicing generates multiple RNA isoforms from a single gene, enriching genetic diversity and impacting gene function. Effective visualization of these isoforms and their expression patterns is crucial but challenging due to limitations in existing tools. Traditional genome browsers lack programmability, while other tools offer limited customization, produce static plots, or cannot simultaneously display structures and expression levels.