Basic Science and Pathogenesis.

Background: While individual etiological hypotheses for AD are researched, few large-scale theoretical integrative efforts linking entities involved in these dysfunctions have been attempted. Experimentally, assessing such a global theory is logistically near impossible to achieve as the number of variables is substantial. Alternatively, computational neuroscience allows for the joint study of multiple entities at this scale, the generation of predictions, and their validation with real data.

Basic Science and Pathogenesis.

Background: Altered neuronal timing and synchrony are biomarkers for Alzheimer's disease (AD) and correlate with memory impairments. Electrical stimulation of the fornix, the main fibre bundle connecting the hippocampus to the septum, has emerged as a potential intervention to restore network synchrony and memory performance in human AD and mouse models. However, electrical stimulation is non-specific and may partially explain why fornix stimulation in AD patients has yielded mixed results.

Basic Science and Pathogenesis.

Background: Drug discovery efforts in neurological diseases, such as Alzheimer's disease (AD), have had particularly poor outcomes due to the lack of models that capture the cerebral vasculature. There is an unmet need to develop models that capture the physiological challenge of overcoming the blood-brain barrier (BBB) and impacts of blood flow-induced shear stress. In this work, we use a microfluidic platform to model the cerebral vasculature in familial AD (fAD) using patient-derived brain endothelial-like cells (BECs) and neurons.

Basic Science and Pathogenesis.

Background: There is a common agreement that Alzheimer's disease (AD) is inherently complex; otherwise, a general disagreement remains on its etiological underpinning, with numerous alternative hypotheses having been proposed. Our objective was to perform a scoping review of original manuscripts describing hypotheses and theories of AD published in past decades.

Methods: We reviewed 127 original manuscripts that fulfilled our inclusion criteria out of more than 13,807 references extracted from open databases (from inception to 14 Sept 2023).

Basic Science and Pathogenesis.

Background: Autosomal dominant progranulin (GRN) mutations are a common genetic cause of frontotemporal lobar degeneration. Though clinical trials for GRN-related therapies are underway, there is an unmet need for biomarkers that can predict symptom onset and track disease progression. We previously showed that presymptomatic GRN carriers exhibit thalamocortical hyperconnectivity that increases with age when they are presumably closer to symptom onset.

Basic Science and Pathogenesis.

Background: Scavenger receptors (SR) are a group of receptors involved in the endocytosis of various ligands, such as modified LDL and soluble β-amyloid, which connects them to Alzheimer's disease (AD). SCARF2 (SREC-II) is part of the SR family, but unlike other scavenger receptors, internalizes a low amount of modified LDL. Its main function revolves around the binding of Aβ (Vo et al.

Basic Science and Pathogenesis.

Background: Replacement, Reduction, and Refinement (3R) guidelines propose the use of alternative models to study human diseases. These models have high homology and are less onerous compared to rodents, which dominate Alzheimer's disease (AD) research. However, it is still necessary to investigate whether evolutionary components are conserved among AD models cross-species.

Basic Science and Pathogenesis.

Background: Our current understanding of the molecular mechanisms underlying amyloidogenesis in Alzheimer's Disease (AD) is limited by the lack of comprehensive models closely resembling human pathology. Human induced pluripotent stem cell (hiPSC) 3-dimensional (3D) models, such as brain organoids and neurospheres, are emerging as innovative approaches to model neurodegenerative diseases in vitro. However, they rely on hiPSC self-organization and are therefore characterized by low reproducibility and homogeneity.

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: Antibodies targeting amyloid beta (Aß) have recently been developed as promising treatments for Alzheimer's Disease (AD). Aducanumab was the first to receive limited FDA approval in 2021 offering much needed new treatment options for AD patients. Aducanumab clears aggregated Aß in the brain, presumably through microglial phagocytosis, although the exact cellular and molecular mechanisms of its effect remain incompletely understood.

Basic Science and Pathogenesis.

Background: Recent studies have suggested a transient glucose hypermetabolism in early phases of Alzheimer's Disease (AD), which is followed by a characteristic glucose hypometabolism in dementia stages. This phenomenon desveres further investigation and it is suggested to be associated to glial/inflammatory or compensatory neuronal responses. Here, we aimed to longitudinally investigate brain glucose metabolism in an AD animal model and explore associated cellular and inflammatory changes.

Basic Science and Pathogenesis.

Background: Dysregulation of endolysosomal trafficking is a major pathogenic mechanism in Alzheimer's disease (AD). From the family of AD-linked endosomal pathway genes, SORL1 stands out as one of the highest risk factors. SORL1 encodes an endocytic sorting receptor that mediates endosomal trafficking and processing of key AD-associated molecules, including pathogenic forms of amyloid-β (e.

Basic Science and Pathogenesis.

Background: Intracellular accumulation of tau tangles in the brain is one of the most prominent manifestations of Alzheimer's disease (AD). Progression thereof across the AD stages has specific temporal and spatial patterns, wherein time is informative of space and vice versa. Here we introduce a novel method, Manifold Component Analysis (MCA), to represent tangle accumulation in 2D, reflecting the spatial aspect of tau propagation stages to further relate it to the temporal aspect thereof.

Basic Science and Pathogenesis.

Background: Previously, we identified macropinocytosis as a novel mechanism for direct and rapid trafficking of cell surface APP to lysosomes, bypassing early and late endosomes. This process depends on the activity of Arf6 and several Rho-GTPases, and inhibition of macropinocytosis reduces amyloid-beta (Aβ) production. Macropinocytosis is relatively unstudied in neurons and neuronal cells.

Basic Science and Pathogenesis.

Background: Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β (Aβ) plaques and tau tangles in the brain, and neurotransmission dysfunctions. Indeed, our group recently demonstrated that the γ-aminobutyric acid (GABA)ergic system is vulnerable to AD pathology in humans. However, whether this vulnerability is also present in AD rodent models is still unknown.

Basic Science and Pathogenesis.

Background: Murine models of Alzheimer's Disease (AD) have resulted in numerous discoveries leading to a better understanding of AD pathogenesis but results poorly translated to novel treatment options. Over the past years, iPSC-derived human neuronal cultures have been developed to better model AD in vitro. One key hallmark of AD is the presence of insoluble Aß plaques in the brain.

Basic Science and Pathogenesis.

Background: The endocannabinoid system has demonstrated roles in Alzheimer's Disease (AD), such as modulation of inflammation. Fatty Acid Amide Hydrolase (FAAH) is the enzyme responsible for the rapid inactivation of the endocannabinoid anandamide into arachidonic acid and ethanolamine. In doing so, FAAH modulates the concentration of anandamide and influences neurobehavioral functions and physiological conditions such as nociception and inflammatory responses.

Basic Science and Pathogenesis.

Background: Altered lipid profiles and lipid processing genes are associated with Alzheimer's disease (AD). There is a reported genetic interaction between the AD risk gene APOE and cholesterol ester transfer protein (CETP). Mice lack functional CETP which is critical to the balance of circulating lipoproteins; this imparts cardioprotective effects and may make mice resistant to AD.

Clinical Manifestations.

Background: Mild Behavioral Impairment (MBI) and functional ability are two non-cognitive markers of dementia. To date, little is known about the impact of functional ability on the clinical manifestation of MBI. Using data from the Australian population-based PATH Through Life Study we examined the impact of functional ability on MBI.

Clinical Manifestations.

Background: Despite the clinical importance and significant social burden of neuropsychiatric symptoms (NPS) in dementia, the underlying neurobiological mechanism remains poorly understood. Recently, neuroimaging-derived brain-age estimation by machine-learning analysis has shown promise as an individual-level biomarker. We investigated the relationship between NPS and brain-age in amnestic mild cognitive impairment (MCI) and early dementia.

Clinical Manifestations.

Background: Globally, females are at twice the risk of AD than males; in Canada, over 700,000 are living with Alzheimer's disease and related dementia (ADRDs), with 72% being female. However, females maintain verbal memory in the face of more AD pathology than men. It is unclear how multilingualism, considered a resilience factor, might interact with the risk and resilience of sex.

Clinical Manifestations.

Background: Multispecialty Interprofessional Team (MINT) Memory Clinics manage dementia care in primary care, allowing for more efficient use of limited specialist resources. This study examined the characteristics of patients on their initial assessment in the MINT clinic and investigated the five-year trajectory of patients with mild cognitive impairment (MCI).

Method: We conducted a retrospective chart review of 751 patients assessed within a MINT Memory Clinic between June 2006 and May 2019 to collect data on age, gender, diagnosis, and MoCA scores.

Clinical Manifestations.

Background: Subjective cognitive decline (SCD), or self-perceived declines in memory/cognition in cognitively healthy older adults is linked to increased cognitive decline, neurodegeneration, and white matter hyperintensity (WMH) burden. However, there is no consistent definition of how to classify people with SCD. This study investigated if individual questions in the Cognitive Change Index (CCI) and Everyday Cognition Scale (ECog), commonly used to classify SCD, are associated with brain volume and WMHs to the same degree.

Clinical Manifestations.

Background: Changes in the structure and use of language are well established clinical characteristics of Alzheimer's disease. In recent years, there has been a concerted effort to objectively quantify these changes using the latest advances in Natural Language Processing (NLP) tools. Much academic research has been conducted to evaluate how these speech characteristics change with the course of illness, but they have yet to be elevated beyond exploratory endpoints in trials.

Clinical Manifestations.

Background: Patients with Primary Progressive Aphasias (PPAs) almost systematically inquire about the longitudinal evolution of their disease in clinics but very little research exists on the issue.

Method: We studied 82 PPA patients from the Research Chair on PPA - Fondation de la Famille Lemaire Cohort over a 10-year span (42 logopenic, 21 non-fluent/agrammatic and 19 semantic PPAs) and collected data from 5 domains (language, cognition, motor, psychiatric, functional) at 5 time points from onset to death. Logistical regression analyses and repeated measures ANOVAs were conducted to delineate the longitudinal profile of each variant PPA.