Biomarkers.

Background: While we know dementia in Alzheimer's disease (AD) results from the accumulation of β-amyloid (Aβ), tau pathology, and hippocampus atrophy (HC), it is still unclear how these factors impose cognitive decline.

Method: We used Structural Equation Models (SEM; lavaan R package) to explore the complex relationships between the neurobiological factors in the early stages preceding AD dementia in the TRIAD cohort. Our sample comprised 333 timepoints of neuropsychological evaluation (MoCA), structural MRI, Aβ ([18F]AZD4694), and tau ([18F]MK6240) PET of cognitively healthy (NC) and mild cognitive impaired (MCI) participants.

Biomarkers.

Background: Alzheimer's disease is characterized by the accumulation of amyloid beta and the formation of tau neurofibrillary tangles (NFTs), leading to irreversible neurodegeneration. The formation of NFTs is believed to follow a stereotypical pattern known as Braak stages. Here, using tau-PET tracer 18F-MK-6240 we aim to analyze patterns of Tau accumulation associated with AD-related cognitive decline and build an in-vivo, data-driven staging system based on longitudinal data, using an estimated latent time of disease onset based on cognitive scores to place all subjects on a common timeline.

Biomarkers.

Background: Alzheimer's disease is a neurodegenerative disease associated with the accumulation of Amyloid-β and Tau neurofibrillary tangles following a pattern known as Thal and Braak stages, respectively (Thal 2002; Braak 1995,2011). Recent research (Pascoal 2020) showed the possibility of recapitulating Braak's histopathological stages in vivo using PET tracer [F]-MK-6240 with manually defined regions of interest. This study analyzes the joint patterns of Amyloid-β and Tau accumulation associated with AD in a completely data-driven fashion.

Biomarkers.

Background: The APOE ε4 variant is the largest known genetic risk factor for late-onset sporadic Alzheimer's disease (AD). Recent blood biomarker models include APOE ε4 status with plasma p-tau217 for higher accuracy for AD pathology. Thus, protein assays that can accurately determine ε4 carriership simultaneously with plasma p-tau217 would be advantageous for clinical use.

Biomarkers.

Background: The Motoric Cognitive Risk Syndrome (MCR) is a predementia stage characterized by slow gait speed and subjective cognitive complaints. Defining the heterogeneity of brain volumetrics in individuals with MCR will improve current dementia risk assessments.

Method: We used data from 6 cohorts from the MCR consortium (N=2,007).

Biomarkers.

Background: Aβ plaques are the first detectable signs of AD pathology. Our group recently demonstrated that the astrocyte activation marker, glial fibrillary acidic protein (GFAP), has a pivotal role in the association between Aβ burden and tau phosphorylation. However, the role of astrocyte activation in individuals that do not present detectable Aβ pathology using biomarkers is still underexplored.

Biomarkers.

Background: PET biomarkers have proven valuable for identifying cognitively unimpaired (CU) individuals at-risk of near-term clinical progression. Given the increasing interest in plasma biomarkers to detect Alzheimer's pathology, we assessed levels of amyloid (Aβ) and tau (p-tau217 and p-tau181) biomarkers in plasma (A+T+) in CU individuals as predictors of clinical progression to mild cognitive impairment (MCI). We then repeated these analyses using cerebrospinal fluid (CSF) and PET biomarkers.

Biomarkers.

Background: The potential clinical utility of plasma biomarkers for biological staging of AD demands definition and validation of cutoff values. Plasma ptau-217 and GFAP have accurately predicted core pathological changes such as tau aggregation and amyloid (Aβ) deposition, being proposed as complementary biomarkers. Thus, we aim to test a staging framework with plasma GFAP and ptau-217 using cuttof values to predict Aβ/Tau PET stages and compare its performance with an artificial intelligence (AI) prediction model.

Biomarkers.

Background: This study aims to investigate the differential patterns of association in tau protein imaging across cortical regions using two distinct Tau imaging agents: [18F]MK6240 and [18F]Flortaucipir. The underlying hypothesis posits that variations in the properties of these tracers, such as affinity and off-target effects, influence the observed patterns of association in neuroimaging.

Method: To test this hypothesis, a comprehensive study was conducted involving 104 subjects part of the HEAD study at McGill University: 53 cognitively normal (CN), 19 with mild cognitive impairment (MCI), 9 with Alzheimer's Disease (AD) and 23 non-AD.

Biomarkers.

Background: The default-mode network (DMN) consists of brain regions with higher resting activity levels. Amyloid-β (Aβ) deposition in Alzheimer's disease (AD) occurs predominantly throughout the DMN, suggesting that activity within the network may facilitate disease processes. Indeed, increased neural activity is positively associated with Aβ production.

Biomarkers.

Background: Identification of cognitively unimpaired (CU) individuals who may progress to mild cognitive impairment (MCI), is a pressing issue in the Alzheimer's disease (AD) field, since therapeutic interventions may be more effective in the absence of cognitive impairment and neurodegeneration. CU individuals positive for amyloid and tau PET are very likely in the AD pathway. In out-patient cognitive screening, we use rapid and simple tests such as The Montreal Cognitive Assessment (MoCA) - a composite of executive, visuospatial, naming, attention, language, abstraction, delayed recall, and orientation performances.

Biomarkers.

Background: In vivo studies using the tau PET tracers have shown high performance for the diagnosis of Alzheimer's disease dementia and patterns of tracer uptake that resemble those observed in post-mortem studies. However, tau tracers present distinct patterns of binding that might influence their performance in detecting AD pathology. In a head-to-head study, we investigated the performance of [F]MK6240 and [F]Flortaucipir for the diagnosis of AD.

Biomarkers.

Background: Astrocytes play a main role in brain energy metabolism, primarily through the metabolic cooperation with neurons. The use of [F]fluorodeoxyglucose(FDG)-PET has become a valuable indicator of neurodegeneration in Alzheimer's disease (AD), revealing a brain hypometabolic signature, but it is sensitive to changes in astrocyte metabolism. It is postulated that the activation of the excitatory amino acid transporter 2 (EAAT2) is the main trigger of FDG-PET uptake in astrocytes.

Biomarkers.

Background: Timely and non-invasive prediction of amyloid status are pivotal in Alzheimer's disease (AD) diagnostics. This research leverages T1 MRI images to predict amyloid positivity or negativity, offering an economical and less invasive alternative to amyloid PET scans. Using the comprehensive TRAID dataset from McGill University, the study evaluates a spectrum of cognitive conditions including AD, atypical AD, Cognitively Normal (CN), Mild Cognitive Impairment (MCI), MCI not due to AD, Suspected Non-Alzheimer's Pathophysiology (SNAP), and Vascular MCI (VMCI).

Biomarkers.

Background: Multiple studies have linked high cortisol levels, a frequently used biomarker of stress, with the Alzheimer's disease (AD) pathophysiology. However, the relationship between cerebrospinal fluid (CSF) cortisol levels and AD-related brain atrophy is not fully understood. This study sought to investigate the cross-sectional and longitudinal association between CSF cortisol levels and brain cortical thickness in patients across the biological and clinical continuum of AD.

Biomarkers.

Background: Glutamate is the main excitatory neurotransmitter in the brain, acting through ionotropic and metabotropic receptors, such as the neuronal metabotropic glutamate receptor 5 (mGluR5). The radiotracer [C]ABP688 binds allosterically to the mGluR5, providing a valuable tool to understand glutamatergic function. We have previously shown that neuronal [C]ABP688 binding is influenced by astrocyte activation.

Developing Topics.

Background: The presence of cortical amyloid-beta pathology is associated with white matter microstructural changes in Alzheimer's disease (AD), especially in tracts associated with memory. However, the relationships between tract-specific neuroinflammation and plasma markers of astrogliosis is underexamined; similarly, the involvement of tau neurofibrillary tangles is unclear in neuroinflammation. Here, we investigated the association between plasma glial fibrillary acidic protein (GFAP) and changing proportion of intravoxel freewater-a microstructural change associated with neuroinflammation-within white matter tracts vulnerable to AD.

Developing Topics.

Background: Tau pathology, a hallmark of Alzheimer's disease (AD), is thought to spread cell-to-cell via axonal connections, beginning focally before expanding throughout the brain. This study uses computational models to investigate the interplay between network spread and regional vulnerability in influencing tau spread, focusing specifically on MAPT and APOE genes, and Aβ plaques.

Method: 66 regional (Desikan-Killiany atlas) tau-PET standardized uptake value ratio (SUVR) values were extracted from participants in the Swedish BioFINDER-2 study: 429 cognitively normal (CN), 91 subjective cognitive decline (SCD), 168 mild cognitive impairment (MCI), and 182 AD.

Developing Topics.

Background: The deposition of β-amyloid (Aβ) plaques is a classical neuropathological feature of Alzheimer's disease (AD). Currently, it is believed that intermediate products of the Aβ fibrillogenesis process, like the β-amyloid oligomers (AβOs), are the most toxic forms, and are involved in neurodegenerative processes in AD. The evaluation of cerebral glucose metabolism in patients with β-amyloid plaque deposition using [F]FDG-PET has been used as a marker of neurodegeneration in AD.

Developing Topics.

Background: Lewy bodies (LB), the main hallmark of Parkinson's disease (PD), are a frequent co-pathology in Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). The varying extents of LB pathology in these disorders can influence disease progression and severity. Consequently, understanding LB impact on the proteomic profile of these diseases is crucial, potentially leading to identifyng novel blood biomarkers related to this pathology which are urgently needed.

Developing Topics.

Background: Alzheimer's disease is characterized by early decreases in cerebral glucose metabolism which are linked to reduced glucose transporter 1 (GLUT1) expression at the blood-brain barrier (BBB). Another key disease hallmark is the abundance of Aβ peptides as plaques in the brain which arise from the processing of the amyloid precursor protein (APP). Autosomal dominant inherited mutations causatively link APP itself to AD, rendering it imperative to fully understand APP's physiological functions to define the underlying biology of AD.

Developing Topics.

Background: Blood-based biomarkers have been revolutionizing the detection, diagnosis and screening of Alzheimer's disease (AD). Antibody-based immunoassays are powerful tools to investigate pathological changes indicated by blood-based biomarkers and have been studied extensively in AD research. A novel proteomic technology - NUcleic acid Linked Immuno-Sandwich Assay (NULISA) - was developed to improve the sensitivity of traditional proximity ligation assays and offer a comprehensive outlook for protein biomarkers in neurodegenerative diseases.

Developing Topics.

Background: Caregiver burden associated with Alzheimer's disease (AD) increases with AD severity, and current treatment options are limited. We aimed to describe the caregiver and treatment landscapes for patients with AD in Canada, split by disease severity.

Method: Data were drawn from the Adelphi Real World AD Disease Specific Programme (DSP)™, a cross-sectional survey of physicians in Canada, from March to October 2023.

Developing Topics.

Background: For individuals on the Alzheimer's disease trajectory, amyloid positivity generally precedes tau positivity, as defined by PET biomarkers. However, multiple studies report amyloid-negative tau-positive PET (A-T+) participants, whose clinical implications remain unclear. Here, utilizing the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort, we examined how A-T+ participants differ from other A/T profiles based on cognition, fluid biomarkers, and neuropathology-we also investigated the longitudinal trajectories of A-T+ participants.

Developing Topics.

Background: Alzheimer's disease (AD) dementia progresses from preclinical brain changes, through mild cognitive impairment (MCI), to AD with dementia. Early diagnosis and confirmation of underlying AD pathology is crucial; however, there is still much to learn about patients' diagnostic journey. We aimed to describe the diagnostic journey and barriers to diagnosis for patients with MCI or dementia due to AD in Canada.