Biomarkers.

Background: Tau-PET imaging allows in-vivo detection of neurofibrillary tangles. One tau-PET tracer (i.e.

Biomarkers.

Background: The heterogeneous etiology of "sporadic" Alzheimer's disease (sAD) includes genetic influences. To better understand synaptic dysfunction in AD pathogenesis, we used protein quantitative train loci (pQTL) assessments and a polygenic risk score (PRS) to examine the relationship between synaptic integrity and longitudinal cognitive performance in the presymptomatic phase of the disease.

Method: The PREVENT-AD cohort includes symptom-free elderly participants at risk of AD because of their family history.

Biomarkers.

Transactive response DNA-binding protein 43 (TDP-43) has emerged as a pivotal player in neurodegenerative diseases, particularly amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and the recently described limbic-predominant age-related TDP-43 encephalopathy (LATE). Detecting TDP-43 pathology in a minimally invasive manner is crucial for early diagnosis, monitoring disease progression and the assessment of therapeutic interventions. This talk explores recent advancements in the discovery and validation of novel biofluid measures aimed at detecting and characterising TDP-43 pathology.

Biomarkers.

Background: Accelerated epigenetic ageing has been associated with various age-related health outcomes, but its relevance for dementia risk prediction is unclear. We investigated whether accelerated midlife epigenetic age associates with poor later-life brain health.

Methods: Participants were 230 individuals from Insight 46, drawn from the 1946 British Birth Cohort, a population-based study of individuals born in the first week of March 1946.

Distinguishing Neural Correlates of Prediction Errors on Perceptual Content and Detection of Content.

Accounting for why discrimination between different perceptual contents is not always accompanied conscious detection of that content remains a challenge for predictive processing theories of perception. Here, we test a hypothesis that detection is supported by a distinct inference within generative models of perceptual content. We develop a novel visual perception paradigm that probes such inferences by manipulating both expectations about stimulus content (stimulus identity) and detection of content (stimulus presence).

Biomarkers.

Background: With the development of disease modifying therapies targeting specific pathologies, accurate in vivo biomarkers have become increasingly important for disease classification. Recently, tests for neuronal α-synuclein (Lewy body) pathology have become available, complementing pre-existing tests for Alzheimer's disease (AD) pathology (Aβ and tau fluid and PET biomarkers) and vascular disease (MRI). Here, we aimed to identify and characterize data-driven pathology-based subtypes using these biomarkers.

Biomarkers.

Background: The driving mechanisms of structural brain alterations in the earliest stages of Alzheimer's disease (AD) are not well understood. Previous heterogeneous findings in preclinical AD, including subtle atrophy and also increased grey matter (GM) volume, underscore the need for further exploration. This study uses an extensive fluid biomarkers panel to identify pathological drivers behind longitudinal GM changes in cognitively unimpaired (CU) adults.

Biomarkers.

Background: The high prevalence of mixed-pathology dementias suggests that multi-drug treatments may improve clinical outcomes; thus, in-vivo biomarkers for co-pathologies are needed. We investigated a novel assay for detecting seeds of misfolded alpha synuclein (αSyn) and explored its relationship to outcomes including Alzheimer's disease (AD) biomarkers, clinical features, and cognitive trajectories, in two community-based cohorts enriched for AD risk.

Method: Cerebrospinal fluid (CSF) obtained from participants in the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center (N=418 participants; 515 LPs; Table 1) was assayed using a clinically validated, qualitative Syn seed amplification assay (SAA; Amprion).

Biomarkers.

Background: Screening and disease monitoring are two core challenges of disease management in Alzheimer's Disease (AD). Digital speech and language features have shown promise as clinical outcomes in related disorders.

Methods: We reviewed how speech digital markers are currently used in AD, focusing on how behaviours are connected to underlying disease pathology.

Biomarkers.

Background: Synaptic dysfunction plays an important role in Alzheimer's disease (AD) and cognitive decline. We investigated the association between cerebrospinal fluid (CSF) synaptic protein levels and quantitative EEG (qEEG) measures, two modalities to measure synaptic dysfunction in AD pathology. We assessed combined and independent prognostic value of both modalities for cognitive decline along the AD continuum.

Biomarkers.

Background: A growing body of evidence demonstrates the relationship between cardiovascular risk and the risk of dementia development. Researchers have identified several genetic links between cardiovascular diseases and Alzheimer's disease, including the apolipoprotein E and methylenetetrahydrofolate reductase (MTHFR) genes. Here we evaluated the impact of cardiovascular polygenic risk on pathological brain changes associated with Alzheimer's disease, to elucidate the potential mechanism by which cardiovascular risk induces brain damage.

Biomarkers.

Background: Diabetes is associated with an increased risk of developing neurodegenerative conditions, including Alzheimer's disease. Abnormal insulin signalling can lead to impaired phosphorylation of protein kinase B and activation of phosphatidylinositol 3-kinase, resulting in hyperphosphorylation of tau and activation of inflammatory pathways. However, people living with diabetes commonly exhibit comorbid cardiovascular risk, which are also linked with cognitive decline.

Biomarkers.

Background: The immune complement system is key to the elimination of redundant neural connections in the brain through a process called synaptic pruning. In neurodegenerative diseases such as Alzheimer's disease (AD), this system may result in excessive synapse loss, leading to brain atrophy and cognitive impairment. While increased cerebrospinal fluid (CSF) levels of complement proteins have been observed in patients with AD dementia, no studies have yet investigated the role of complement in the pre-symptomatic phase of AD, nor throughout its progression.

Biomarkers.

Background: Co-pathology between Alzheimer's disease (AD), Parkinson's disease (PD), and dementia with Lewy bodies (DLB) remains poorly understood but is relevant for trial design. We aimed to compare CSF markers of amyloid, tau, and neurodegeneration (ATN) and α-synuclein between AD, PD, DLB and controls, and investigate the influence of demographical, genetic, and clinical factors on amyloid positivity.

Method: As part of the EPND study, we included 337 individuals with AD, PD, DLB and controls from 6 centers.

Biomarkers.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by cognitive decline, memory loss, and impaired daily functioning. As the global population ages, the prevalence of AD continues to rise, emphasising the urgent need for effective preventive and therapeutic strategies. Carotenoids, a group of naturally occurring pigments with antioxidant properties, have gained attention for their potential neuroprotective effects.

Biomarkers.

Background: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 having the greatest utility. Increased and simplified access to blood biomarkers is crucial for early diagnosis, proper patient management and prompt initiation of disease-modifying treatments. The DROP-AD project investigates the capability of finger-prick collection to accurately measure p-tau217, neurofilament light (NfL), and glial fibrillary acidic protein (GFAP).

Biomarkers.

Background: Recent research reveals that Alzheimer's Disease blood-based biomarkers (BBB) are influenced by demographics as well as kidney function and comorbidities. Data on differences in BBBs by race and ethnicity are sparse. We examined whether racial/ethnic differences in BBBs persist after controlling for kidney function and comorbidities.

Biomarkers.

Background: Familial Alzheimer's disease (fAD), arising from mutations in amyloid-precursor-protein (APP) and presenilin (PSEN1/2) genes, leads to the production of longer, aggregation-prone amyloid-beta (Aβ) peptides-a hallmark of Alzheimer's disease. Age-at-onset (AAO) varies among carriers of different mutations. Recent evidence challenges the Aβ42:40 ratio as the leading and predictor of AAO between different pathogenic variants, prompting exploration of peptide combinations as potential biomarkers for these tasks.

Biomarkers.

Background: Hippocampal atrophy is being characterized as a key biomarker in neurodegenerative disease, especially for dementia. Nevertheless, detecting hippocampus relied on magnetic resonance imaging (MRI), it's very costly and time-consuming. Our objective is to develop a predictive score to detect MRI-related hippocampal volume based on large-scale blood proteomics.

Biomarkers.

Background: Chronic kidney disease (CKD) has relatively high prevalence and independently increases dementia risk. Currently, there is a lack of high-performance dementia prediction tools designed for the CKD population in clinical practice. Through proteomics discovery, this study aimed to discover more efficient dementia risk models in CKD patients.

Biomarkers.

Background: Understanding when Aβ positive cognitively normal individuals develop tau pathology has important implications for treatment with anti-Aβ therapies. We employed a changepoint regression approach to estimate time from Aβ-PET positivity to regionally elevated tau-PET in a population-based cohort of primarily cognitively unimpaired individuals.

Method: Participants from Insight 46 (1946 British birth cohort) underwent two [F]florbetapir Aβ-PET scans and a sub-sample enriched for Aβ were also scanned with [F]MK-6240 tau-PET, characteristics are presented in Table 1.

Biomarkers.

Background: In murine models, peripheral blood factors have been identified as having either a brain rejuvenating or ageing effect. However, it is unclear whether these blood factors have similar effects in humans. We aimed at testing the association between these blood factors and cognitive performance in cognitively unimpaired (CU) individuals at risk of Alzheimer's disease (AD).

Biomarkers.

Background: The Cardiovascular risk factors, aging, and dementia (CAIDE) risk score is a validated tool estimating dementia risk. We investigated the association of CAIDE score with 12 markers of glucose and lipid metabolism, in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) participants.

Methods: The FINGER trial had 1260 participants, aged 60-77 years, with a CAIDE score ≥6, without substantial cognitive impairment.

Biomarkers.

Background: Recently, the development of ultra-sensitive immunoassays has allowed for the detection, in blood, of proteins related to the pathophysiology of Alzheimer's disease (AD), with phosphorylated tau (p-tau) being the most promising. However, current methods are often limited by their ability to measure one analyte, lacking the potential for discovery and inclusion of additional biomarkers with supplemental value. In this pilot study, we explored proteomic changes using the novel NUcleic acid Linked Immuno-Sandwich Assay (NULISA™) platform, focusing on patients with mild cognitive impairment (MCI).