Developing Topics.

Background: New blood-based and digital biomarkers for Alzheimer's disease (AD) make early detection possible at stages when novel, disease-specific therapies are likely to be most effective. These approaches may offer less invasive, more cost-effective alternatives to traditional methods such as cerebrospinal fluid (CSF) collection or positron emission tomography (PET) imaging for diagnosing and staging AD. Building care pathways leveraging blood-based and digital biomarkers starts with understanding the current biomarker landscape and considering opportunities for widespread implementation in primary care clinical practice.

Developing Topics.

Background: Alzheimer's disease (AD) is a highly complex neurological disorder, with Late-Onset AD (LOAD) being its most common form. INPP5D has been identified as a risk gene for AD and is involved in the TREM2 signaling pathway, which is crucial for microglial activity. INPP5D encodes SHIP1, a protein phosphatase that disrupts TREM2 signaling by converting PIP3 into PIP2, thereby inhibiting the PI3K-mediated activation of Akt-dependent signaling, which is essential for the clearance of amyloid oligomers, fibrils, and plaques.

Developing Topics.

Background: Early-onset Alzheimer's disease (EOAD) occurs before age 65 and has more diverse disease presentations than late-onset AD. To improve our understanding of phenotypic heterogeneity among EOAD individuals, we analyzed cognitive scores using data-driven statistical analysis.

Method: Baseline cognitive data from 286 sporadic EOAD individuals from the Longitudinal EOAD study (LEADS) were transformed to z-scores using data from 95 cognitively normal (CN) individuals.

Developing Topics.

Background: Alzheimer's disease (AD) is characterized by longitudinal changes of biomarker endophenotypes over the course of the disease prodrome, onset, and progression. The genetic pathways that influence these heterogenous changes in longitudinal endophenotype trajectories may provide insight into disease mechanisms and represent potential therapeutic targets.

Methods: Longitudinal endophenotypes from the Alzheimer's Disease Neuroimaging Initiative (ADNI) were selected: amyloid-β (Amyloid PET and CSF), total tau and phosphorylated tau (CSF), glucose metabolism (FDG PET), neurodegeneration (atrophy on MRI), and cognition (composite scores for memory and executive functioning).

Developing Topics.

Background: Vascular pathology profoundly comorbid with AD pathology could worsen disease progression and reduce treatment efficacy. Knowledge of small vessels and cerebrovascular function in AD mouse models is limited. Investigating vascular related aspects for preclinical AD studies is essential for biomarker development and treatment trials.

Developing Topics.

Background: A common neuropsychological test for assessing episodic memory is the Rey Auditory Verbal Learning Test (RAVLT), a sequence of 8 word-list learning and recall tasks (five learning trials, immediate recall of an intrusion list, short-delay and long-delay recall). There is extensive research correlating patterns of RAVLT performance with clinical dementia syndromes, but little work relating these patterns to biomarkers in early-onset dementia. Here, we analyze the relationship between patterns of tau deposition and RAVLT performance in early-onset populations.

Developing Topics.

Background: Analyzing disease-linked genetic variants via expression quantitative trait loci (eQTLs) is crucial for identifying disease-causing genes. Previous research prioritized genes by integrating Genome-Wide Association Study (GWAS) results with tissue-level eQTLs. Recent studies explored brain cell type-specific eQTLs, but they lack a systematic analysis across various AD GWAS datasets, nor did they compare effects between tissue and cell type levels or across different cell type-specific eQTL datasets.

Developing Topics.

Background: Previous models of resilience to Alzheimer's Disease (AD) have relied on cross-sectional designs and inclusion of measures of neuropathology. Here, we present a novel modeling approach incorporating longitudinal data and the use of APOE and higher order interaction terms to approximate neuropathological resilience, vastly increasing participant diversity and statistical power. We validate this approach and report novel genetic associations with neuropathological resilience.

Alzheimer's Imaging Consortium.

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

Alzheimer's Imaging Consortium.

Background: Recent research emphasizes the significance of white matter tracts and the free-water (FW) component in understanding cognitive decline. The goal of this study is to conduct a large-scale assessment on the role of white matter microstructure on longitudinal cognitive decline.

Method: This study used a cohort collated from seven longitudinal cohorts of aging (ADNI, BIOCARD, BLSA, NACC, ROS/MAP/MARS, VMAP, and WRAP).

Alzheimer's Imaging Consortium.

Background: The timing of tau-PET accumulation and cognitive decline in sporadic early-onset Alzheimer's disease (eoAD, age-at-onset<65) has not been established and is needed to optimize tau-PET as an outcome measure in clinical trials. Here we leverage large-sample, longitudinal data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) to model tau-PET accumulation in three regions relative to cognitive decline.

Method: Longitudinal [18F]Flortaucipir-PET (FTP) and CDR-SB scores were acquired in 195 amyloid-PET-positive, sporadic eoAD patients with MCI or mild dementia due to AD at baseline (Table 1).

Alzheimer's Imaging Consortium.

Background: Diffusion MRI (dMRI) metrics of brain microstructure offer valuable insight into Alzheimer's disease (AD) pathology; recent reports have identified dMRI metrics that (1) tightly link with CSF or PET measures of amyloid and tau burden; and (2) mediate the relationship between CSF markers of AD and delayed logical memory performance, commonly impaired in early AD [1,2]. To better localize white matter tract disruption in AD, our BUndle ANalytic (BUAN) [3] tractometry pipeline allows principled use of statistical methods to map factors affecting microstructural metrics along the 3D length of the brain's fiber tracts. Here, we extended BUAN to pool data from multiple scanning protocols/sites - using a new harmonized tractometry approach, based on ComBat [4,5], a widely-used harmonization method modeling variations in multi-site datasets due to site- and scanner-specific effects.

Alzheimer's Imaging Consortium.

Background: The hippocampus, a region vital for memory and cognition, is prone to abnormal deposition of beta-amyloid (Aß) during the early stages of the Alzheimer's disease. Aß-associated pathophysiological mechanisms instigate dendritic deficit, neuronal loss, and neuroinflammation, leading to abnormal functional and behavioral changes. These factors directly impact tissue microstructures.

Alzheimer's Imaging Consortium.

Background: Large-scale studies comparing sporadic early-onset AD (EOAD, age<65) and late-onset AD (LOAD, age = 65) are lacking. We compared amyloid-PET outcomes (positivity rate and amyloid burden) between patients clinically diagnosed with sporadic EOAD vs LOAD, leveraging data from the Longitudinal Early-Onset AD Study (LEADS) and the Alzheimer's Disease Neuroimaging Initiative 3 (ADNI3).

Method: 731 patients meeting the 2011 NIA-AA criteria for AD dementia or MCI were included (505 early-onset from LEADS, 226 late-onset from ADNI3, Table 1).

Alzheimer's Imaging Consortium.

Background: Diagnosing sporadic early-onset AD (EOAD, age-at-onset<65) is challenging: in the multi-center Longitudinal Early-onset Alzheimer's Disease Study, ∼25% of patients with clinically diagnosed EOAD are amyloid-PET-negative. Here we used FDG-PET to characterize the heterogeneity of hypometabolic profiles in these patients and better identify underlying etiologies.

Method: Seventy-four amyloid-PET-negative patients with clinical diagnosis of sporadic EOAD (MCI or mild dementia stage) underwent FDG-PET.

Alzheimer's Imaging Consortium.

Background: Alzheimer's disease (AD) exhibits substantial heterogeneity in its disease trajectory. A subset of AD patients with unmatched cognitive decline/tauopathy severity has not been well studied. We identified such atypical subgroups in post-mortem AD brain studies.

Alzheimer's Imaging Consortium.

Background: Understanding how early-onset Alzheimer's disease (EOAD) differs from typical late-onset AD (LOAD) is an important goal of AD research that may help increase the sensitivity of unique biomarkers for each phenotype. Building upon prior work based on small samples, here we leveraged two large, well-characterized natural history study cohorts of AD patients (LEADS and ADNI3) to test the hypothesis that EOAD patients would show more prominent lateral and medial parietal and lateral temporal cortical atrophy sparing the medial temporal lobe (MTL), whereas LOAD patients would show prominent MTL atrophy.

Method: We investigated differences in the spatial topography of cortical atrophy between EOAD and LOAD patients by analyzing structural MRI data collected from 211 patients with sporadic EOAD and 88 cognitively unimpaired (CU) participants from the LEADS cohort as well as 144 patients with LOAD and 365 CU participants from the ADNI3 cohort.

Alzheimer's Imaging Consortium.

Background: Changes in brain network organization are influenced by aging. Accumulation of amyloid-beta (Aß) and neurodegeneration in the neocortex are also expected to alter neuronal networks. Therefore, we examined the relationship between aging and brain functional connectivity (FC), as well as the effect of brain Aß on this relationship.

Alzheimer's Imaging Consortium.

Background: Dementia is age-related with a significant genetic contribution, yet genome-wide association studies have not fully accounted for heritability. This discrepancy may in part be due to reliance on SNPs and small indels. Whole-genome sequencing (WGS) data in the Japanese population may reveal population-specific susceptibility loci for dementia.

Alzheimer's Imaging Consortium.

Background: Adults with Down syndrome (DS) overproduce amyloid precursor protein, develop amyloid plaques at an early age, and are diagnosed with Alzheimer's disease (AD) dementia at a high frequency. There is emerging evidence that cerebrovascular disease is elevated across the AD continuum in older adults with DS, independent of age and vascular risk, around the same time as amyloid and tau, but the regional rates of accumulation within individuals are unknown.

Method: Adults with DS from the multisite Alzheimer's Biomarker Consortium-Down Syndrome study (ABC-DS; n = 78; age = 50±6; 40% women) have two timepoints of T2 FLAIR MRI (1.

Drug Development.

Background: Our previous study identified that Sildenafil (a phosphodiesterase type 5 [PDE5] inhibitor) is a candidate repurposable drug for Alzheimer's Disease (AD) using in silico network medicine approach. However, the clinically meaningful size and mechanism-of-actions of sildenafil in potential prevention and treatment of AD remind unknown.

Method: We conducted new patient data analyses using both the MarketScan® Medicare with Supplemental database (n = 7.

Drug Development.

Background: Epidemiological studies report an elevated risk of neurodegenerative disorders, particularly Parkinson's disease (PD), in patients with type 2 diabetes mellitus (T2DM) that is mitigated in those prescribed incretin mimetics or dipeptidyl peptidase 4 inhibitors (DPP-4Is). Incretin mimetic repurposing appears promising in human PD and Alzheimer's disease (AD) clinical trials. DPP-4Is are yet to be evaluated in PD or AD human studies.

Drug Development.

Background: The TREAT-AD centers aim to improve Alzheimer's Disease (AD) research by offering free, high-quality tools and technologies. Lyn is a tyrosine kinase that belongs to the Src family kinases. The expression of Lyn and its activity have been implicated in AD.

Drug Development.

Background: Focusing on novel AD treatments, the TREAT-AD centers offer an array of free research tools, shared via the AD Knowledge Portal in a Target Enablement Package (TEP). This abstract showcases the research conducted by the IUSM-Purdue TREAT-AD Center, specifically focusing on Targeting class-II PI3K's as a potential breakthrough in AD therapy. Endocytosis within the brain encompasses diverse pathways for internalizing extracellular cargoes and receptors into cells.

Drug Development.

Background: TREM2 signaling has been implicated in Alzheimer's Disease (AD). TREM2 regulates microglial states and functions such as phagocytosis. The most prominent TREM signaling adapter is DAP12, encoded by TYROBP.