Late-life emergence of neuropsychiatric symptoms and risk of cognitive impairment in cognitively unimpaired individuals.

Introduction: Neuropsychiatric symptoms (NPS) often precede cognitive impairment. We investigated the longitudinal relationship between emergent, significant NPS and cognitive decline in cognitively unimpaired older adults. We also assessed the combined effect of NPS and Alzheimer's disease (AD) biomarkers on subsequent cognitive impairment.

Alzheimer's Disease Research Center Down Syndrome Cores: Experience from two sites.

Down syndrome (DS) is the most common genetic cause of Alzheimer's disease (AD). As individuals with DS live longer, the prevalence of AD-related dementia increases, underscoring a growing public health concern. Historically, research efforts have largely overlooked the early manifestations and neuropathological trajectory of AD in DS, limiting our understanding of how closely it mirrors or diverges from sporadic AD in the general population.

Cholinotrophic basal forebrain connectome dysfunction in Down syndrome with and without dementia.

Cholinotrophic basal forebrain (CTBF) neurons depend upon the complex interaction of both upstream and downstream nerve growth factor (NGF) signaling pathways for survival and function. Although dysfunction of the NGF system occurs in both Down syndrome (DS), not all individuals with DS develop dementia. Whether NGF system dysregulation differs between demented individuals with DS (DSD+) versus those without dementia (DSD-) is unknown.

Down syndrome and Alzheimer's disease: insights into biomarkers, clinical symptoms, and pathology.

Background: Individuals with Down syndrome have a genetically determined form of Alzheimer's disease, due to an additional copy of the APP gene. Nearly all individuals with Down syndrome develop Alzheimer's disease pathology by age 40 years, and approximately 70% are diagnosed with dementia by around age 54 years, with an overall lifetime risk of 95%. Moreover, Alzheimer's disease is the leading cause of death in adults with Down syndrome older than 35 years.

Longitudinal diffusion tensor imaging correlates with amyloid burden in Down syndrome.

Introduction: Adults with Down syndrome (DS) accumulate amyloid beta (Aβ) plaques faster and earlier on average than neurotypical adults with sporadic Alzheimer's disease (AD). White matter (WM) microstructure characterized with diffusion tensor imaging (DTI) can indicate underlying architectural changes in longitudinal studies, suggestive of neurodegeneration. This study investigated relationships between DTI and Aβ in DS along the AD continuum.

U1-70K and U1A and tau pathogenesis in demented and non-demented individuals with Down syndrome.

Introduction: Splicing protein mislocalization is associated with tau pathogenesis, but its role in Down syndrome (DS) is under-investigated.

Methods: Spliceosome associations with tau and plaque pathology were examined in frontal cortex from DS with dementia (DSD+) and without dementia (DSD-) using quantitative immunoblotting and immunohistochemistry.

Results: U1-70K and U1A levels were downregulated, and hnRNPA2B1, 3Rtau, and 4Rtau were upregulated, whereas SRSF2 and CLK1 were unchanged in DSD+.

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

Background: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis.

Results: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.

Age and sex are associated with Alzheimer's disease neuropathology in Down syndrome.

Introduction: This study investigates the association of age and biological sex with Alzheimer's disease (AD) neuropathology in Down syndrome (DS).

Methods: We examined the frontal/occipital cortex in people with DS (n = 14/13, 1-39 years), DS with AD (DSAD) neuropathology (n = 18/19, 42-61 years), late-onset AD (n = 15/16, 72-96 years), and age-matched controls (n = 50/47)(n = 156). The area occupied by AT8 and 6E10 immunolabeling, representing tangle and plaque loads, respectively, was used for segmented linear regression analyses.

Genome-wide association of tau neuroimaging and plasma biomarkers in adults with Down syndrome.

Introduction: Plasma biomarkers in Down syndrome (DS) accurately detect Alzheimer's disease (AD) pathology. This study aimed to identify genetic loci associated with plasma tau biomarkers (phosphorylated tau [p-tau]181, p-tau217, total tau [t-tau]) and tau positron emission tomography (PET) in DS.

Methods: We examined 375 people with DS from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) with data on all four tau biomarkers, and 133 subjects from another study of DS with plasma t-tau.

Genome-wide association analyses identify candidate loci for amyloid imaging and plasma biomarkers in adults with Down syndrome.

Background: People with Down syndrome (DS) overproduce amyloid-beta (Aβ) due to triplication of the amyloid precursor protein (APP) gene on chromosome 21, and consequently accumulate brain amyloid load at younger ages. We conducted genome-wide association (GWA) analyses on amyloid imaging and plasma biomarkers to discern the genetic architecture of amyloid burden in DS.

Methods: GWA analyses were performed on amyloid positron emission tomography (PET) and plasma biomarkers (Aβ40, Aβ42, Aβ42/40 ratio) in participants from the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) and on plasma Aβ biomarkers available in an independent DS cohort, followed by meta-analysis of plasma Aβ biomarker data.

Leptin levels are associated with body mass index and Alzheimer's disease in Down syndrome.

Introduction: Higher body mass index (BMI) is linked to greater risk of Alzheimer's disease (AD) and elevated plasma leptin levels correlate with cognitive decline and AD. Since obesity is a frequent feature in individuals with Down syndrome (DS), we investigated the association between obesity, the leptin pathway, and AD neuropathology in people with DS.

Methods: Plasma concentrations of leptin and AD biomarkers were measured in 40 individuals (aged controls, Down syndrome and Alzheimer's disease [DSAD], and AD participants).

Joint spatial associations of amyloid beta and tau pathology in Down syndrome and preclinical Alzheimer's disease: Cross-sectional associations with early cognitive impairments.

Introduction: Individuals with Down syndrome (DS) have elevated risks for Alzheimer's disease (AD) due to amyloid beta (Aβ) precursor protein overexpression, with nearly all developing AD pathology by age 40 at autopsy. This study examined spatial associations between Aβ and tau burden in DS and neurotypical aging.

Methods: Data included 145 DS (25-67 years) and 191 neurotypical aging individuals (63-89 years).

Physical activity as a resistance or resilience mechanism in Down syndrome Alzheimer's disease.

Introduction: Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD). Lifestyle factors such as engagement in moderate-to-vigorous physical activity (MVPA) reduce risk or delay the onset of AD. This study aimed to determine whether MVPA confers a (AD pathology) or (cognitive decline) effect on the relationship between AD pathology and cognitive decline in DS.

Gait variability as a marker of white matter integrity in individuals with Down syndrome.

Introduction: Individuals with Down syndrome (DS) face a significant risk of neurodegeneration, and gait variability may serve as a clinical biomarker of neurological health. This longitudinal parent substudy aimed to explore relationships between gait, white matter (WM) integrity, and cognitive function in DS.

Methods: The associations were investigated between magnetic resonance imaging diffusion tensor imaging (DTI), cognition, and self-paced gait data from 22 DS participants (mean age ± SD 37 ± 7.

PET-measured amyloid beta accumulates at an accelerated rate in Down syndrome compared to neurotypical populations.

Introduction: Individuals with Down syndrome (DS) have a high prevalence of Alzheimer's disease (AD) and reveal an earlier age of amyloid beta (Aβ) onset compared to sporadic AD. Differences in amyloid accumulation rates between DS and sporadic AD populations have not been established.

Methods: Participants with ≥ 3 [C-11]PiB scans (spanning > 6 years) and transitioning to Aβ+ were included, resulting in 20 DS and 23 neurotypical (NT) participants.

Longitudinal study of body mass index in relation to Alzheimer's disease pathology and symptomatology in Down syndrome.

Introduction: Weight loss has been linked to early Alzheimer's disease (AD) pathology, possibly through metabolic dysregulation. We examined changes in body mass index (BMI) in relation to AD biomarkers (amyloid beta [Aβ] and tau) and cognitive decline in adults with Down syndrome (DS). We hypothesized that BMI decline would track with early AD pathology and cognitive decline.

The future of biomarkers for vascular contributions to cognitive impairment and dementia (VCID): proceedings of the 2025 annual workshop of the Albert research institute for white matter and cognition.

Advances in biomarkers and pathophysiology of vascular contributions to cognitive impairment and dementia (VCID) are expected to bring greater mechanistic insights, more targeted treatments, and potentially disease-modifying therapies. The 2025 Annual Workshop of the Albert Research Institute for White Matter and Cognition, sponsored by the Leo and Anne Albert Charitable Trust since 2015, focused on novel biomarkers for VCID. The meeting highlighted the complexity of dementia, emphasizing that the majority of cases involve multiple brain pathologies, with vascular pathology typically present.

Prediction of amyloid and tau brain deposition and cognitive decline in people with Down syndrome using plasma biomarkers: a longitudinal cohort study.

Background: Plasma biomarkers associated with Alzheimer's disease could improve prognostic assessment for people with Down syndrome in both clinical practice and research settings. We aimed to identify the plasma biomarkers that most accurately predict longitudinal changes in Alzheimer's disease-related pathology and cognitive functioning in individuals with Down syndrome.

Methods: This longitudinal cohort study included data from 258 adults (aged ≥25 years) with Down syndrome who were followed up prospectively every 16 months as part of the longitudinal Alzheimer's Biomarker Consortium-Down Syndrome study (recruited from seven university sites in the USA and UK between July 13, 2016, and Jan 15, 2019).

Down syndrome with Alzheimer's disease brains have increased iron and associated lipid peroxidation consistent with ferroptosis.

Introduction: Cerebral microbleeds (MBs) are associated with sporadic Alzheimer's disease (AD) and Down syndrome with AD (DSAD). Higher MB iron may cause iron-mediated lipid peroxidation. We hypothesize that amyloid deposition is linked to MB iron and that amyloid precursor protein (APP) triplication increases iron load and lipid peroxidation.

Applying machine learning to assist in the morphometric assessment of brain arteriolosclerosis through automation.

Objective quantification of brain arteriolosclerosis remains an area of ongoing refinement in neuropathology, with current methods primarily utilizing semi-quantitative scales completed through manual histological examination. These approaches offer modest inter-rater reliability and do not provide precise quantitative metrics. To address this gap, we present a prototype end-to-end machine learning (ML)-based algorithm, Arteriolosclerosis Segmentation (ArtSeg), followed by Vascular Morphometry (VasMorph) - to assist persons in the morphometric analysis of arteriolosclerotic vessels on whole slide images (WSIs).

The history of Down syndrome-associated Alzheimer's disease; past, present, and future.

The landscape of Down syndrome-associated Alzheimer's disease (DSAD) research reflects decades of scientific endeavor and collaborative effort, charting a remarkable journey from initial observations to the elucidation of complex genetic and molecular mechanisms. This perspective article chronicles key milestones and breakthroughs, paying homage to the pioneering scientists and advancements that have shaped the field. A thorough review of historical and contemporary literature offers a comprehensive narrative, highlighting the evolution of knowledge surrounding DSAD, from early recognition to the characterization of clinical presentation and natural history.

SARS-CoV-2 infection of human cortical cells is influenced by the interaction between aneuploidy and biological sex: insights from a Down syndrome in vitro model.

Individuals with Down Syndrome (DS) represent one of the most susceptible populations for developing severe COVID-19, and a unique human genetic condition for investigating molecular mechanisms underlying susceptibility of neurologically vulnerable individuals to SARS-CoV-2 infection. Human Chromosome-21 (HSA21) triplication in DS causes global transcriptional deregulation, affecting multiple genes that may directly (e.g.

Apolipoprotein E abundance is elevated in the brains of individuals with Down syndrome-Alzheimer's disease.

Trisomy of chromosome 21, the cause of Down syndrome (DS), is the most commonly occurring genetic cause of Alzheimer's disease (AD). Here, we compare the frontal cortex proteome of people with Down syndrome-Alzheimer's disease (DSAD) to demographically matched cases of early onset AD and healthy ageing controls. We find dysregulation of the proteome, beyond proteins encoded by chromosome 21, including an increase in the abundance of the key AD-associated protein, APOE, in people with DSAD compared to matched cases of AD.

The Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS): A 10-year report.

Introduction: Virtually all adults with Down syndrome (DS) will accumulate the neuropathologies associated with Alzheimer's disease (AD) by age 40, with the majority having a clinical dementia diagnosis by their middle 50s.

Methods: This paper complements a 2020 publication describing the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) methodology by highlighting protocol changes since initial funding in 2015. It describes available clinical, neuropsychological, neuroimaging, and biofluid data and bio-specimen repository.

Common neuropathologic change drivers of hippocampal sclerosis of ageing.

Hippocampal sclerosis of ageing (HS-A)-severe cell loss and gliosis in the hippocampal formation-is a neuropathologic change (NC) that affects up to 20% of elderly persons with dementia. The aetiology of HS-A is heterogeneous, but HS-A is strongly associated with limbic-predominant age-related TDP-43 encephalopathy NC (LATE-NC). Other NCs have also been implicated in relation to HS-A, but these associations have been inconsistent across previous studies.