Elizabeth Head

University of Kentucky | UKY · Department of Molecular & Biomedical Pharmacology

TDP-43 proteinopathy is a salient neuropathologic feature in a subset of frontotemporal lobar degeneration (FTLD-TDP), in amyotrophic lateral sclerosis (ALS-TDP), and in limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC), and is associated with hippocampal sclerosis of aging (HS-A). We examined TDP-43-related path...

Background: Older adults with mild cognitive impairment (MCI) exhibit deficits in cerebrovascular reactivity (CVR), suggesting CVR is a biomarker for vascular contributions to MCI. This study examined if spontaneous CVR is associated with MCI and memory impairment. Methods: 161 older adults free of dementia or major neurological/psychiatric disorde...

Background Higher order regulation of autonomic function is maintained by the coordinated activity of specific cortical and subcortical brain regions, collectively referred to as the central autonomic network (CAN). Autonomic changes are frequently observed in Alzheimer’s disease (AD) and dementia, but no studies to date have investigated whether p...

In this neuropathology case report, we present findings from an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition. Notably, her ApoE genotype was E2/3...

Adults with Down syndrome have a genetic form of Alzheimer’s disease (AD) and evidence of cerebrovascular disease across the AD continuum, despite few systemic vascular risk factors. The onset and progression of AD in Down syndrome is highly age-dependent, but it is unknown at what age cerebrovascular disease emerges and what factors influence its...

The SARS-CoV-2 virus that led to COVID-19 is associated with significant and long-lasting neurologic symptoms in many patients, with an increased mortality risk for people with Alzheimer’s disease (AD) and/or Down syndrome (DS). However, few studies have evaluated the neuropathological and inflammatory sequelae in postmortem brain tissue obtained f...

Numerous research groups worldwide have focused on postmortem imaging to bridge the resolution gap between clinical neuroimaging and neuropathology data. We developed a standardized protocol for brain embedding, imaging, and processing, facilitating alignment between antemortem MRI, postmortem MRI, and pathology to observe brain atrophy and structu...

Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease and is li...

Blood pressure variability (BPV) and arterial stiffness are age-related hemodynamic risk factors for neurodegenerative disease, but it remains unclear whether they exert independent or interactive effects on brain health. When combined with high inter-beat BPV, increased intra-beat BPV indicative of arterial stiffness could convey greater pressure...

Introduction Sleep disturbance increases Alzheimer’s disease (AD) biomarkers, but it remains unclear whether the magnitiude of this effect differs by cognitive status. Addressing this unknown will elucidate when it is most critical to intervene to moderate AD pathophysiology and slow or arrest clinical progression. Methods A total of 155 participa...

INTRODUCTION People with Down syndrome (DS) have a 75% to 90% lifetime risk of Alzheimer's disease (AD). AD pathology begins a decade or more prior to onset of clinical AD dementia in people with DS. It is not clear if plasma biomarkers of AD pathology are correlated with early cognitive and functional impairments in DS, and if these biomarkers cou...

Aging dogs serve as a valuable preclinical model for Alzheimer's disease (AD) due to their natural age-related development of β-amyloid (Aβ) plaques, human-like metabolism, and large brains that are ideal for studying structural brain aging trajectories from serial neuroimaging. Here we examined the effects of chronic treatment with the calcineurin...

While challenging, identifying individuals displaying resilience to Alzheimers disease (AD) and understanding the underlying mechanism holds great promise for the development of new therapeutic interventions to effectively treat AD. Down syndrome (DS), or trisomy 21, is the most common genetic cause of AD. Interestingly, some people with DS, despit...

INTRODUCTION Late‐onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long‐Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics. METHODS We conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six indepen...

INTRODUCTION Virtually all people with Down syndrome (DS) develop neuropathology associated with Alzheimer's disease (AD). Atrophy of the hippocampus and entorhinal cortex (EC), as well as elevated plasma concentrations of neurofilament light chain (NfL) protein, are markers of neurodegeneration associated with late‐onset AD. We hypothesized that h...

Individuals with Down syndrome (DS) have a partial or complete trisomy of chromosome 21, resulting in an increased risk for early‐onset Alzheimer's disease (AD)‐type dementia by early midlife. Despite ongoing clinical trials to treat late‐onset AD, individuals with DS are often excluded. Furthermore, timely diagnosis or management is often not avai...

Background Individuals with Down Syndrome (DS) have an increased risk of developing Alzheimer’s Disease (AD) with nearly all individuals exhibiting neuropathological changes in the brain by age 40 years, and with a mean diagnosis of dementia by age ∼55 years. The purpose of this postmortem study was to characterize the age‐associated burden of seve...

Background Astrocytic Aquaporin 4 (AQP4) is a water channel that is typically expressed in astrocytic endfeet, associated with the blood brain barrier (BBB). This association is thought to facilitate the removal of waste products (e.g. beta amyloid (Aβ)) via the ‘glymphatic system’. With Aβ plaque deposition in Alzheimer’s Disease (AD), AQP4 become...

Background Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex...

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 r...

Background People with Down syndrome (DS) are at genetic risk of developing early‐onset Alzheimer’s disease (AD). By age 40 years, virtually all people with DS develop beta amyloid plaques and tau neurofibrillary tangles, typically followed by the development of AD dementia over a decade later. Despite having a low frequency of vascular risk factor...

Background Cerebrovascular disease contributes to clinical onset and course of Alzheimer’s disease (AD) but it is unclear if it is related directly to AD pathogenesis. In late onset AD, MRI markers of small vessel cerebrovascular disease relate to AD diagnosis, genetic risk for AD, and severity of AD symptoms, but it is not possible to determine wh...

Background People with Down syndrome (DS) have a higher risk of developing Alzheimer disease (AD), due to an extra copy of the amyloid precursor protein (APP) gene on chromosome 21. Overexpression of APP is associated with increased production of amyloid beta (Aβ) in DS, and contributes to early onset of AD. Some studies suggest women with DS are a...

Background Individuals with Down syndrome (DS) are the largest population at genetic risk of developing early‐onset Alzheimer’s disease (AD). Throughout their lifespan, individuals with DS develop the spectrum of AD neuropathology. By 40 years of age, mature amyloid beta plaques and tau neurofibrillary tangles are present in DS brains, followed by...

Background Triplication of the APP allele in Down syndrome (DS) leads to excess amyloid production and Alzheimer’s disease (AD) related cognitive decline. Key biomarkers (amyloid, tau, neurodegeneration) can identify pathological processes that occur before clinical symptoms and more precisely stage adults with DS along the AD continuum. Previous r...

Background The locus coeruleus (LC) innervates the cerebrovasculature and plays a critical role in optimally regulating cerebral blood flow. However, few studies have examined potential relationships between these systems in humans with widely available neuroimaging methods, and none have explored how relationships may change in the presence of gro...

Background Amyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET)...

Background Hippocampal sclerosis of aging (HS) is characterized by neuronal loss and astrogliosis in subiculum and/or CA1 subfield of hippocampus. Using a novel quantitative approach, we studied the prevalence and localization of HS pathology in a well‐characterized oldest‐old cohort and examined its association with other neuropathologic changes a...

Background The aging beagle is an exceptional model for longitudinal preclinical studies of Alzheimer’s disease due to their endogenous accumulation of beta‐amyloid plaques linked to cognitive impairment in aging, human‐like metabolisms, and ability to undergo serial neuroimaging. However, studies that use standardized analysis methods for evaluati...

Background The pathogenesis of Alzheimer’s disease (AD) varies greatly depending on environmental and heritable factors. Neuropathological scores aid in the understanding of disease severity in postmortem tissue, but fail to provide insights into disease onset and progression. Conversely, mouse models of AD like 5XFAD offer predictable timelines of...

Background Adult‐onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a rare human disease that is caused by mutations in CSF1R, a gene that is critical for the differentiation, proliferation, and survival of microglia. ALSP patients typically develop dementia, motor impairments, and seizures during their 30s or 40s. Upon au...

Background By age 40 over 90% of adults with Down syndrome (DS) develop Alzheimer’s disease (AD) pathology and most progress to dementia. Despite having fewer systemic vascular risk factors than neurotypical adults, recent studies demonstrate evidence of significant cerebrovascular disease in individuals with DS that track with the clinical progres...

Background Calcineurin/NFAT signaling increases in Alzheimer disease (AD) and is associated with neurodegeneration, neuroinflammation, amyloid‐β (Aβ) production, and cognitive decline. Hence, calcineurin/NFAT inhibitors (e.g., tacrolimus and Q134R) are attractive potential therapeutics to improve/prevent AD‐associated cognitive impairments. In AD m...

Background Adults with Down Syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia as they age. This is attributed to triplication of the amyloid precursor protein gene. Recent work demonstrated that amyloid is elevated in DS and accumulates in a similar topography to autosomal dominant AD (ADAD). Tau accumulation is the second ha...

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 r...

Background Down syndrome (DS) is associated with early development of Alzheimer’s disease pathology. Both the severity of tau pathology and the increase of neurofilament light chain (NfL) protein are correlated with cognitive decline in the neurotypical populations. Here, we assessed whether tau accumulation in the hippocampus and entorhinal cortex...

Objective The locus coeruleus (LC) innervates the cerebrovasculature and plays a crucial role in optimal regulation of cerebral blood flow. However, no human studies to date have examined links between these systems with widely available neuroimaging methods. We quantified associations between LC structural integrity and regional cortical perfusion...

Objective Individuals with Down syndrome (DS) experience intellectual disability, such that measures of cognitive and adaptive functioning are near the normative floor upon evaluation. Individuals with DS are also at increased risk for Alzheimer's disease (AD) beginning around age 40; and test performances and adaptive ratings at the normative floo...

Objective Aggregation of phosphorylated tau (pTau) is a hallmark feature of Alzheimer’s disease (AD). Novel assays now allow pTau to be measured in plasma. Elevated plasma pTau predicts subsequent development of AD, cortical atrophy and AD-related pathologies in the brain. We aimed to determine whether elevated pTau is associated with cognitive fun...

Antibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβ17–36 β-hairpins and the generation and study of polyclona...

Alzheimer’s disease-related protein amyloid beta (Aβ) plasma levels increase with age, and Aβ40 levels are associated with greater mortality. Most plasma Aβ40 is produced via platelets. Platelet activity is regulated by endothelial cells, which are stimulated by blood flow. Slow paced breathing with a 10-second cycle maximizes heart rate oscillatio...

Importance: By age 40 years over 90% of adults with Down syndrome (DS) have Alzheimer's disease (AD) pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with DS have elevated cerebrovascular disease (CVD) markers that track with the clinical progression of AD, suggesting a role for CVD that is hyp...

Individuals with Down syndrome (DS) are less likely to have hypertension than neurotypical adults. However, whether blood pressure measures are associated with brain health and clinical outcomes in this population has not been studied in detail. Here, we assessed whether pulse pressure is associated with markers of cerebrovascular disease, entorhin...

We present data from the Heart Rate Variability and Emotion Regulation (HRV-ER) randomized clinical trial testing effects of HRV biofeedback. Younger (N = 121) and older (N = 72) participants completed baseline magnetic resonance imaging (MRI) including T1-weighted, resting and emotion regulation task functional MRI (fMRI), pulsed continuous arteri...

The pathogenesis of Alzheimer's disease (AD) depends on environmental and heritable factors, with remarkable differences evident between individuals at the molecular level. Here we present a transcriptomic survey of AD using spatial transcrip- tomics (ST) and single-nucleus RNA-seq in cortical samples from early-stage AD, late-stage AD, and AD in D...

Background: Trisomy 21 causes Down syndrome (DS) and is a recognized cause of early-onset Alzheimer's disease (AD). Objective: The current study sought to determine if premorbid intellectual disability level (ID) was associated with variability in age-trajectories of AD biomarkers and cognitive impairments. General linear mixed models compared t...

Introduction: People with Down syndrome (DS) often develop Alzheimer's disease (AD). Here, we asked whether ultrasensitive plasma immunoassays for a tau N-terminal fragment (NT1-tau) and Aβ isoforms predict cognitive impairment. Methods: Plasma NT1-tau, Aβ37 , Aβ40 , and Aβ42 levels were measured in a longitudinal discovery cohort (N = 85 partic...

Hippocampal sclerosis of aging (HS-A) is a common age-related neuropathological lesion characterized by neuronal loss and astrogliosis in subiculum and CA1 subfield of hippocampus. HS-A is associated with cognitive decline that mimics Alzheimer’s disease. Pathological diagnosis of HS-A is traditionally binary based on presence/absence of the lesion...

Background Genetic mutations affecting β‐amyloid (Αβ) production suggest that decreasing Αβ levels in healthy adults could prevent AD. However, evidence for behavioral interventions that decrease Αβ levels is lacking. The current study examined whether heart rate variability (HRV) biofeedback affects plasma Αβ levels. This intervention involves bre...

Antibodies that target the β-amyloid peptide (Aβ) and its associated assemblies are important tools in Alzheimer’s disease research and have emerged as promising Alzheimer’s disease therapies. This paper reports the creation and characterization of a triangular Aβ trimer mimic composed of Aβ l7-36 β-hairpins, and the generation and study of polyclo...

Introduction: We tested whether Alzheimer's disease (AD) pathology predicts memory deficits in non-demented older adults through its effects on medial temporal lobe (MTL) subregional volume. Methods: Thirty-two, non-demented older adults with cerebrospinal fluid (CSF) (amyloid-beta [Aβ]42/Aβ40, phosphorylated tau [p-tau]181, total tau [t-tau]),...

Early markers are needed for more effective prevention of Alzheimer’s disease. We previously showed that individuals with Alzheimer’s disease have decreased plasma DYRK1A levels compared to controls. We assessed DYRK1A in the plasma of cognitively healthy elderly volunteers, individuals with either Alzheimer’s disease (AD), tauopathies or Down synd...

Dilation of perivascular spaces (PVS) in the brain may indicate poor fluid drainage due to the accumulation of perivascular cell debris, waste, and proteins, including amyloid-beta (Aβ). No prior study has assessed whether plasma Aβ levels are related to PVS in older adults without dementia. Independently living older adults (N = 56, mean age = 68....

Introduction: People with Down syndrome (DS) often develop Alzheimer disease (AD). Here we asked whether ultrasensitive plasma immunoassays for a tau N-terminal fragment (NT1-tau) and Aβ isoforms predict cognitive impairment. Methods: Plasma NT1-tau, Aβ37, Aβ40, and Aβ42 levels were measured in a longitudinal discovery cohort (N = 85 participants,...

Slow paced breathing via heart rate variability (HRV) biofeedback stimulates vagus-nerve pathways that counter noradrenergic stress and arousal pathways that can influence production and clearance of Alzheimer's disease (AD)-related proteins. Thus, we examined whether HRV biofeedback intervention affects plasma Αβ40, Αβ42, total tau (tTau), and pho...

Background: Important insights into the early pathogenesis of Alzheimer's disease can be provided by studies of autosomal dominant Alzheimer's disease and Down syndrome. However, it is unclear whether the timing and spatial distribution of amyloid accumulation differs between people with autosomal dominant Alzheimer's disease and those with Down s...

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid‐β (Aβ) overproduction and earlier onset of Aβ deposits compared to sporadic late‐onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound‐B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relationship with h...

Background Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may...

Positron emission tomography (PET) imaging studies of Alzheimer's disease (AD) patients show progressive increases of fibrillar Aβ‐amyloid. Because current PET ligands underestimate nonfibrillar forms, we assayed soluble Aβ in AD and controls. To identify the mechanisms responsible for soluble Aβ in AD brains, we examined lipid rafts (LRs), where a...

Background: Virtually all adults with Down syndrome (DS) develop Alzheimer's disease (AD) pathology, but research gaps remain in understanding early signs of AD in DS. Objective: The goal of the present study was to determine if unintentional weight loss is part of AD in DS. The specific aims were to: 1) examine relation between chronological ag...

The recent National Institute of Health (NIH) INCLUDE (INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE) initiative has bolstered capacity for the current increase in clinical trials involving individuals with Down syndrome (DS). This new NIH funding mechanism offers new opportunities to expand and develop no...

Calcineurin (CN) is a Ca2+/calmodulin‐dependent phosphatase that regulates diverse cellular phenotypes through activation of NFAT transcription factor1. CN/NFAT signaling increases in Alzheimer’s disease (AD)2,3 and is associated with synaptic loss, neuron degeneration, neuroinflammation, amyloid‐β production, and cognitive decline4,5. Thus, calcin...

Pick’s disease (PiD), a behavioral variant of frontotemporal dementia, is one of the common neurodegenerative dementia that is characterized by tau lesions. Despite the distinct tau aggregation observed in Pick’s disease compared with the tauopathy of Alzheimer’s disease (AD), the similarity in cognitive and behavioral impairments during the progre...

Given the triplication of chromosome 21 and the location of the amyloid precursor protein gene on chromosome 21, almost all adults with Down syndrome (DS) develop Alzheimer disease (AD)‐like pathology and dementia during their lifetime. Comparing amyloid accumulation in DS to autosomal dominant AD (ADAD), another genetic form of AD, may improve our...

Introduction Synaptic failure, a hallmark of Alzheimer's disease (AD), is correlated with reduced levels of synaptic proteins. Though people with Down syndrome (DS) are at markedly increased risk for AD (AD-DS), few studies have addressed synapse dysfunction. Methods Synaptic proteins were measured in the frontal cortex of DS, AD-DS, sporadic AD c...

Research focused on Down syndrome continued to gain momentum in the last several years and is advancing our understanding of how trisomy 21 (T21) modifies molecular and cellular processes. The Trisomy 21 Research Society (T21RS) is the premier scientific organization for researchers and clinicians studying Down syndrome. During the COVID pandemic,...

Blood pressure variability is an emerging risk factor for Alzheimer’s disease in older adults, independent of average blood pressure levels. Growing evidence suggests increased blood pressure variability is linked to Alzheimer’s disease pathophysiology indexed by cerebrospinal fluid and positron emission tomography markers, but relationships with p...

Aging adults with Down syndrome (DS) develop Alzheimer disease neuropathology (AD) by the age of 40 years, primarily due to the overexpression of the amyloid precursor protein on chromosome 21. Lewy bodies (LBs), containing alpha-synuclein protein, are observed in 7-60% of AD patients in the amygdala and in cortex. Prior DS studies (n=20-56 cases)...

Objective: Informant ratings of adaptive functioning are a valuable source of information that can support diagnosis and treatment planning and monitor change. The Adaptive Behavior Assessment System (ABAS-II) and Vineland Adaptive Behavior Scales (VABS-II) are well-known adaptive functioning questionnaires used in clinical practice. This study ass...

Women are disproportionately affected by Alzheimer's disease (AD), yet little is known about sex-specific effects on the development of AD in the Down syndrome (DS) population. DS is caused by a full or partial triplication of chromosome 21, which harbors the amyloid precursor protein (APP) gene, among others. The majority of people with DS in thei...

Microglia are strongly implicated in the development and progression of Alzheimer’s disease (AD), yet their impact on pathology and lifespan remains unclear. Here we utilize a CSF1R hypomorphic mouse to generate a model of AD that genetically lacks microglia. The resulting microglial-deficient mice exhibit a profound shift from parenchymal amyloid...

The impact of apolipoprotein E ε4 (APOE4), the strongest genetic risk factor for Alzheimer’s disease (AD), on human brain cellular function remains unclear. Here, we investigated the effects of APOE4 on brain cell types derived from population and isogenic human induced pluripotent stem cells, post-mortem brain, and APOE targeted replacement mice....

Research suggests a link between Alzheimer's Disease in Down Syndrome (DS) and the overproduction of amyloid plaques. Using Positron Emission Tomography (PET) we can assess the in-vivo regional amyloid load using several available ligands. To measure amyloid distributions in specific brain regions, a brain atlas is used. A popular method of creatin...

We determined the extent to which obstructive sleep apnea (OSA) is associated with increased cerebrovascular disease and amyloid burden, and the relation of the two processes across clinical Alzheimer’s disease (AD) diagnostic groups in adults with Down syndrome (DS). Adults with DS from the Biomarkers of Alzheimer’s Disease in Down Syndrome (ADDS)...

People with Down syndrome (DS) have increased risk of Alzheimer disease (AD), presumably conferred through genetic predispositions arising from trisomy 21. These predispositions necessarily include triplication of the amyloid precursor protein (APP), but also other Ch21 genes that confer risk directly or through interactions with genes on other chr...

Background The Down syndrome population has been disproportionately affected by Coronavirus 2019 (COVID-19) in terms of experiencing severe illness and death. Societal efforts to curb the spread of COVID-19 may also have taken a heavy toll on the daily lives of individuals with Down syndrome. Objective/Hypothesis The goal of the study was to under...

Cerebrovascular disease is associated with symptoms and pathogenesis of Alzheimer's disease (AD) among adults with Down syndrome (DS). The cause of increased dementia‐related cerebrovascular disease in DS is unknown. We explored whether protein markers of neuroinflammation are associated with markers of cerebrovascular disease among adults with DS....

Down syndrome (DS), the most common genetic cause of intellectual disability, is characterized by the triplication of chromosome 21. The triplication of the amyloid precursor protein gene, amyloid precursor protein (APP), is thought to be the underlying reason why Alzheimer's disease (AD) pathology develops in the DS brain with age. In this chapter...

Cerebrovascular disease is common in older adults and is associated with cognitive decline and Alzheimer's disease (AD) risk. Adults with Down syndrome (DS) have vascular risk profiles that are distinct from individuals in the general population and include lower rates of hypertension and atherosclerosis but higher rates of congenital heart disease...

This chapter will serve to summarize the book and discuss future directions for the field.

Microglia are critical for brain development and play a central role in Alzheimers disease (AD) etiology. Down syndrome (DS), also known as trisomy 21, is the most common genetic origin of intellectual disability and the most common risk factor for AD. Surprisingly, little information is available on the impact of trisomy of human chromosome 21 (Hs...

Background Cerebral amyloid angiopathy (CAA) is a form of cerebrovascular pathology characterized by the deposition of beta‐amyloid in the leptomeningeal and cortical blood vessels of the brain. CAA is a critical factor contributing to dementia in sporadic Alzheimer’s disease (AD). Many individuals with Down syndrome (DS) develop CAA due to the ove...

Background: The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell-types. Understanding these regulatory programs requires a holistic experimental and analytical approach, especially in understanding neurodegenerative disorders such as Alzheimer's Di...

Background: Down syndrome (DS) is associated with increased risk for Alzheimer's disease (AD). In neurotypical individuals, clinical AD is preceded by reduced resting state functional connectivity in the default mode network (DMN), but it is unknown whether changes in DMN connectivity predict clinical onset of AD in DS. Objective: Does lower DMN...

Introduction: People with Down syndrome (DS) are predisposed to Alzheimer's disease (AD). The amyloid hypothesis informs studies of AD. In AD-DS, but not sporadic AD, increased APP copy number is necessary, defining the APP gene dose hypothesis. Which amyloid precursor protein (APP) products contribute needs to be determined. Methods: Brain leve...

Adults with Down syndrome develop the neuropathological hallmarks of Alzheimer's disease and are at very high risk of developing early-onset dementia, which is now the leading cause of death in this population. Diagnosis of dementia remains a clinical challenge because of the lack of validated diagnostic criteria in this population, and because sym...

Background Individuals with Down syndrome (DS) are at high risk for dementia, specifically Alzheimer's disease. However, many measures regularly used for the detection of dementia in the general population are not suitable for individuals with DS due in part to floor effects. Some measures, including the Severe Impairment Battery (SIB), Brief Praxi...

Primary care integration of Down syndrome (DS)-specific dementia screening is strongly advised. The current study employed principal components analysis (PCA) and classification and regression tree (CART) analyses to identify an abbreviated battery for dementia classification. Scale- and subscale-level scores from 141 participants (no dementia n =...

The gene-regulatory landscape of the brain is highly dynamic in health and disease, coordinating a menagerie of biological processes across distinct cell types. Here, we present a multi-omic single-nucleus study of 191,890 nuclei in late-stage Alzheimer’s disease (AD), accessible through our web portal, profiling chromatin accessibility and gene ex...

Background Adults with Down syndrome are at an ultra-high risk of Alzheimer's disease, but diagnosis of Alzheimer's disease in this population is challenging. We aimed to validate the clinical utility of plasma neurofilament light chain (NfL) for the diagnosis of symptomatic Alzheimer's disease in Down syndrome, assess its prognostic value, and est...

Individuals with Down syndrome (DS) have a genetic predisposition for amyloid-β (Aβ) overproduction and earlier onset of Aβ deposits compared to patients with sporadic late-onset Alzheimer’s disease (AD). Positron emission tomography (PET) with Pittsburgh Compound-B (PiB) detects fibrillar Aβ pathology in living people with DS and AD, but its relat...

Down syndrome (DS) is the largest genetically determined form of early-onset Alzheimer disease (AD). Adults with DS develop AD pathology by 40 years of age mainly because of overexpression of the APP gene on chromosome 21 that results in the early accumulation of amyloid-β (Aβ) plaques and cerebral amyloid angiopathy followed by tau pathology, neur...

Elderly cats develop age-related behavioral and neuropathological changes that ultimately lead to cognitive dysfunction syndrome (CDS). These neuropathologies share similarities to those seen in the brains of humans with Alzheimer’s disease (AD), including the extracellular accumulation of ß -amyloid (Aβ) and intraneuronal deposits of hyperphosphor...

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathological aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using...

Introduction: Down syndrome (DS), a genetic variant of early onset Alzheimer's disease (AD), lacks a suitable outcome measure for prevention trials targeting pre-dementia stages. Methods: We used cognitive test data collected in several longitudinal aging studies internationally from 312 participants with DS without dementia to identify composit...

With improved healthcare, the Down syndrome (DS) population is both growing and aging rapidly. However, with longevity comes a very high risk of Alzheimer’s disease (AD). The LIFE-DSR study (NCT04149197) is a longitudinal natural history study recruiting 270 adults with DS over the age of 25. The study is designed to characterize trajectories of ch...