564 pubs · 36,283 cites · h-index 96
APOE ε4 is the strongest common genetic risk factor for late-onset Alzheimers disease, but how ApoE isoforms shape physiology before disease remains unclear. Across the ancestral-to-derived ApoE4→ApoE3→ApoE2 sequence, we examined antioxidant regulation during aging. Young humanized ApoE4 mice had lower antioxidant protein abundance and oxidized phospholipid reduction before detectable oxidative damage, yet accumulated lipid peroxidation products with age despite antioxidant remodeling. ApoE4 cells mounted the strongest antioxidant transcriptional response to sulforaphane but accumulated less protein from targets supporting proteostasis, glutathione synthesis and ferroptosis suppression, alongside altered eIF2α signaling and translation kinetics. Antioxidant transcription shifted from an ApoE4 bias in youth toward ApoE2 with age, and adult APOE4-to-APOE2 switching redirected expression in astrocytes and microglia. Cognitively normal human brains showed regional reductions in nuclear Nrf2 and antioxidant proteins, with transcriptomic analyses supporting context-dependent organization. ApoE isoforms differentially couple stress-responsive transcription to protein output, linking age-dependent antioxidant adaptation to neurodegenerative vulnerability.
Alzheimer disease is characterized by extracellular amyloid-β deposition that contributes to neuronal dysfunction and degeneration. Although anti-amyloid-β antibodies reduce plaque burden, their use requires monitoring for amyloid-related imaging abnormalities. Here, phage display against immobilized Aβ40 fibrils representing a patient-relevant polymorph identified J8, a fibril-selective, Fc-free single-domain antibody. J8 bound fibrils with high apparent affinity, showed no detectable binding to monomeric Aβ40, decorated fibril surfaces, and recognized plaque-associated amyloid in Alzheimer disease brain tissue. During concurrent fibril exposure, J8 reduced apoptotic signaling in human induced pluripotent stem cell (iPSC)-derived cortical neurons and forebrain organoids. Single-nucleus profiling of pooled organoids identified fibril-associated stress programs and opposite-direction expression patterns in the FibJ8 condition; fibril-associated changes showed the strongest directional concordance with advanced disease pathology. These findings identify J8 as a fibril-selective candidate and support organoid-based evaluation of anti-amyloid reagents as a fit-for-purpose preclinical tool.
Individuals with Down syndrome (DS) are at high risk for Alzheimer's disease (AD), yet accessible tools for routine clinical screening of AD in individuals with DS remain limited. Using data from the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS), we show that integrating plasma pTau217 with performance on the modified cued recall task identifies a subgroup of cognitively stable individuals at markedly elevated risk of developing clinical impairment in the next 7 years. This low-burden, multimodal framework improves prognosis, supports more informed clinical management and efficient trial enrichment in Down syndrome. ANN NEUROL 2026.
Neighborhood disadvantage is a risk factor for dementia, but the mechanisms involved are not well understood. In this study, we explored the relationship between neighborhood deprivation and whole-brain cerebrovascular reactivity (CVR) in 132 older adults without history of clinical stroke or dementia. Participants underwent brain MRI and venipuncture. Relative neighborhood deprivation was quantified using the Area Deprivation Index. Spontaneous CVR was calculated as the percent change in resting cerebral blood flow per unit change in end-tidal CO 2 . Greater neighborhood deprivation was associated with lower whole-brain CVR when adjusted for age and sex ( p = 0.027). Further adjustment for APOE ε4 carrier status, vascular risk factors, and plasma Alzheimer’s disease (AD) biomarker p-tau217 did not alter the results. These findings show that older adults in more disadvantaged environments exhibit reduced cerebrovascular function, independent of traditional vascular risk and AD-related pathology. However, further investigation with more diverse samples and a life-course model is warranted to better understand these microvascular differences.
Alzheimer's disease progresses heterogeneously across diverse cohorts, yet current predictive models fail to capture this complexity while remaining clinically interpretable. Here we present a multi-dimensional attention framework that simultaneously captures both temporal dynamics and biomarker importance to predict disease progression across three fundamentally different populations: the general late-onset population using the Alzheimer's Disease Prediction Of Longitudinal Evolution (TADPOLE) dataset (N = 1669), cases with Down Syndrome-associated Alzheimer's disease using the Alzheimer's Biomarker Consortium - Down Syndrome (ABC-DS) dataset (N = 396), and cases with autosomal dominant Alzheimer's disease using the Dominantly Inherited Alzheimer Network (DIAN) dataset (N = 425). Trained on each dataset independently, our framework achieved multi-class Area Under the Receiver Operating Characteristic Curve (mAUC) values of 0.793 (TADPOLE), 0.680 (ABC-DS), and 0.902 (DIAN) when predicting individuals' future diagnostic status (cognitively normal/stable, mild cognitive impairment, or Alzheimer's disease) from their longitudinal biomarker history, outperforming conventional approaches. The model generates individual-specific attention maps revealing distinct biomarker importance over time. Transfer learning from TADPOLE—which included neuroimaging data—improved prediction performance on the imaging-free ABC-DS dataset from 0.680 to 0.771, demonstrating that disease mechanisms transcend both etiological boundaries and data modalities. Ultimately, this framework could enable precision medicine approaches for data-limited cohorts across the Alzheimer's disease spectrum.
Background: In the United States, the prevalence of Alzheimer disease (AD) is projected to double over the next 30 years, with associated familial and societal costs estimated at US $1 trillion annually if current trends continue. Although pharmacological treatments of AD are showing promise, the adoption of healthy lifestyle behaviors, particularly during the preclinical phase of AD, may reduce dementia rates by up to 45%. Subjective cognitive decline (SCD), defined as persistent self-perceived declines in cognitive functioning compared with previously normal cognitive abilities, has been identified as a potential preclinical stage of AD. Objective: This randomized controlled trial aims to evaluate the feasibility and acceptability of an internet-based, asynchronous mindfulness-based stress reduction program compared with an active control group (an internet-based lifestyle education program). Secondary objectives include examining preliminary effects of each intervention on SCD, plasma-based biomarkers of amyloid and tau pathology, and everyday mind-wandering. Methods: Sixty adults aged 50 years and older will be screened for SCD in the absence of objective cognitive impairment, based on the Uniform Data Set Neuropsychological Battery (version 3.0) from the National Alzheimer's Coordinating Center. Eligible and consenting participants will complete behavioral and imaging-based tasks of sustained attention and mind-wandering, as well as blood draws at baseline and after the 8-week intervention. After baseline assessments, participants will be randomized to either an internet-based, asynchronous mindfulness-based stress reduction program or the internet-based lifestyle education program. Both programs have been adapted from our manualized in-person programs and refined through focus group interviews with the target population. Results: The study was funded in April 2024. Phase 1 focused on iterative development of the 2 programs based on focus group feedback. Recruitment for the randomized controlled trial (internet-based mind-body training trial) began in June 2025 and is ongoing. Recruitment is expected to conclude in September 2026, with data collection ending in December 2026. Conclusions: Behavioral, lifestyle-based interventions that emphasize experiential practices show promise as preventative strategies to prevent decline in cognitive and brain health. Yet, there remain significant barriers to engaging with in-person programs, including limited accessibility, time and schedule constraints, and travel logistics. The internet-based mind-body training trial will evaluate the feasibility and acceptability of 2 fully online, mind-body training programs for adults at risk for AD. Future Stage II and Stage III studies will be necessary to establish the efficacy of these programs for improving AD biomarkers and cognitive outcomes and their broader dissemination to adults noticing subtle changes in cognitive functioning.
Randomized trial reveals mindfulness lowers plasma amyloid beta in Alzheimer's disease, suggesting breathing affects outcomes.
Hypothesis-generating in one observational study; leaves open whether targeting ARV or AASI affects neurodegeneration.
Background: Intrinsic low frequency oscillations in BOLD signal (BOLD LFOs) are generally considered nuisance signal in connectivity analysis and discarded. However, recent evidence suggests BOLD LFOs may shed light on cerebrovascular dysfunction and early Alzheimers disease pathophysiology, but the mechanisms remain unclear. No investigations to date have assessed the relationship between BOLD LFOs and plasma pTau217, or how this relationship differs in apolipoprotein e4 (APOE4) carriers who are vulnerable to cerebrovascular dysfunction and genetically predisposed to AD pathophysiology. Methods: Independently living older adults (N=118) without major neurological or psychiatric disorder were recruited from the community. Participants underwent resting-state brain functional MRI and venipuncture. Total BOLD LFOs were quantified as signal power within the 0.01 to 0.10 Hz frequency range. Plasma level of pTau217 was assessed and linear regression was used to quantify the interactive effect of APOE4 carrier status and BOLD LFOs on plasma pTau217. 2x2 ANCOVA was used to compare BOLD LFOs across APOE4 carrier and amyloid positivity statuses based on previously reported pTau217 cutoffs. Results: The interactive effect of APOE4 carrier status and BOLD LFO power was significantly associated with plasma pTau217 (β=-.65, p=.004). This relationship was driven by an inverse relationship between BOLD LFOs and plasma pTau217 in APOE4 carriers (β=-.49, p=.003). Amyloidβ positive APOE4 carriers displayed lower BOLD LFOs than amyloidβ negative APOE4 carriers (p=.02) and amyloid-β positive APOE4 non carriers (p=.04). All models were adjusted for age and sex. Conclusion: Present study findings suggests that BOLD LFOs are implicated early in AD pathophysiology in an APOE4 dependent manner, adding support for the continued study of BOLD LFOs in the context of cerebrovascular contributions to AD genetic risk.
Down syndrome (DS) stands out as the most prevalent genetic contributor to intellectual disability, marked by the presence of an extra copy of chromosome 21 (HSA21). Notably, individuals with DS exhibit significant neuropathological changes for a diagnosis of Alzheimer's disease (AD), typically by the age of 50 years. To search for and identify biomarkers crucial for detecting and understanding the mechanisms involved in DS neuropathology, we conducted a protein expression analysis of post-mortem brain samples. We evaluated the frontal cortex of post-mortem brain samples from patients with DS both before and after the onset of AD pathology (DSAD), in comparison with age-matched healthy patients (CTRY and CTRO). Employing a comprehensive label-free shotgun proteomics approach, we sought to gain a deeper understanding of the intricate protein profiles associated with DS and its progression into DSAD. Collected results have been analyzed using specific databases and bioinformatics analysis software to understand relevant pathways, networks, and functions related to the experimental data. Our data support a genotype effect in DS at young and old ages that promotes specific proteome signatures associated with AD development. Notably, the affected signalling pathways encompass energy-related processes, synaptic transmission, and stress response. With aging, the dynamic shift in protein expression contributes to accelerating the neurodegenerative process, culminating in the manifestation of the AD phenotype.
Characterizing the timing and progression of Alzheimer's disease biomarker onset in Down syndrome (DS) and contrasting potential timing differences with neurotypical adults is needed to identify optimal Alzheimer's disease therapeutic treatment windows in DS. In this study, 198 adults with DS from the Alzheimer Biomarker Consortium-Down Syndrome and 172 neurotypical adults from the Wisconsin Registry for Alzheimer's Prevention with available longitudinal beta-amyloid PET, tau PET and plasma p-tau217 analysed on the Lilly Meso Scale Delivery Platform were included. Individuals with DS had a significantly higher lifetime risk of beta-amyloid plaque onset. Temporal modelling of longitudinal biomarker measures revealed earlier age at positivity of beta-amyloid plaques, p-tau217 and neurofibrillary tau tangles in DS relative to the neurotypical cohort. The onset of p-tau217 and tau PET positivity in DS occurred nearly simultaneously, roughly 4-6 years following beta-amyloid onset, whereas the neurotypical group displayed greater temporal latency between positivity of the two biomarkers. The early and simultaneous onset of these biomarkers in DS highlights the necessity for early therapeutic interventions in this population. This work, combined with the upcoming anti-amyloid safety and efficacy clinical trials for DS will help to identify optimal treatment windows for these individuals.
Down syndrome (DS) is a common and recognizable genetic condition. Altered neurodevelopmental programs caused by trisomy 21 lead to the hallmark intellectual disability in early life. The increased lifespan of individuals with DS in the latter half of the twentieth century revealed the emergence of Alzheimer's disease (AD) earlier and with a higher prevalence in individuals with DS than in the general population. Thus, neuropathology in DS progresses along a continuum from prenatal disruptions to the manifestations of age-related conditions and AD. This review discusses our current understanding of the mechanisms of altered neurodevelopment and the precocious onset of AD in DS. We highlight the gaps in our understanding of how neurodevelopment and neurodegeneration are linked and describe how advancements in molecular technology and computational modeling are revealing molecular neuropathology in DS across the lifespan.
The study of transcriptomic and epigenomic variations in neurodegenerative diseases, particularly tauopathies like Pick's disease (PiD) and Alzheimer's disease (AD), offers insights into their underlying regulatory mechanisms. Here, we identified critical regulatory changes driving disease progression, revealing potential therapeutic targets. Our comparative analyses uncovered disease-enriched noncoding regions and genome-wide transcription factor (TF) binding differences, linking them to target genes. Notably, we identified a distal human-gained enhancer (HGE) associated with E3 ubiquitin ligase (UBE3A), highlighting disease-specific regulatory alterations. Additionally, fine mapping of AD risk genes uncovered loci enriched in microglial enhancers and accessible in other cell types. Shared and distinct TF binding patterns were observed in neurons and glial cells across PiD and AD. We validated our findings using CRISPR to excise a predicted enhancer region in UBE3A and developed an interactive database, scROAD, to visualize predicted single-cell TF occupancy and regulatory networks.
Down syndrome is characterized by triplication of chromosome 21, leading to early-onset Alzheimer's disease pathology, with nearly all individuals with Down syndrome developing amyloid and tau pathology. In the new era of amyloid-modifying therapies, it is vital to identify early biomarkers for Alzheimer's disease pathology in Down syndrome. Striatal amyloid may begin to accumulate sooner than cortical amyloid in Down syndrome. Tau phosphorylation at specific sites, including 217, can be quantified in plasma and may represent an important mechanistic step in the development of tau pathology. This study had two aims: (i) to compare the relative age at increase of multiple biomarkers (cortical amyloid, striatal amyloid, plasma pTau217 and summary tau pathology); and (ii) to test whether plasma pTau217 can identify both the current presence and likely future accumulation of amyloid and tau pathology. To identify optimal biomarkers for early intervention, we examined longitudinal cortical and striatal amyloid PET, plasma pTau217 and tau PET in 328 individuals with Down syndrome enrolled in the Alzheimer Biomarker Consortium-Down Syndrome study. To compare the timing of biomarker changes, we modelled longitudinal biomarkers using generalized additive mixed models relative to age. We used receiver operating characteristic curve analysis to identify thresholds for both current and likely future accumulation of amyloid and tau pathology. For all comparisons, we used age as the null model, performing DeLong's tests to evaluate the performance of age relative to biomarker-based prediction. Imaging biomarkers increased at around 40 years old, with plasma pTau217 increasing somewhat later than the three PET biomarkers. Striatal amyloid increased before cortical amyloid in some participants; however, this was not uniform across individuals. If an individual was classified as a reliable accumulator with one biomarker, he or she was likely to be a reliable accumulator in other biomarkers. Age was as sensitive as plasma pTau217 in its ability to both detect preclinical Alzheimer's disease pathology and predict near future accumulation of both amyloid and tau. These results suggest that all adults with Down syndrome should be screened for Alzheimer's disease pathology starting shortly before age 40 years and considered for clinical trials. Age alone was as effective at detecting both current pathology and likely future accumulation as plasma pTau217. Because this disease is so closely concurrent with age in individuals with Down syndrome, plasma pTau217 may not provide more diagnostic benefits than age.
Relationships between Alzheimer’s disease (AD) pathologies in cognitively unimpaired adults and in vivo neurometabolic properties measured directly from the hippocampus, a vulnerable region early along the AD continuum, are not well-understood in the earliest stages of AD. In a 3T 1 H-MRS study, we assessed age and AD-related changes in estimates of absolute concentrations of neurometabolites in the right hippocampus. Participants included older adults (age range: 60-85, n=19) primarily cognitively unimpaired (CU, n=16), as well as some with cognitive impairment (n=3). All participants previously received a lumbar puncture for AD disease staging from cerebrospinal fluid (CSF) AD biomarkers (Aβ42, p-tau181 and t-tau), where all were amyloid positive (A+) and most had subthreshold tau pathology (T-). Hippocampal 1 H-MRS metabolites included total N-acetylaspartate (tNAA), myo-inositol (mIns), total creatine (tCr) and total choline (tCho). Regression analyses were performed for assessing relationships among CSF biomarkers, age, and 1 H-MRS metabolites measured as tissue-corrected estimates of absolute concentrations (millimoles/kilogram) and as ratios (/tCr and tNAA/mIns). We identified age-related decreases to mIns/tCr, where estimated absolute concentrations revealed that tCr increased while mIns remained stable. Concentrations for tNAA and mIns were positively associated with CSF p-tau181 and t-tau. Levels of tCr and tCho were not associated with any CSF biomarkers. Overall, our results demonstrate that sub-threshold tau pathologies in cognitively unimpaired A+ individuals are associated with hippocampal metabolite changes related to neural metabolism and glial reactivity early in disease progression. • Aging increases hippocampal creatine suggesting neuroinflammation. • Tau links to MRS estimates of N-acetylaspartate and myo-inositol in A+ adults. • MRS may track neuroinflammation and neuronal dysfunction early in aging and AD.
The synergistic interaction of high beat-to-beat blood pressure variability and arterial stiffness is independently associated with structural brain atrophy and elevated plasma markers of neurodegeneration in older adults.
Background Lifetime incidence of Alzheimer's disease (AD) in Down syndrome (DS) exceeds 90%. In adults with and without DS, low moderate-to-vigorous physical activity (MVPA) and obesity have independently been associated with AD. Research across other disease conditions indicates MVPA may attenuate some negative consequences of obesity. Objective To evaluate the potential joint association of obesity and MVPA on cognitive function in adults with DS. Methods Seventy-five adults with DS (age 39.1 years, 46.7% female) enrolled in the Alzheimer Biomarker Consortium-Down Syndrome (ABC-DS) study and completed a 7-day accelerometer protocol. Cognitive function was assessed using the ABC-DS cognitive battery. Participants were categorized with Obesity (body mass index (BMI) ≥ 30 kg/m 2 ) or No Obesity (BMI < 30 kg/m 2 ). A median split of MVPA was then used to create four groups: No Obesity/High PA (n = 18), No Obesity/Low PA (n = 16), Obesity/High PA (n = 20), and Obesity/Low PA (n = 21). Linear models were used to compare cognitive function across groups. Results The Obesity/High PA group performed better than the No Obesity/Low PA group for episodic memory (β = 4.86, p = 0.009), executive functioning (β = 3.07, p = 0.013), and dementia symptoms (β = −6.57, p = 0.022). The Obesity/High PA group also performed better than the Obesity/Low PA group for memory and orientation (β = 4.43, p = 0.012), social functioning (β = 4.52, p = 0.006), visuo-spatial processing (β = −2.39, p = 0.038), and overall dementia symptoms (β = −7.21, p = 0.016). There were no assessments for which either high PA group performed worse than either Low PA group. Conclusions Physical activity may benefit AD-related cognitive function in persons with DS, regardless of obesity status.
Age increases of brain amyloid plaques may be mediated by prior increase of soluble Aβ42. Here, we show that frontal cortex samples from brains of cognitively normal aging humans had progressively increased levels of soluble amyloid peptide Aβ40 throughout the lifespan. Aggregated amyloid fraction was subsequently obtained by formic acid, where Aβ42 showed increases only in humans over 90 years old when compared to those younger than 50. Similarly, aging wild-type mice without amyloid plaques had increases of both soluble Aβ40 and Aβ42, as previously shown in normal aging rats. Aging also alters secretase enzymes and processing of amyloid precursor protein (APP). Here, we isolate membrane domains known as lipid rafts, a site of APP cleavage. We found that lipid rafts isolated from mouse and human cerebral cortex showed age increases of β-secretase enzyme activity, while amyloidogenic secretase proteins levels BACE1 and PS1 decreased with age in mouse. Lipid rafts merit further study in aging and neurodegeneration.
INTRODUCTION: In the neurotypical population, metabolic syndrome (MetS) is associated with Alzheimer's disease (AD). However, this has not been well studied in adults with Down syndrome (DS). METHODS: The prevalence of MetS and its subcomponents was examined in adults with DS using the Alzheimer Biomarkers Consortium - Down Syndrome data (ABC-DS, N = 389). Logistic regression was used to examine the relationship between MetS and AD at baseline visits. RESULTS: Prevalence of MetS, diabetes, hypertension, and hyperlipidemia was low with DS, even though the prevalence of obesity was elevated. Obesity was positively associated with AD in adults with DS (odds ratio = 2.79, P = 0.021), but there was no association between MetS and AD in DS. DISCUSSION: The prevalence of MetS was low in adults with DS. Although MetS was not associated with AD, obesity, a subcomponent of MetS, was associated with AD in adults with DS. This may inform targeted treatments in the future. HIGHLIGHTS: There was a low prevalence of metabolic syndrome (MetS) in adults with Down syndrome (DS). Overall MetS was not associated with dementia in adults with DS. Obesity, a subcomponent of MetS, had a high prevalence in adults with DS. Obesity was positively associated with dementia in adults with DS.
Observational analysis associated higher white matter hyperintensity and glial fibrillary acidic protein with Alzheimer's progression in Down syndrome, suggesting new diagnostic pathways.