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Alzheimer's disease (AD) is marked by cognitive dysfunction emerging from neuropathological processes impacting brain function. AD affects brain dynamics at the local level, such as changes in the balance of inhibitory and excitatory neuronal populations, as well as long-range changes to the global network. Individual differences in these changes as they relate to behaviour are poorly understood. Here, we use a multi-scale neurophysiological model, "The Virtual Brain (TVB)", based on empirical multi-modal neuroimaging data, to study how local and global dynamics correlate with individual differences in cognition. In particular, we modeled individual resting-state functional activity of 124 individuals across the behavioural spectrum from healthy aging, to amnesic Mild Cognitive Impairment (MCI), to AD. The model parameters required to accurately simulate empirical functional brain imaging data correlated significantly with cognition, and exceeded the predictive capacity of empirical connectomes.

Background/aimsThe role of cognitive reserve in Parkinson's disease (PD)-mild cognitive impairment (MCI) is incompletely understood.MethodsThe relationships between PD-MCI, years of education, and estimated premorbid IQ were examined in 119 consecutive non-demented PD patients using logistic regression models.ResultsHigher education and IQ were associated with reduced odds of PD-MCI in univariate analysis. In multivariable analysis, a higher IQ was associated with a significantly decreased odds of PD-MCI, but education was not.ConclusionThe association of higher IQ and decreased odds of PD-MCI supports a role for cognitive reserve in PD, but further studies are needed to clarify the interaction of IQ and education and the impact of other contributors such as employment and hobbies.

Brain plasticity and cognitive compensation in the elderly are of increasing interest, and Alzheimer's disease (AD) offers an opportunity to elucidate how the brain may overcome damage. We provide neurophysiological evidence of a short-latency event-related potential (ERP) component (C145) linked to stimulus relevancy that may reflect cognitive compensation in early-stage AD. Thirty-six subjects with early-stage, mild AD and 36 like-aged normal elderly (controls) had their EEG recorded while performing our Number-Letter task, a cognitive/perceptual paradigm that manipulates stimulus relevancies. ERP components, including C145, were extracted from ERPs using principal components analysis. C145 amplitudes and spatial distributions were compared among controls, AD subjects with high performance on the Number-Letter task, and AD subjects with low performance. Compared to AD subjects, control subjects showed enhanced C145 processing of visual stimuli in the occipital region where differential processing of relevant stimuli occurred. AD high performers recruited central brain areas in processing task relevancy. Controls and AD low performers did not show a significant task relevancy effect in these areas. We conclude that short-latency ERP components can detect electrophysiological differences in early-stage AD that reflect altered cognition. Differences in C145 amplitudes between AD and normal elderly groups regarding brain locations and types of task effects suggest compensatory mechanisms can occur in the AD brain to overcome loss of normal functionality, and this early compensation may have a profound effect on the cognitive efficiency of AD individuals. [ABSTRACT FROM AUTHOR]

The article reports a study on the common complaint of memory loss during the menopausal transition in women. The study reported 67 percent of women with some degree of memory loss, 41 percent with moderate forgetfulness and 13 percent women were reported on the borderline-impaired to impaired range memory measure. Factors involved for memory loss, including depressive symptoms, somatic complaints, anxiety and sleep problems, are also discussed.

Background: Preclinical data have shown that low levels of metabolites with anti-inflammatory properties may impact metabolic disease processes. However, the association between mid-life levels of such metabolites and long-term ASCVD risk is not known., Methods: We characterised the plasma metabolomic profile (1228 metabolites) of 1852 participants (58.1 ± 7.5 years old, 69.6% female, 43.6% self-identified as Black) enrolled in the Heart Strategies Concentrating on Risk Evaluation (Heart SCORE) study. Logistic regression was used to assess the impact of metabolite levels on ASCVD risk (nonfatal MI, revascularisation, and cardiac mortality). We additionally explored the effect of genetic variants neighbouring ASCVD-related genes on the levels of metabolites predictive of ASCVD events. The Atherosclerosis Risk in Communities (ARIC) study (n = 4790; 75.5 ± 5.1 years old, 57.4% female, 19.5% self-identified as Black) was used as an independent validation cohort., Findings: In fully adjusted models, alpha-ketobutyrate [AKB] (OR 0.62 [95% CI, 0.49-0.80]; p < 0.001), and 1-palmitoyl-2-linoleoyl-GPI [OR, 0.62, 95% CI, 0.47-0.83; p < 0.001], two metabolites in amino acid and phosphatidylinositol lipid pathways, respectively, showed a significant protective association with incident ASCVD risk in both Heart SCORE and ARIC cohorts. Three plasmalogens and a bilirubin derivative, whose levels were regulated by genetic variants neighbouring FADS1 and UGT1A1, respectively, exhibited a significant protective association with ASCVD risk in the Heart SCORE only., Interpretation: Higher mid-life levels of AKB and 1-palmitoyl-2-linoleoyl-GPI metabolites may be associated with lower risk late-life ASCVD events. Further research can determine the causality and therapeutic potential of these metabolites in ASCVD., Funding: This study was funded by the Pennsylvania Department of Health (ME-02-384). The department specifically disclaims responsibility for any analyses, interpretations, or conclusions. Additional funding was provided by National Institutes of Health (NIH) grant R01HL089292 and UL1 TR001857 (Steven Reis). Further, NIH funded R01HL141824 and R01HL168683 were used for the ARIC study validation (Bing Yu)., Competing Interests: Declaration of interests The authors report no conflicts of interest relevant to this work. Anum Saeed is supported by 23CDA1055489 by the American Heart Association. Steven Reis has received funding for this study by the Department of Health of Commonwealth of Pennsylvania and National Institute of Health (NIH). Mark Mapstone is supported by U19 AG078109, U19 AG068054, R01 AG058644 and R01AG056726 by the National Aging Institute (NIA) and National Institute for Child Health and Development and reports royalty payments by the University of Rochester and consulting fees from NovoGlia and Ireneo Health. Ann D. Cohen is supported by the NIH/NIA and reports travel support by Biogen, spouse is a Quest employee, and honoraria received from UT Austin. Oscar L. Lopez receives consulting fees from Novo Nordisk which is not relevant to this work. Chris McKennan receives consulting fees from Signature Dx (unrelated to this manuscript) and grant funding from the NIH NIA and NIAID and reports participation in DUSK trial, RIGHT Study, and DEEP trial. The remaining authors have no disclosures relevant to this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Introduction: Aging adults with Down syndrome (DS) accumulate Alzheimer's disease (AD) neuropathology, including amyloid beta plaques and neurofibrillary tangles, by age 40., Methods: We present findings from an individual with DS who remained cognitively stable despite AD neuropathology. Clinical assessments, fluid biomarkers, neuroimaging, and neuropathological examinations were conducted to characterize her condition., Results: Her apolipoprotein E was ε2/ε3 and genome-wide association study data indicated mosaicism. Neuroimaging revealed stable yet elevated amyloid and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies. The participant demonstrated stable cognitive functioning in her 60s, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment., Discussion: These findings emphasize the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and inform future interventions., Highlights: Findings from clinical assessments, fluid biomarkers, genotyping, neuroimaging, and neuropathological examinations of an individual with Down syndrome (DS) who remained cognitively stable despite Alzheimer's disease (AD) neuropathology are presented. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body and cerebrovascular pathologies. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to genetic variations, cognitive resilience, and environmental enrichment, emphasizing the complexity of AD progression in DS., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Alzheimer's disease (AD) in Down syndrome (DS) is associated with changes in brain structure. It is unknown if thickness and volumetric changes can identify AD stages and if they are similar to other genetic forms of AD., Methods: Magnetic resonance imaging scans were collected for 178 DS adults (106 nonclinical, 45 preclinical, and 27 symptomatic). Cortical thickness and subcortical volumes were compared between DS groups and evaluated as a staging metric using receiver operating characteristic analyses. Thickness patterns were compared to those previously reported in autosomal-dominant AD (ADAD)., Results: Decreased parietal and temporal lobe thickness differentiated amyloid positivity (area under the curve [AUC] = 0.83) and impairment (AUC = 0.81), and slightly outperformed subcortical volumes (AUC = 0.8/0.74). Thickness differences in DS were more widespread, severe, and had better discriminative ability than ADAD., Discussion: Cortical thickness can stage AD pathology in DS. Identification of brain regions affected by AD may aid in tracking disease course and evaluating treatment effects., Highlights: DSAD is associated with reduced temporal and parietal cortical thickness. DSAD is associated with smaller hippocampal and striatal volumes. Thickness differences can stage DSAD better than other forms of AD. DSAD thickness differences are more extensive and severe than ADAD., (© 2025 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Development of Alzheimer's disease (AD) pathology in Down's syndrome (DS) occurs within a compressed timeline compared to sporadic or other genetic forms of AD., Methods: Plasma glial fibrillary acidic protein (GFAP) and plasma pTau-217 levels were compared by AD pathophysiology (amyloid (A+) and tau (T+) positron emission tomography [PET]) in persons with DS (N = 348) and sibling controls (N = 42). Plasma GFAP, plasma pTau-217, amyloid-PET, and tau-PET levels were compared with regard to estimated years to onset of clinical symptoms (52.5 years old). We evaluated if plasma GFAP mediated the relationship between amyloid PET and plasma pTau-217 or tau PET., Results: Plasma GFAP, a measure of astrogliosis, was elevated in A+/T- and A+/T+ individuals with DS. Plasma pTau-217 was elevated in A+/T+ individuals with DS. GFAP partially mediated the relationship between amyloid-PET and tau-PET (15.3%) and amyloid-PET and plasma pTau-217 (42.1%)., Discussion: Astrogliosis is a key component in the advancement of preclinical AD pathophysiology in DS., Highlights: Amyloid may be a necessary precursor for stimulating astrocytes. Astrogliosis may play a key role in modifications to tau phosphorylation. Targeting neuroinflammation may only aid amyloid positive individuals. Alzheimer's disease timecourse is compressed in individuals with Down's syndrome., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Blood-based biomarkers continue to be explored for disease detection, monitoring of progression, and therapeutic outcomes as the diagnostic determination of Alzheimer's Disease in Down Syndrome (DS-AD) remains challenging in clinical settings. This perspective highlights the current status of this effort. Overall, amyloid (A), tau (T), and neurodegeneration (AT[N]) blood-based biomarkers have been shown to increase with disease pathology for individuals with DS. Phosphorylated tau biomarkers (p-tau217, p-tau181) have been consistently shown to track disease progression for DS-AD and are likely good candidates for use in clinical settings. Biomarkers of inflammation (glial fibrillary acidic protein) also show promise; however, additional work is needed. Findings from stability work of blood-based biomarkers conducted among non-DS also support the potential longitudinal utility of biomarkers such as neurofilament light chain and p-tau181 in DS. Gaps in our knowledge are highlighted, and a potential role for sex differences in biomarker outcomes is noted, along with recommendations for determining the appropriate context of use when translating biomarkers into clinical applications. HIGHLIGHTS: An overview of blood-based biomarkers for Alzheimer's disease (AD) was provided for consideration of their utility among individuals with Down syndrome when looking toward potential clinical applications. Longitudinal stability of many blood biomarkers and improvement in detection sensitivity make blood such as plasma a viable source for exploring AD pathology. Variability in reviewed findings regarding the application of blood biomarkers highlights the importance of understanding and defining the appropriate context of use, particularly when translating them into clinical practice., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Adults with Down syndrome demonstrate striatum-first amyloid accumulation with [ 11 C]PiB PET imaging, which has not been replicated with [ 18 F]florbetapir (FBP). Early striatal accumulation has not been temporally quantified with respect to global cortical measures., Methods: Longitudinal PiB (n=175 participants) and FBP (n=92 participants) data from the Alzheimer Biomarkers Consortium-Down Syndrome were used to measure cortical and striatal binding. Generalized temporal models for cortical and striatal amyloid accumulation were created using the sampled iterative local approximation (SILA) method., Results: PiB demonstrated greater striatal-to-cortical ratios than FBP. SILA analysis revealed striatal amyloid burden occurs 3.40 (2.39) years earlier than the cortex in PiB. There was no difference between the cortex and striatum in FBP., Discussion: Among adults with Down syndrome, the striatum consistently accumulates amyloid earlier than the cortex when measured with PiB. This suggests the striatum is more sensitive to the onset of PiB PET-detectable amyloid in Down syndrome.

Background: Adults with Down syndrome are at risk for Alzheimer's disease. Natural history cohort studies have characterised the progression of Alzheimer's disease biomarkers in people with Down syndrome, with a focus on amyloid β-PET and tau-PET. In this study, we aimed to leverage these well characterised imaging biomarkers in a large cohort of individuals with Down syndrome, to examine the timeline to symptomatic Alzheimer's disease based on estimated years since the detection on PET of amyloid β-positivity, referred to here as amyloid age, and in relation to tau burden as assessed by PET., Methods: In this prospective, longitudinal, observational cohort study, data were collected at four university research sites in the UK and USA as part of the Alzheimer's Biomarker Consortium-Down Syndrome (ABC-DS) study. Eligible participants were aged 25 years or older with Down syndrome, had a mental age of at least 3 years (based on a standardised intelligence quotient test), and had trisomy 21 (full, mosaic, or translocation) confirmed through karyotyping. Participants were assessed twice between 2017 and 2022, with approximately 32 months between visits. Participants had amyloid-PET and tau-PET scans, and underwent cognitive assessment with the modified Cued Recall Test (mCRT) and the Down Syndrome Mental Status Examination (DSMSE) to assess cognitive functioning. Study partners completed the National Task Group-Early Detection Screen for Dementia (NTG-EDSD). Generalised linear models were used to assess the association between amyloid age (whereby 0 years equated to 18 centiloids) and mCRT, DSMSE, NTG-EDSD, and tau PET at baseline and the 32-month follow-up. Broken stick regression was used to identify the amyloid age that corresponded to decreases in cognitive performance and increases in tau PET after the onset of amyloid β positivity., Findings: 167 adults with Down syndrome, of whom 92 had longitudinal data, were included in our analyses. Generalised linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and at the 32-month follow-up. Using broken stick regression models, differences in mCRT total scores were detected beginning 2·7 years (95% credible interval [CrI] 0·2 to 5·4; equating to 29·8 centiloids) after the onset of amyloid β positivity in cross-sectional models. Based on cross-sectional data, increases in tau deposition started a mean of 2·7-6·1 years (equating to 29·8-47·9 centiloids) after the onset of amyloid β positivity. Mild cognitive impairment was observed at a mean amyloid age of 7·4 years (SD 6·6; equating to 56·8 centiloids) and dementia was observed at a mean amyloid age of 12·7 years (5·6; equating to 97·4 centiloids)., Interpretation: There is a short timeline to initial cognitive decline and dementia from onset of amyloid β positivity and tau deposition in people with Down syndrome. This newly established timeline based on amyloid age (or equivalent centiloid values) is important for clinical practice and informing the design of Alzheimer's disease clinical trials, and it avoids the limitations of timelines based on chronological age., Funding: National Institute on Aging and the National Institute for Child Health and Human Development., Competing Interests: Declaration of interests MZ received honoraria from LuMind International Down Syndrome Community and a travel award from the Trisomy21 Research Society. BH receives royalties from two co-authored books; is paid consulting fees from Patient-Centered Outcomes Research Institute grant; received honoraria from the University of North Carolina; and served on a data monitoring board for a Department of Defense funded grant. TB has received honoraria from National Institutes of Health and Intermountain Healthcare; and travel support from University College London, the Alzheimer's Association, and National Institutes of Health. DLT participated in the REMBRAND study advisory board. SZ reports grants from Cambridgeshire and Peterborough Foundation National Health Service Trust and serves on committees for the Trisomy21 Research Society. MM receives royalties from University of Rochester; and consulting fees from NovoGlia and Ireneo Health; has US patents (numbers 7 645 140, 10 578 629, #10 718 021, 10 890 589, 10 900 977, and 10 900 980); serves on the scientific advisory board for Brain Neurotherapy Bio, Davis Phinney Foundation for Parkinson's, and Alzheon; is the chair of data and safety monitoring board for the Aerobic Exercise and Cognitive Training Trial; and owns stock in Ireneo Health. EH reports grants from Brightfocus and the Alzheimer's Association. ES, JW AC, BA, CL, BC, and SH declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Individuals with Down syndrome (DS) are at high risk of early-onset Alzheimer's disease (AD); yet, some 20 percent do not develop any signs of dementia until after 65 years or in their lifetime. Mosaicism could contribute to this phenotypic variation, where some disomic cells could lead to lower levels of gene products from chromosome 21., Methods: We examined longitudinal neuropsychological and biomarker data from two large studies of DS: the Alzheimer Biomarker Consortium-Down syndrome study (ABC-DS) (n = 357); and a legacy study (n = 468). We assessed mosaicism using karyotyping or GWAS data. Participants had data on plasma AD biomarkers (Aβ 40 , Aβ 42 , tau, and NfL) and longitudinal cognitive measures. A subset had cerebrospinal fluid biomarkers (Aβ 40 , Aβ 42 , tau, ptau181, and NfL) and amyloid and tau PET data., Findings: For both cohorts, the prevalence of mosaicism was <10% (ABC-DS: 7.3%; Legacy: 9.6%), and those with mosaicism had lower plasma Aβ 40 and Aβ 42 concentrations. For the older legacy cohort, when compared to those with full trisomy, those with mosaicism had significantly smaller decline in total and annualized neurocognitive scores, and lower incidence and prevalence of dementia., Interpretation: Mosaicism in DS was associated with lower concentrations of plasma Aβ peptides, possibly leading to lower AD risk. However, its clinical impact was less clear in the younger ABC-DC cohort, and a follow-up study is warranted., Funding: National Institutes of Health (R01AG014673, P01HD035897, R56AG061837), NIA (U01AG051412, U19AG068054), NICHD, ADRC programs, the Eunice Kennedy Shriver Intellectual and Developmental Disabilities Research Centers Program, and NCATS (UL1TR001873)., Competing Interests: Declaration of interests BA is a member of VCID Advisory Board without payment. BH receives funding from National Institute of Child Health and Human Development, Autism Speaks, and Roche Pharmaceuticals. EH has consulted for Alzheon and Cyclotherapeutics and received royalties from Elsevier Press. JHL is part of the external advisory board for the Alzheimer's Disease Resource Center for Minority Aging Research, University of Texas, and for the Center of Life Science, Nazarbayev University, Astana, Kazakhstan. MM is an inventor on patents related to biomarkers of neurodegenerative diseases owned by Georgetown University and the University of Rochester. SH is the vice-chair of the ISTAART Down syndrome PIA. SKM is an employee for the New York State Office for People with Developmental Disabilities (OPWDD) and is a consultant for the NIH grant R01-HD098179. SZ is the chair of the scientific committee of the T21 Research Society receiving paid registration to the biannual meeting. The other authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

The amyloid beta (Aβ) 42/40 ratio has been widely studied as a biomarker in Alzheimer's disease (AD); however, other Aβ peptides could also represent relevant biomarkers. We measured levels of Aβ38/40/42 in plasma samples from cognitively-unimpaired older adults and determined the relationships between Aβ levels and amyloid positron-emission-tomography (PET) and performance on a learning and memory task. We found that all Aβ peptides individually and the Aβ42/40 ratio, but not the Aβ42/38 ratio, were significantly correlated with brain amyloid (Aβ-PET). Multiple linear modeling, adjusting for age, sex, education, APOE4 and Aβ-PET showed significant associations between the Aβ42/38 ratio and memory. Further, associations between the Aβ42/38 ratio and learning scores were stronger in males and in Aβ-PET-negative individuals. In contrast, no significant associations were detected between the Aβ42/40 ratio and any learning measure. These studies implicate the Aβ42/38 ratio as a biomarker to assess early memory deficits and underscore the utility of the Aβ38 fragment as an important biomarker in the AD field., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

By age 40 years, over 90% of adults with Down syndrome have Alzheimer's disease pathology and most progress to dementia. Despite having few systemic vascular risk factors, individuals with Down syndrome have elevated cerebrovascular disease markers that track with the clinical progression of Alzheimer's disease, suggesting a role of cerebrovascular disease that is hypothesized to be mediated by inflammatory factors. This study examined the pathways through which small vessel cerebrovascular disease contributes to Alzheimer's disease-related pathophysiology and neurodegeneration in adults with Down syndrome. One hundred eighty-five participants from the Alzheimer's Biomarkers Consortium-Down Syndrome [mean (SD) age = 45.2 (9.3) years] with available MRI and plasma biomarker data were included in this study. White matter hyperintensity (WMH) volumes were derived from T2-weighted fluid-attenuated inversion recovery MRI scans, and plasma biomarker concentrations of amyloid beta 42/40, phosphorylated tau 217, astrocytosis (glial fibrillary acidic protein) and neurodegeneration (neurofilament light chain) were measured with ultrasensitive immunoassays. We examined the bivariate relationships of WMH, amyloid beta 42/40, phosphorylated tau 217 and glial fibrillary acidic protein with age-residualized neurofilament light chain across Alzheimer's disease diagnostic groups. A series of mediation and path analyses examined statistical pathways linking WMH and Alzheimer's disease pathophysiology to promote neurodegeneration in the total sample and groups stratified by clinical diagnosis. There was a direct and indirect bidirectional effect through the glial fibrillary acidic protein of WMH on phosphorylated tau 217 concentration, which was associated with neurofilament light chain concentration in the entire sample. Amongst cognitively stable participants, WMH was directly and indirectly, through glial fibrillary acidic protein, associated with phosphorylated tau 217 concentration, and in those with mild cognitive impairment, there was a direct effect of WMH on phosphorylated tau 217 and neurofilament light chain concentrations. There were no associations of WMH with biomarker concentrations among those diagnosed with dementia. The findings from this cross-sectional study suggest that among individuals with Down syndrome, cerebrovascular disease promotes neurodegeneration by increasing astrocytosis and tau pathophysiology in the presymptomatic phases of Alzheimer's disease, but future studies will need to confirm these associations with longitudinal data. This work joins an emerging literature that implicates cerebrovascular disease and its interface with neuroinflammation as a core pathological feature of Alzheimer's disease in adults with Down syndrome., Competing Interests: O.H. has received consulting fees for AC Immune, Amylyx, ALZpath, BioArctic, Biogen, Cerveau, Eisai, Eli Lilly, Fujirebio, Merck, Novartis, Novo Nordisk, Roche, Sanofi and Siemens; S.Z. has received consulting fees from Lundbeck; D.M.W. has received consulting fees from Biohaven Therapeutics; E.H. has received consulting fees for Alzheon and Cyclo Therapeutics; A.M.B. has received consulting fees from Cogstate, Cognito Therapeutics, IQVIA, and Cognition Therapeutics., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Adults with Down syndrome (DS) are at risk for Alzheimer's disease (AD). Recent natural history cohort studies have characterized AD biomarkers, with a focus on PET amyloid-beta (Aβ) and PET tau. Leveraging these well-characterized biomarkers, the present study examined the timeline to symptomatic AD based on estimated years since reaching Aβ+, referred to as "amyloid age", and in relation to tau in a large cohort of individuals with DS., Methods: In this multicenter cohort study, 25 - 57-year-old adults with DS (n = 167) were assessed twice from 2017 to 2022, with approximately 32 months between visits as part of the Alzheimer Biomarker Consortium - Down Syndrome. Adults with DS completed amyloid and tau PET scans, and were administered the modified Cued Recall Test and the Down Syndrome Mental Status Examination. Study partners completed the National Task Group-Early Detection Screen for Dementia., Findings: Mixed linear regressions showed significant quadratic associations between amyloid age and cognitive performance and cubic associations between amyloid age and tau, both at baseline and across 32 months. Using broken stick regression models, differences in mCRT scores were detected beginning 2.7 years following Aβ+ in cross-sectional models, with an estimated decline of 1.3 points per year. Increases in tau began, on average, 2.7 - 6.1 years following Aβ+. On average, participants with mild cognitive impairment were 7.4 years post Aβ+ and those with dementia were 12.7 years post Aβ+., Interpretation: There is a short timeline to initial cognitive decline and dementia from Aβ+ (Centiloid = 18) and tau deposition in DS relative to late onset AD. The established timeline based on amyloid age (or equivalent Centiloid values) is important for clinical practice and informing AD clinical trials, and avoids limitations of timelines based on chronological age. Funding. National Institute on Aging and the National Institute for Child Health and Human Development., Research in Context: Evidence before this study: We searched PubMed for articles published involving the progression of Aβ and tau deposition in adults with Down syndrome from database inception to March 1, 2024. Terms included "amyloid", "Down syndrome", "tau", "Alzheimer's disease", "cognitive decline", and "amyloid chronicity," with no language restrictions. One previous study outlined the progression of tau in adults with Down syndrome without consideration of cognitive decline or clinical status. Other studies reported cognitive decline associated with Aβ burden and estimated years to AD symptom onset in Down syndrome. Amyloid age estimates have also been created for older neurotypical adults and compared to cognitive performance, but this has not been investigated in Down syndrome. Added value of this study: The timeline to symptomatic Alzheimer's disease in relation to amyloid, expressed as duration of Aβ+, and tau has yet to be described in adults with Down syndrome. Our longitudinal study is the first to provide a timeline of cognitive decline and transition to mild cognitive impairment and dementia in relation to Aβ+. Implications of all the available evidence: In a cohort study of 167 adults with Down syndrome, cognitive decline began 2.7 - 5.4 years and tau deposition began 2.7 - 6.1 years following Aβ+ (Centiloid = 18). Adults with Down syndrome converted to MCI after ~7 years and dementia after ~12-13 years of Aβ+. This shortened timeline to AD symptomology from Aβ+ and tau deposition in DS based on amyloid age (or corresponding Centiloid values) can inform clinical AD intervention trials and is of use in clinical settings.

Background: Variants in ABCA7, a member of the ABC transporter superfamily, have been associated with increased risk for developing late onset Alzheimer's disease (LOAD)., Methods: CRISPR-Cas9 was used to generate an Abca7 V1613M variant in mice, modeling the homologous human ABCA7 V1599M variant, and extensive characterization was performed., Results: Abca7 V1613M microglia show differential gene expression profiles upon lipopolysaccharide challenge and increased phagocytic capacity. Homozygous Abca7 V1613M mice display elevated circulating cholesterol and altered brain lipid composition. When crossed with 5xFAD mice, homozygous Abca7 V1613M mice display fewer Thioflavin S-positive plaques, decreased amyloid beta (Aβ) peptides, and altered amyloid precursor protein processing and trafficking. They also exhibit reduced Aβ-associated inflammation, gliosis, and neuronal damage., Discussion: Overall, homozygosity for the Abca7 V1613M variant influences phagocytosis, response to inflammation, lipid metabolism, Aβ pathology, and neuronal damage in mice. This variant may confer a gain of function and offer a protective effect against Alzheimer's disease-related pathology., Highlights: ABCA7 recognized as a top 10 risk gene for developing Alzheimer's disease. Loss of function mutations result in increased risk for LOAD. V1613M variant reduces amyloid beta plaque burden in 5xFAD mice. V1613M variant modulates APP processing and trafficking in 5xFAD mice. V1613M variant reduces amyloid beta-associated damage in 5xFAD mice., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome., Methods: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD)., Results: Eighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA). Metabolomic diversity differences were observed in females, however no individual metabolites were differentially abundant. hAβ-KI mice microbiomes were distinguishable from 3xTg-AD animals (81% accuracy by random forest modeling), with separation primarily driven by Romboutsia ilealis and Turicibacter species. Microbiomes were highly cage specific, with cage assignment accounting for more than 40% of the PERMANOVA variance between the groups., Discussion: These findings highlight a sex-dependent variation in the microbiomes of hAβ-KI mice and underscore the importance of considering the microbiome when designing studies that use murine models for AD., Highlights: Microbial diversity and the abundance of several species differed in human amyloid beta knock-in (hAβ-KI) females but not males. Correlations to Alzheimer's disease (AD) genotype were stronger for the microbiome than the metabolome. Microbiomes from hAβ-KI mice were distinct from 3xTg-AD mice. Cage effects accounted for most of the variance in the microbiome and metabolome., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

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, which is associated with a decreased risk of dementia. Neuroimaging revealed stable yet elevated amyloid profiles and moderately elevated tau levels, while neuropathology indicated intermediate AD neuropathologic change with Lewy body pathology and cerebrovascular pathology. Despite the presence of AD pathology, the participant demonstrated intact cognitive functioning, potentially attributed to factors such as genetic variations, cognitive resilience, and environmental enrichment. The findings suggest a dissociation between clinical symptoms and neuropathological changes, emphasizing the complexity of AD progression in DS. Further investigation into factors influencing cognitive resilience in individuals with DS, including comorbidities and social functioning, is warranted. Understanding the mechanisms underlying cognitive stability in DS could offer insights into resilience to AD neuropathology in people with DS and in the general population and inform future interventions.