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Optimal decision-making balances exploration for new information against exploitation of known rewards, a process mediated by the locus coeruleus and its norepinephrine projections. We predicted that an exploitation-bias that emerges in older adulthood would be associated with lower microstructural integrity of the locus coeruleus. Leveraging in vivo histological methods from quantitative MRI-magnetic transfer saturation-we provide evidence that older age is associated with lower locus coeruleus integrity. Critically, we demonstrate that an exploitation bias in older adulthood, assessed with a foraging task, is sensitive and specific to lower locus coeruleus integrity. Because the locus coeruleus is uniquely vulnerable to Alzheimer's disease pathology, our findings suggest that aging, and a presymptomatic trajectory of Alzheimer's related decline, may fundamentally alter decision-making abilities in later life.
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Envelhecimento , Tomada de Decisões , Locus Cerúleo , Imageamento por Ressonância Magnética , Locus Cerúleo/diagnóstico por imagem , Locus Cerúleo/fisiologia , Humanos , Tomada de Decisões/fisiologia , Idoso , Masculino , Feminino , Envelhecimento/fisiologia , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , RecompensaRESUMO
Elevated iron deposition in the brain has been observed in older adult humans and persons with Alzheimer's disease (AD), and has been associated with lower cognitive performance. We investigated the impact of iron deposition, and its topographical distribution across hippocampal subfields and segments (anterior, posterior) measured along its longitudinal axis, on episodic memory in a sample of cognitively unimpaired older adults at elevated familial risk for AD (N = 172, 120 females, 52 males; mean age = 68.8 ± 5.4 years). MRI-based quantitative susceptibility maps were acquired to derive estimates of hippocampal iron deposition. The Mnemonic Similarity Task was used to measure pattern separation and pattern completion, two hippocampally mediated episodic memory processes. Greater hippocampal iron load was associated with lower pattern separation and higher pattern completion scores, both indicators of poorer episodic memory. Examination of iron levels within hippocampal subfields across its long axis revealed topographic specificity. Among the subfields and segments investigated here, iron deposition in the posterior hippocampal CA1 was the most robustly and negatively associated with the fidelity memory representations. This association remained after controlling for hippocampal volume and was observed in the context of normal performance on standard neuropsychological memory measures. These findings reveal that the impact of iron load on episodic memory performance is not uniform across the hippocampus. Both iron deposition levels as well as its spatial distribution, must be taken into account when examining the relationship between hippocampal iron and episodic memory in older adults at elevated risk for AD.
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Doença de Alzheimer , Hipocampo , Ferro , Imageamento por Ressonância Magnética , Memória Episódica , Humanos , Feminino , Masculino , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/patologia , Doença de Alzheimer/psicologia , Idoso , Hipocampo/metabolismo , Hipocampo/diagnóstico por imagem , Hipocampo/patologia , Ferro/metabolismo , Pessoa de Meia-IdadeRESUMO
INTRODUCTION: We investigate the role of osteopontin (OPN) in participants with Pre-symptomatic Alzheimer's disease (AD), mild cognitive impairment (MCI), and in AD brains. METHODS: Cerebrospinal fluid (CSF) OPN, AD, and synaptic biomarker levels were measured in 109 cognitively unimpaired (CU), parental-history positive Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease (PREVENT-AD) participants, and in 167 CU and 399 participants with MCI from the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort. OPN levels were examined as a function of amyloid beta (Aß) and tau positivity. Survival analyses investigated the link between OPN and rate of conversion to AD. RESULTS: In PREVENT-AD, CSF OPN was positively correlated with synaptic biomarkers. In PREVENT-AD and ADNI, OPN was elevated in CSF Aß42/40(+)/total tau(+) and CSF Aß42/40(+)/phosphorylated tau181(+) individuals. In ADNI, OPN was increased in Aß(+) positron emission tomography (PET) and tau(+) PET individuals, and associated with an accelerated rate of conversion to AD. OPN was elevated in autopsy-confirmed AD brains. DISCUSSION: Strong associations between CSF OPN and key markers of AD pathophysiology suggest a significant role for OPN in tau neurobiology, particularly in the early stages of the disease. HIGHLIGHTS: In the Pre-symptomatic Evaluation of Experimental or Novel Treatments for Alzheimer's Disease cohort, we discovered that cerebrospinal fluid (CSF) osteopontin (OPN) levels can indicate early synaptic dysfunction, tau deposition, and neuronal loss in cognitively unimpaired elderly with a parental history. CSF OPN is elevated in amyloid beta(+) positron emission tomography (PET) and tau(+) PET individuals. Elevated CSF OPN is associated with an accelerated rate of conversion to Alzheimer's disease (AD). Elevated CSF OPN is associated with an accelerated rate of cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive subscale 13, Montreal Cognitive Assessment, Mini-Mental State Examination, and Clinical Dementia Rating Scale Sum of Boxes. OPN mRNA and protein levels are significantly upregulated in the frontal cortex of autopsy-confirmed AD brains.
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The e4 allele of the apolipoprotein E gene is the strongest genetic risk factor for sporadic Alzheimer's disease. Nevertheless, how APOE is regulated is still elusive. In a trans-eQTL analysis, we found a genome-wide significant association between transmembrane protein 106B (TMEM106B) genetic variants and cortical APOE mRNA levels in human brains. The goal of this study is to determine whether TMEM106B is mis-regulated in Alzheimer's disease or in other neurodegenerative conditions. Available genomic, transcriptomic and proteomic data from human brains were downloaded from the Mayo Clinic Brain Bank and the Religious Orders Study and Memory and Aging Project. An in-house mouse model of the hippocampal deafferentation/reinnervation was achieved via a stereotaxic lesioning surgery to the entorhinal cortex, and mRNA levels were measured using RNAseq technology. In human temporal cortices, the mean TMEM106B expression was significantly higher in Alzheimer's disease compared to cognitively unimpaired individuals. In the mouse model, hippocampal Tmem106b reached maximum levels during the early phase of reinnervation. These results suggest an active response to tissue damage that is consistent with compensatory synaptic and terminal remodeling.
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Doença de Alzheimer , Proteínas de Membrana , Proteínas do Tecido Nervoso , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Humanos , Animais , Camundongos , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Apolipoproteínas E/genética , Masculino , Feminino , Doenças Neurodegenerativas/genética , Doenças Neurodegenerativas/metabolismo , Hipocampo/metabolismo , Idoso , Estudo de Associação Genômica Ampla , Modelos Animais de DoençasRESUMO
Background: Apolipoproteins and contactin 5 are proteins associated with Alzheimer's disease (AD) pathophysiology. Apolipoproteins act on transport and clearance of cholesterol and phospholipids during synaptic turnover and terminal proliferation. Contactin 5 is a neuronal membrane protein involved in key processes of neurodevelopment. Objective: To investigate the interactions between contactin 5 and apolipoproteins in AD, and the role of these proteins in response to neuronal damage. Methods: Apolipoproteins (measured by Luminex), contactin 5 (measured by Olink's proximity extension assay), and cholesterol (measured by liquid chromatography mass spectrometry) were assessed in the cerebrospinal fluid (CSF) and plasma of cognitively unimpaired participants (nâ=â93). Gene expression was measured using polymerase chain reaction in the frontal cortex of autopsied-confirmed AD (nâ=â57) and control subjects (nâ=â31) and in the hippocampi of mice following entorhinal cortex lesions. Results: Contactin 5 positively correlated with apolipoproteins B (pâ=â5.4×10-8), D (pâ=â1.86×10-4), E (pâ=â2.92×10-9), J (pâ=â2.65×10-9), and with cholesterol (pâ=â0.0096) in the CSF, and with cholesterol (pâ=â0.02), HDL (pâ=â0.0143), and LDL (pâ=â0.0121) in the plasma. Negative correlations were seen between CNTN5, APOB (pâ=â0.034) and APOE (pâ=â0.015) mRNA levels in the brains of control subjects. In the mouse model, apoe and apoj gene expression increased during the reinnervation phase (pâ< â0.05), while apob (pâ=â0.023) and apod (pâ=â0.006) increased in the deafferentation stage. Conclusions: Extensive interactions were observed between contactin 5 and apolipoproteins and cholesterol, possibly due to neuronal damage. The alterations in gene expression of apolipoproteins suggest a role in axonal, terminal, and synaptic remodeling in response to entorhinal cortex damage.
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Doença de Alzheimer , Humanos , Camundongos , Animais , Doença de Alzheimer/metabolismo , Apolipoproteínas/genética , Apolipoproteínas E/metabolismo , Apolipoproteínas B , Colesterol , ContactinasRESUMO
We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower P-tau181 and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.
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We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early Tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower p(181)Tau and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.
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Doença de Alzheimer , Biomarcadores , Polimorfismo de Nucleotídeo Único , Sinapses , Proteínas tau , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Biomarcadores/líquido cefalorraquidiano , Encéfalo/metabolismo , Encéfalo/patologia , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/genética , Proteínas Tirosina Fosfatases Classe 2 Semelhantes a Receptores/metabolismo , Sinapses/metabolismo , Sinapses/patologia , Proteína 25 Associada a Sinaptossoma/metabolismo , Proteína 25 Associada a Sinaptossoma/genética , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Sinaptotagmina I/metabolismo , Sinaptotagmina I/genética , Proteínas tau/líquido cefalorraquidiano , Proteínas tau/metabolismoRESUMO
STUDY OBJECTIVES: Although short sleep could promote neurodegeneration, long sleep may be a marker of ongoing neurodegeneration, potentially as a result of neuroinflammation. The objective was to evaluate sleep patterns with age of expected Alzheimer's disease (AD) onset and neuroinflammation. METHODS: We tested 203 dementia-free participants (68.5â ±â 5.4 years old, 78M). The PREVENT-AD cohort includes older persons with a parental history of AD whose age was nearing their expected AD onset. We estimated expected years to AD onset by subtracting the participants' age from their parent's at AD dementia onset. We extracted actigraphy sleep variables of interest (times of sleep onset and morning awakening, time in bed, sleep efficiency, and sleep duration) and general profiles (sleep fragmentation, phase delay, and hypersomnia). Cerebrospinal fluid (CSF) inflammatory biomarkers were assessed with OLINK multiplex technology. RESULTS: Proximity to, or exceeding, expected age of onset was associated with a sleep profile suggestive of hypersomnia (longer sleep and later morning awakening time). This hypersomnia sleep profile was associated with higher CSF neuroinflammatory biomarkers (IL-6, MCP-1, and global score). Interaction analyses revealed that some of these sleep-neuroinflammation associations were present mostly in those closer/exceeding the age of expected AD onset, APOE4 carriers, and those with better memory performance. CONCLUSIONS: Proximity to, or exceeding, parental AD dementia onset was associated with a longer sleep pattern, which was related to elevated proinflammatory CSF biomarkers. We speculate that longer sleep may serve a compensatory purpose potentially triggered by neuroinflammation as individuals are approaching AD onset. Further studies should investigate whether neuroinflammatory-triggered long sleep duration could mitigate cognitive deficits.
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Doença de Alzheimer , Biomarcadores , Humanos , Doença de Alzheimer/fisiopatologia , Doença de Alzheimer/genética , Masculino , Feminino , Idoso , Biomarcadores/líquido cefalorraquidiano , Actigrafia , Sono/fisiologia , Doenças Neuroinflamatórias/fisiopatologia , Idade de Início , Pais , Pessoa de Meia-Idade , Estudos de Coortes , Duração do SonoRESUMO
INTRODUCTION: Measuring day-to-day sleep variability might reveal unstable sleep-wake cycles reflecting neurodegenerative processes. We evaluated the association between Alzheimer's disease (AD) fluid biomarkers with day-to-day sleep variability. METHODS: In the PREVENT-AD cohort, 203 dementia-free participants (age: 68.3 ± 5.4; 78 males) with a parental history of sporadic AD were tested with actigraphy and fluid biomarkers. Day-to-day variability (standard deviations over a week) was assessed for sleep midpoint, duration, efficiency, and nighttime activity count. RESULTS: Lower cerebrospinal fluid (CSF) ApoE, higher CSF p-tau181/amyloid-ß (Aß)42, and higher plasma p-tau231/Aß42 were associated with higher variability of sleep midpoint, sleep duration, and/or activity count. The associations between fluid biomarkers with greater sleep duration variability were especially observed in those that carried the APOE4 allele, mild cognitive impairment converters, or those with gray matter atrophy. DISCUSSION: Day-to-day sleep variability were associated with biomarkers of AD in at-risk individuals, suggesting that unstable sleep promotes neurodegeneration or, conversely, that AD neuropathology disrupts sleep-wake cycles.
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The neuromodulatory subcortical nuclei within the isodendritic core (IdC) are the earliest sites of tauopathy in Alzheimer's disease (AD). They project broadly throughout the brain's white matter. We investigated the relationship between IdC microstructure and whole-brain white matter microstructure to better understand early neuropathological changes in AD. Using multiparametric quantitative magnetic resonance imaging we observed two covariance patterns between IdC and white matter microstructure in 133 cognitively unimpaired older adults (age 67.9 ± 5.3 years) with familial risk for AD. IdC integrity related to 1) whole-brain neurite density, and 2) neurite orientation dispersion in white matter tracts known to be affected early in AD. Pattern 2 was associated with CSF concentration of phosphorylated-tau, indicating AD specificity. Apolipoprotein-E4 carriers expressed both patterns more strongly than non-carriers. IdC microstructure variation is reflected in white matter, particularly in AD-affected tracts, highlighting an early mechanism of pathological development.
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Doença de Alzheimer , Imageamento por Ressonância Magnética , Tauopatias , Substância Branca , Proteínas tau , Humanos , Substância Branca/diagnóstico por imagem , Substância Branca/patologia , Substância Branca/metabolismo , Feminino , Masculino , Idoso , Pessoa de Meia-Idade , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Doença de Alzheimer/líquido cefalorraquidiano , Doença de Alzheimer/metabolismo , Doença de Alzheimer/diagnóstico por imagem , Tauopatias/diagnóstico por imagem , Tauopatias/metabolismo , Tauopatias/patologia , Tauopatias/genética , Tauopatias/líquido cefalorraquidiano , Proteínas tau/metabolismo , Proteínas tau/líquido cefalorraquidiano , Encéfalo/patologia , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Apolipoproteína E4/genética , Apolipoproteína E4/metabolismo , Neuritos/metabolismo , Neuritos/patologiaRESUMO
STUDY OBJECTIVES: Apolipoprotein E É4 (APOE4) is the strongest genetic risk factor for Alzheimer's disease (AD). In addition, APOE4 carriers may exhibit sleep disturbances, but conflicting results have been reported, such that there is no clear consensus regarding which aspects of sleep are impacted. Our objective was to compare objective sleep architecture between APOE4 carriers and non-carriers, and to investigate the modulating impact of age, sex, cognitive status, and obstructive sleep apnea (OSA). METHODS: A total of 198 dementia-free participants aged >55 years old (mean age: 68.7 ± 8.08 years old, 40.91% women, 41 APOE4 carriers) were recruited in this cross-sectional study. They underwent polysomnography, APOE4 genotyping, and a neuropsychological evaluation. ANCOVAs assessed the effect of APOE4 status on sleep architecture, controlling for age, sex, cognitive status, and the apnea-hypopnea index. Interaction terms were added between APOE4 status and covariates. RESULTS: Rapid eye movement (REM) sleep percentage (Fâ =â 9.95, pâ =â .002, ηp2â =â 0.049) and duration (Fâ =â 9.23, pâ =â .003, ηp2â =â 0.047) were lower in APOE4 carriers. The results were replicated in a subsample of 112 participants without moderate-to-severe OSA. There were no significant interactions between APOE4 status and age, sex, cognitive status, and OSA in the whole sample. CONCLUSIONS: Our results show that APOE4 carriers exhibit lower REM sleep duration, including in cognitively unimpaired individuals, possibly resulting from early neurodegenerative processes in regions involved in REM sleep generation and maintenance.
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Apolipoproteína E4 , Heterozigoto , Polissonografia , Apneia Obstrutiva do Sono , Sono REM , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Alelos , Apolipoproteína E4/genética , Cognição/fisiologia , Estudos Transversais , Genótipo , Testes Neuropsicológicos/estatística & dados numéricos , Apneia Obstrutiva do Sono/genética , Apneia Obstrutiva do Sono/fisiopatologia , Sono REM/fisiologia , Sono REM/genéticaRESUMO
Importance: Positron emission tomography (PET) biomarkers are the gold standard for detection of Alzheimer amyloid and tau in vivo . Such imaging can identify cognitively unimpaired (CU) individuals who will subsequently develop cognitive impartment (CI). Plasma biomarkers would be more practical than PET or even cerebrospinal fluid (CSF) assays in clinical settings. Objective: Assess the prognostic accuracy of plasma p-tau217 in comparison to CSF and PET biomarkers for predicting the clinical progression from CU to CI. Design: In a cohort of elderly at high risk of developing Alzheimer's dementia (AD), we measured the proportion of CU individuals who developed CI, as predicted by Aß (A+) and/or tau (T+) biomarker assessment from plasma, CSF, and PET. Results from each method were compared with (A-T-) reference individuals. Data were analyzed from June 2023 to April 2024. Setting: Longitudinal observational cohort. Participants: Some 228 participants from the PREVENT-AD cohort were CU at the time of biomarker assessment and had 1 - 10 years of follow-up. Plasma was available from 215 participants, CSF from 159, and amyloid- and tau-PET from 155. Ninety-three participants had assessment using all three methods (main group of interest). Progression to CI was determined by clinical consensus among physicians and neuropsychologists who were blind to plasma, CSF, PET, and MRI findings, as well as APOE genotype. Exposures: Plasma Aß 42/40 was measured using IP-MS; CSF Aß 42/40 using Lumipulse; plasma and CSF p-tau217 using UGOT assay. Aß-PET employed the 18 F-NAV4694 ligand, and tau-PET used 18 F-flortaucipir. Main Outcome: Prognostic accuracy of plasma, CSF, and PET biomarkers for predicting the development of CI in CU individuals. Results: Cox proportional hazard models indicated a greater progression rate in all A+T+ groups compared to A-T-groups (HR = 6.61 [95% CI = 2.06 - 21.17] for plasma, 3.62 [1.49 - 8.81] for CSF and 9.24 [2.34 - 36.43] for PET). The A-T+ groups were small, but also characterized with individuals who developed CI. Plasma biomarkers identified about five times more T+ than PET. Conclusion and relevance: Plasma p-tau217 assessment is a practical method for identification of persons who will develop cognitive impairment up to 10 years later. Key Points: Question: Can plasma p-tau217 serve as a prognostic indicator for identifying cognitively unimpaired (CU) individuals at risk of developing cognitive impairments (CI)?Findings: In a longitudinal cohort of CU individuals with a family history of sporadic AD, almost all individuals with abnormal plasma p-tau217 concentrations developed CI within 10 years, regardless of plasma amyloid levels. Similar findings were obtained with CSF p-tau217 and tau-PET. Fluid p-tau217 biomarkers had the main advantage over PET of identifying five times more participants with elevated tau.Meaning: Elevated plasma p-tau217 levels in CU individuals strongly indicate future clinical progression.