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Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.
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Enfermedad de Alzheimer , Encéfalo , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Humanos , Animales , Encéfalo/metabolismo , Encéfalo/patología , Ratones , Transcriptoma/genética , Proteómica/métodos , Masculino , Biomarcadores/metabolismo , Metabolómica/métodos , Aprendizaje Automático , Femenino , Progresión de la Enfermedad , Anciano , Modelos Animales de Enfermedad , MultiómicaRESUMEN
OBJECTIVE: A clock relating amyloid positron emission tomography (PET) to time was used to estimate the timing of biomarker changes in sporadic Alzheimer disease (AD). METHODS: Research participants were included who underwent cerebrospinal fluid (CSF) collection within 2 years of amyloid PET. The ages at amyloid onset and AD symptom onset were estimated for each individual. The timing of change for plasma, CSF, imaging, and cognitive measures was calculated by comparing restricted cubic splines of cross-sectional data from the amyloid PET positive and negative groups. RESULTS: The amyloid PET positive sub-cohort (n = 118) had an average age of 70.4 ± 7.4 years (mean ± standard deviation) and 16% were cognitively impaired. The amyloid PET negative sub-cohort (n = 277) included individuals with low levels of amyloid plaque burden at all scans who were cognitively unimpaired at the time of the scans. Biomarker changes were detected 15-19 years before estimated symptom onset for CSF Aß42/Aß40, plasma Aß42/Aß40, CSF pT217/T217, and amyloid PET; 12-14 years before estimated symptom onset for plasma pT217/T217, CSF neurogranin, CSF SNAP-25, CSF sTREM2, plasma GFAP, and plasma NfL; and 7-9 years before estimated symptom onset for CSF pT205/T205, CSF YKL-40, hippocampal volumes, and cognitive measures. INTERPRETATION: The use of an amyloid clock enabled visualization and analysis of biomarker changes as a function of estimated years from symptom onset in sporadic AD. This study demonstrates that estimated years from symptom onset based on an amyloid clock can be used as a continuous staging measure for sporadic AD and aligns with findings in autosomal dominant AD. ANN NEUROL 2024;95:951-965.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Tomografía de Emisión de Positrones , Humanos , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Femenino , Masculino , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Anciano , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Persona de Mediana Edad , Fragmentos de Péptidos/líquido cefalorraquídeo , Fragmentos de Péptidos/sangre , Anciano de 80 o más Años , Estudios Transversales , Factores de Tiempo , Edad de Inicio , Estudios de Cohortes , Progresión de la Enfermedad , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/sangre , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/sangre , Placa Amiloide/diagnóstico por imagen , Placa Amiloide/patologíaRESUMEN
The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024;96:453-459.
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Péptidos beta-Amiloides , Esclerosis Múltiple , Humanos , Femenino , Masculino , Péptidos beta-Amiloides/metabolismo , Péptidos beta-Amiloides/sangre , Esclerosis Múltiple/patología , Esclerosis Múltiple/sangre , Persona de Mediana Edad , Adulto , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , AncianoRESUMEN
Background Visual assessment of amyloid PET scans relies on the availability of radiologist expertise, whereas quantification of amyloid burden typically involves MRI for processing and analysis, which can be computationally expensive. Purpose To develop a deep learning model to classify minimally processed brain PET scans as amyloid positive or negative, evaluate its performance on independent data sets and different tracers, and compare it with human visual reads. Materials and Methods This retrospective study used 8476 PET scans (6722 patients) obtained from late 2004 to early 2023 that were analyzed across five different data sets. A deep learning model, AmyloidPETNet, was trained on 1538 scans from 766 patients, validated on 205 scans from 95 patients, and internally tested on 184 scans from 95 patients in the Alzheimer's Disease Neuroimaging Initiative (ADNI) fluorine 18 (18F) florbetapir (FBP) data set. It was tested on ADNI scans using different tracers and scans from independent data sets. Scan amyloid positivity was based on mean cortical standardized uptake value ratio cutoffs. To compare with model performance, each scan from both the Centiloid Project and a subset of the Anti-Amyloid Treatment in Asymptomatic Alzheimer's Disease (A4) study were visually interpreted with a confidence level (low, intermediate, high) of amyloid positivity/negativity. The area under the receiver operating characteristic curve (AUC) and other performance metrics were calculated, and Cohen κ was used to measure physician-model agreement. Results The model achieved an AUC of 0.97 (95% CI: 0.95, 0.99) on test ADNI 18F-FBP scans, which generalized well to 18F-FBP scans from the Open Access Series of Imaging Studies (AUC, 0.95; 95% CI: 0.93, 0.97) and the A4 study (AUC, 0.98; 95% CI: 0.98, 0.98). Model performance was high when applied to data sets with different tracers (AUC ≥ 0.97). Other performance metrics provided converging evidence. Physician-model agreement ranged from fair (Cohen κ = 0.39; 95% CI: 0.16, 0.60) on a sample of mostly equivocal cases from the A4 study to almost perfect (Cohen κ = 0.93; 95% CI: 0.86, 1.0) on the Centiloid Project. Conclusion The developed model was capable of automatically and accurately classifying brain PET scans as amyloid positive or negative without relying on experienced readers or requiring structural MRI. Clinical trial registration no. NCT00106899 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Bryan and Forghani in this issue.
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Enfermedad de Alzheimer , Encéfalo , Aprendizaje Profundo , Tomografía de Emisión de Positrones , Humanos , Tomografía de Emisión de Positrones/métodos , Estudios Retrospectivos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/clasificación , Masculino , Femenino , Anciano , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Amiloide/metabolismo , Anciano de 80 o más AñosRESUMEN
OBJECTIVE: Maintaining attention underlies many aspects of cognition and becomes compromised early in neurodegenerative diseases like Alzheimer's disease (AD). The consistency of maintaining attention can be measured with reaction time (RT) variability. Previous work has focused on measuring such fluctuations during in-clinic testing, but recent developments in remote, smartphone-based cognitive assessments can allow one to test if these fluctuations in attention are evident in naturalistic settings and if they are sensitive to traditional clinical and cognitive markers of AD. METHOD: Three hundred and seventy older adults (aged 75.8 +/- 5.8 years) completed a week of remote daily testing on the Ambulatory Research in Cognition (ARC) smartphone platform and also completed clinical, genetic, and conventional in-clinic cognitive assessments. RT variability was assessed in a brief (20-40 seconds) processing speed task using two different measures of variability, the Coefficient of Variation (CoV) and the Root Mean Squared Successive Difference (RMSSD) of RTs on correct trials. RESULTS: Symptomatic participants showed greater variability compared to cognitively normal participants. When restricted to cognitively normal participants, APOE ε4 carriers exhibited greater variability than noncarriers. Both CoV and RMSSD showed significant, and similar, correlations with several in-clinic cognitive composites. Finally, both RT variability measures significantly mediated the relationship between APOE ε4 status and several in-clinic cognition composites. CONCLUSIONS: Attentional fluctuations over 20-40 seconds assessed in daily life, are sensitive to clinical status and genetic risk for AD. RT variability appears to be an important predictor of cognitive deficits during the preclinical disease stage.
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Enfermedad de Alzheimer , Tiempo de Reacción , Humanos , Enfermedad de Alzheimer/fisiopatología , Enfermedad de Alzheimer/genética , Anciano , Masculino , Femenino , Tiempo de Reacción/fisiología , Anciano de 80 o más Años , Pruebas Neuropsicológicas , Apolipoproteína E4/genética , Teléfono Inteligente , Atención/fisiologíaRESUMEN
Handedness has been a topic of scientific interest for many years. However, false and misleading ideas have dominated this field with a still limited amount of research into the association with clinical disorders like Alzheimer disease (AD). In accordance with PRISMA guidelines, PubMed, Embase, and Cochrane Library were searched for studies regarding the association of handedness and AD. Twelve articles were included. Case-control studies show that left-handedness is not a risk factor for late-onset AD (LOAD). However, nonright handedness was found to be more prevalent in patients with early-onset AD (EOAD). Moreover, handedness does not seem to affect neuropsychological performance. We also show that collapsing versus separating mixed and left-handedness may yield different results. Future research on the relation between handedness and AD may provide new insight into disease pathogenesis, improve rehabilitation, and help identify patients who will progress, aiding the design of prevention trials.
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Enfermedad de Alzheimer , Lateralidad Funcional , Humanos , Lateralidad Funcional/fisiología , Factores de Riesgo , Pruebas NeuropsicológicasRESUMEN
INTRODUCTION: Alzheimer disease (AD) has a long preclinical phase in which AD pathology is accumulating without detectable clinical symptoms. It is critical to identify participants in this preclinical phase as early as possible since treatment plans may be more effective in this stage. Monitoring for changes in driving behavior, as measured with GPS sensors, has been explored as a low-burden, easy-to-administer method for detecting AD risk. However, driving is a complex, multifaceted process that is likely influenced by other factors, including personality traits, that may change in preclinical AD. METHODS: We examine the moderating influence of neuroticism and conscientiousness on longitudinal changes in driving behavior in a sample of 203 clinically normal older adults who are at varying risk of developing AD. RESULTS: Neuroticism moderated rates of change in the frequency of speeding as well as the number of trips taken at night. Conscientiousness moderated rates of change in typical driving space. CONCLUSIONS: Personality traits change in early AD and also influence driving behaviors. Studies that seek to utilize naturalistic driving behavior to establish AD risk need to accommodate interpersonal differences, of which personality traits are one of many possible factors. Future studies should explicitly establish how much benefit is provided by including personality traits in predictive models of AD progression.
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Enfermedad de Alzheimer , Conducción de Automóvil , Personalidad , Humanos , Enfermedad de Alzheimer/psicología , Conducción de Automóvil/psicología , Masculino , Femenino , Anciano , Personalidad/fisiología , Estudios Longitudinales , Neuroticismo , Anciano de 80 o más AñosRESUMEN
The Dominantly Inherited Alzheimer Network (DIAN) initially was funded by the National Institute on Aging (NIA) in 2008 and thus was able to adopt and incorporate the protocols developed by the Alzheimer's Disease Neuroimaging Initiative (ADNI) that had been established by the NIA in 2004. The use of ADNI protocols for DIAN neuroimaging studies and assays of biological fluids for Alzheimer disease (AD) biomarkers permitted examination of the hypothesis that autosomal dominant AD (ADAD), studied by DIAN, and "sporadic" late-onset AD (LOAD), studied by ADNI, shared the same pathobiological construct. In a collaborative effort, the longitudinal DIAN and ADNI databases were compared and the findings supported the conclusion that ADAD and LOAD share a similar pathophysiology. The importance of the DIAN study thus is amplified by its relevance to LOAD, as characterized by the "parent" ADNI program.
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INTRODUCTION: Reversion, or change in cognitive status from impaired to normal, is common in aging and dementia studies, but it remains unclear what factors predict reversion. METHODS: We investigated whether reverters, defined as those who revert from a Clinical Dementia Rating® (CDR®) scale score of 0.5 to CDR 0) differed on cognition and biomarkers from unimpaired participants (always CDR 0) and impaired participants (converted to CDR > 0 and had no reversion events). Models evaluated relationships between biomarker status, apolipoprotein E (APOE) ε4 status, and cognition. Additional models described predictors of reversion and predictors of eventual progression to CDR > 0. RESULTS: CDR reversion was associated with younger age, better cognition, and negative amyloid biomarker status. Reverters that eventually progressed to CDR > 0 had more visits, were older, and were more likely to have an APOE ε4 allele. DISCUSSION: CDR reversion occupies a transitional phase in disease progression between cognitive normality and overt dementia. Reverters may be ideal candidates for secondary prevention Alzheimer's disease (AD) trials. HIGHLIGHTS: Reverters had more longitudinal cognitive decline than those who remained cognitively normal. Predictors of reversion: younger age, better cognition, and negative amyloid biomarker status. Reverting from CDR 0.5 to 0 is a risk factor for future conversion to CDR > 0. CDR reversion may be a transitional phase in Alzheimer's Disease progression. CDR reverters may be ideal for Alzheimer's disease secondary prevention trials.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/genética , Disfunción Cognitiva/psicología , Cognición , Pruebas de Estado Mental y Demencia , Biomarcadores , Progresión de la EnfermedadRESUMEN
INTRODUCTION: Plasma has been proposed as an alternative to cerebrospinal fluid (CSF) for measuring Alzheimer's disease (AD) biomarkers, but no studies have analyzed in detail which biofluid is more informative for genetics studies of AD. METHOD: Eleven proteins associated with AD (α-synuclein, apolipoprotein E [apoE], CLU, GFAP, GRN, NfL, NRGN, SNAP-25, TREM2, VILIP-1, YKL-40) were assessed in plasma (n = 2317) and CSF (n = 3107). Both plasma and CSF genome-wide association study (GWAS) analyses were performed for each protein, followed by functional annotation. Additional characterization for each biomarker included calculation of correlations and predictive power. RESULTS: Eighteen plasma protein quantitative train loci (pQTLs) associated with 10 proteins and 16 CSF pQTLs associated with 9 proteins were identified. Plasma and CSF shared some genetic loci, but protein levels between tissues correlated weakly. CSF protein levels better associated with AD compared to plasma. DISCUSSION: The present results indicate that CSF is more informative than plasma for genetic studies in AD. HIGHLIGHTS: The identification of novel protein quantitative trait loci (pQTLs) in both plasma and cerebrospinal fluid (CSF). Plasma and CSF levels of neurodegeneration-related proteins correlated weakly. CSF is more informative than plasma for genetic studies of Alzheimer's disease (AD). Neurofilament light (NfL), triggering receptor expressed on myeloid cells 2 (TREM2), and chitinase-3-like protein 1 (YKL-40) tend to show relatively strong inter-tissue associations. A novel signal in the apolipoprotein E (APOE) region was identified, which is an eQTL for APOC1.
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INTRODUCTION: Cerebrospinal fluid (CSF) tau phosphorylation at multiple sites is associated with cortical amyloid and other pathologic changes in Alzheimer's disease. These relationships can be non-linear. We used an artificial neural network to assess the ability of 10 different CSF tau phosphorylation sites to predict continuous amyloid positron emission tomography (PET) values. METHODS: CSF tau phosphorylation occupancies at 10 sites (including pT181/T181, pT217/T217, pT231/T231 and pT205/T205) were measured by mass spectrometry in 346 individuals (57 cognitively impaired, 289 cognitively unimpaired). We generated synthetic amyloid PET scans using biomarkers and evaluated their performance. RESULTS: Concentration of CSF pT217/T217 had low predictive error (average error: 13%), but also a low predictive range (ceiling 63 Centiloids). CSF pT231/T231 has slightly higher error (average error: 19%) but predicted through a greater range (87 Centiloids). DISCUSSION: Tradeoffs exist in biomarker selection. Some phosphorylation sites offer greater concordance with amyloid PET at lower levels, while others perform better over a greater range. HIGHLIGHTS: Novel pTau isoforms can predict cortical amyloid burden. pT217/T217 accurately predicts cortical amyloid burden in low-amyloid individuals. Traditional CSF biomarkers correspond with higher levels of amyloid.
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INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. HIGHLIGHTS: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.
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Enfermedad de Alzheimer , Cuerpos de Lewy , alfa-Sinucleína , Humanos , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/líquido cefalorraquídeo , alfa-Sinucleína/líquido cefalorraquídeo , alfa-Sinucleína/genética , Femenino , Masculino , Persona de Mediana Edad , Cuerpos de Lewy/patología , Anciano , Mutación , Encéfalo/patología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Progresión de la EnfermedadRESUMEN
Alzheimer disease (AD) and Alzheimer Disease and Related Dementias (AD/ADRD) are growing public health challenges globally affecting millions of older adults, necessitating concerted efforts to advance our understanding and management of these conditions. AD is a progressive neurodegenerative disorder characterized pathologically by amyloid plaques and tau neurofibrillary tangles that are the primary cause of dementia in older individuals. Early and accurate diagnosis of AD dementia is crucial for effective intervention and treatment but has proven challenging to accomplish. Although testing for AD brain pathology with cerebrospinal fluid (CSF) or positron emission tomography (PET) has been available for over 2 decades, most patients never underwent this testing because of inaccessibility, high out-of-pocket costs, perceived risks, and the lack of AD-specific treatments. However, in recent years, rapid progress has been made in developing blood biomarkers for AD/ADRD. Consequently, blood biomarkers have emerged as promising tools for non-invasive and cost-effective diagnosis, prognosis, and monitoring of AD progression. This review presents the evolving landscape of blood biomarkers in AD/ADRD and explores their potential applications in clinical practice for early detection, prognosis, and therapeutic interventions. It covers recent advances in blood biomarkers, including amyloid beta (Aß) peptides, tau protein, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). It also discusses their diagnostic and prognostic utility while addressing associated challenges and limitations. Future research directions in this rapidly evolving field are also proposed.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Biomarcadores , Proteínas tau , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/sangre , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Proteínas tau/sangre , Proteínas tau/líquido cefalorraquídeo , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteína Ácida Fibrilar de la Glía/sangre , Proteína Ácida Fibrilar de la Glía/líquido cefalorraquídeo , Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Tomografía de Emisión de Positrones/métodosRESUMEN
BACKGROUND AND OBJECTIVES: With the aging US population and increasing incidence of Alzheimer disease (AD), understanding factors contributing to driving cessation among older adults is crucial for clinicians. Driving is integral for maintaining independence and functional mobility, but the risk factors for driving cessation, particularly in the context of normal aging and preclinical AD, are not well understood. We studied a well-characterized community cohort to examine factors associated with driving cessation. METHODS: This prospective, longitudinal observation study enrolled participants from the Knight Alzheimer Disease Research Center and The DRIVES Project. Participants were enrolled if they were aged 65 years or older, drove weekly, and were cognitively normal (Clinical Dementia Rating [CDR] = 0) at baseline. Participants underwent annual clinical, neurologic, and neuropsychological assessments, including ß-amyloid PET imaging and CSF (Aß42, total tau [t-Tau], and phosphorylated tau [p-Tau]) collection every 2-3 years. The primary outcome was time from baseline visit to driving cessation, accounting for death as a competing risk. The cumulative incidence function of driving cessation was estimated for each biomarker. The Fine and Gray subdistribution hazard model was used to examine the association between time to driving cessation and biomarkers adjusting for clinical and demographic covariates. RESULTS: Among the 283 participants included in this study, there was a mean follow-up of 5.62 years. Driving cessation (8%) was associated with older age, female sex, progression to symptomatic AD (CDR ≥0.5), and poorer performance on a preclinical Alzheimer cognitive composite (PACC) score. Aß PET imaging did not independently predict driving cessation, whereas CSF biomarkers, specifically t-Tau/Aß42 (hazard ratio [HR] 2.82, 95% CI 1.23-6.44, p = 0.014) and p-Tau/Aß42 (HR 2.91, 95% CI 1.28-6.59, p = 0.012) ratios, were independent predictors in the simple model adjusting for age, education, and sex. However, in the full model, progression to cognitive impairment based on the CDR and PACC score across each model was associated with a higher risk of driving cessation, whereas AD biomarkers were not statistically significant. DISCUSSION: Female sex, CDR progression, and neuropsychological measures of cognitive functioning obtained in the clinic were strongly associated with future driving cessation. The results emphasize the need for early planning and conversations about driving retirement in the context of cognitive decline and the immense value of clinical measures in determining functional outcomes.
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Enfermedad de Alzheimer , Péptidos beta-Amiloides , Conducción de Automóvil , Biomarcadores , Proteínas tau , Humanos , Femenino , Masculino , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/epidemiología , Enfermedad de Alzheimer/diagnóstico , Anciano , Biomarcadores/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Péptidos beta-Amiloides/metabolismo , Proteínas tau/líquido cefalorraquídeo , Anciano de 80 o más Años , Estudios Longitudinales , Estudios Prospectivos , Tomografía de Emisión de Positrones , Pruebas Neuropsicológicas , Cognición/fisiología , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Age-related declines in the frequency of mind-wandering are well established. Theories of mind-wandering have attempted to explain why this decline occurs, but no one theory firmly predicts such changes. One problem with these theoretical views, and the studies that have grown out of them, is their reliance on cross-sectional methods, which do not account for within-person changes over time in mind-wandering, and it is well-documented that cross-sectional and longitudinal changes in some cognitive domains do not align. We present a novel analysis of longitudinal change in subjective and objective indicators of mind-wandering during a sustained attention task. Cognitively normal adults (N = 277, age range 42-94) completed a sustained attention task with thought probes to measure mind-wandering repeatedly over several years. Linear mixed effect models revealed baseline differences in subjective mind-wandering reports among middle-aged and older adults. However, longitudinally, middle-aged participants showed a significant increase in subjective mind-wandering, whereas older participants showed no change. Changes in mind-wandering could not be explained by attentional control ability or contemporaneous estimates of interest and perceived difficulty, but they were explained by baseline levels of conscientiousness. Objective measures of mind-wandering did not show these same patterns and were largely only associated with participants perceived difficulty. Our results build on previous cross-sectional research and suggest that incorporating longitudinal analyses into theories of ageing and mind-wandering and mind-wandering more broadly is important for refining these theories. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
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Envejecimiento , Atención , Humanos , Estudios Transversales , Estudios Longitudinales , Anciano , Femenino , Masculino , Persona de Mediana Edad , Atención/fisiología , Adulto , Envejecimiento/fisiología , Envejecimiento/psicología , Anciano de 80 o más Años , Pensamiento/fisiología , Cognición/fisiologíaRESUMEN
Introduction: Disrupted sleep is common in individuals with Alzheimer's disease (AD) and may be a marker for AD risk. The timing of sleep affects sleep-wake activity and is also associated with AD, but little is known about links between sleep architecture and the midpoint of sleep in older adults. In this study, we tested if the midpoint of sleep is associated with different measures of sleep architecture, AD biomarkers, and cognitive status among older adults with and without symptomatic AD. Methods: Participants (Nâ =â 243) with a mean age of 74 underwent standardized cognitive assessments, measurement of CSF AD biomarkers, and sleep monitoring via single-channel EEG, actigraphy, a home sleep apnea test, and self-reported sleep logs. The midpoint of sleep was defined by actigraphy. Results: A later midpoint of sleep was associated with African-American race and greater night-to-night variability in the sleep midpoint. After adjusting for multiple potential confounding factors, a later sleep midpoint was associated with longer rapid-eye movement (REM) onset latency, decreased REM sleep time, more actigraphic awakenings at night, and higherâ <â 2 Hz non-REM slow-wave activity. Conclusions: Noninvasive in vivo markers of brain function, such as sleep, are needed to track both future risk of cognitive impairment and response to interventions in older adults at risk for AD. Sleep timing is associated with multiple other sleep measures and may affect their utility as markers of AD. The midpoint of sleep may be changed through behavioral intervention and should be taken into account when using sleep as a marker for AD risk.
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INTRODUCTION: For many patients and caregivers, a major goal of disease-modifying treatments (DMT) for Alzheimer disease (AD) dementia is to extend independence in instrumental and basic activities of daily living (IADLs and BADLs). The goal of this study was to estimate the effect of treatments on the time remaining independent in IADLs and BADLs. METHODS: Participants at the Knight Alzheimer Disease Research Center were selected who were potentially eligible for recent DMT trials: age ≥ 60 years at baseline, clinical diagnosis of very mild or mild AD dementia (global Clinical Dementia Rating® (CDR®) score 0.5 or 1), biomarker confirmation of amyloid pathology, and at least one follow-up CDR assessment within 5 years. For IADLs, a subset of the Functional Assessment Questionnaire (FAQ) was examined that rated the degree of independence in the following: paying bills, driving, remembering medications and appointments, and preparing meals. For BADLs, the Personal Care domain of the CDR was used. Mixed-effects logistic and ordinal regression models were used to examine the relationship between CDR Sum Boxes (CDR-SB) and the individual functional outcomes and their components. The change in CDR-SB over time was estimated with linear mixed effects models. RESULTS: 282 participants were followed for an average of 2.9 years (SD 1.3 years). For 50% of individuals, loss of independence in IADLs occurred at CDR-SB>4.5 and in BADLs at CDR-SB>11.5. For individuals with a baseline CDR-SB=2, treatment with lecanemab would extend independence in IADLs for 10 months (95% CI 4-18 months) and treatment with donanemab in the low/medium tau group would extend independence in IADLs by 13 months (95% CI 6-24 months). DISCUSSION: Independence in ADLs can be related to CDR-SB and used to demonstrate the effect of AD treatments in extending the time of independent function, a meaningful outcome for patients and their families.
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Sex and age are major risk factors for chronic diseases. Recent studies examining age-related molecular changes in plasma provided insights into age-related disease biology. Cerebrospinal fluid (CSF) proteomics can provide additional insights into brain aging and neurodegeneration. By comprehensively examining 7,006 aptamers targeting 6,139 proteins in CSF obtained from 660 healthy individuals aged from 43 to 91 years old, we subsequently identified significant sex and aging effects on 5,097 aptamers in CSF. Many of these effects on CSF proteins had different magnitude or even opposite direction as those on plasma proteins, indicating distinctive CSF-specific signatures. Network analysis of these CSF proteins revealed not only modules associated with healthy aging but also modules showing sex differences. Through subsequent analyses, several modules were highlighted for their proteins implicated in specific diseases. Module 2 and 6 were enriched for many aging diseases including those in the circulatory systems, immune mechanisms, and neurodegeneration. Together, our findings fill a gap of current aging research and provide mechanistic understanding of proteomic changes in CSF during a healthy lifespan and insights for brain aging and diseases.
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OBJECTIVE: We aimed to illustrate how complex cognitive data can be used to create domain-specific and general cognitive composites relevant to Alzheimer disease research. METHOD: Using equipercentile equating, we combined data from the Charles F. and Joanne Knight Alzheimer Disease Research Center that spanned multiple iterations of the Uniform Data Set. Exploratory factor analyses revealed four domain-specific composites representing episodic memory, semantic memory, working memory, and attention/processing speed. The previously defined preclinical Alzheimer disease cognitive composite (PACC) and a novel alternative, the Knight-PACC, were also computed alongside a global composite comprising all available tests. These three composites allowed us to compare the usefulness of domain and general composites in the context of predicting common Alzheimer disease biomarkers. RESULTS: General composites slightly outperformed domain-specific metrics in predicting imaging-derived amyloid, tau, and neurodegeneration burden. Power analyses revealed that the global, Knight-PACC, and attention and processing speed composites would require the smallest sample sizes to detect cognitive change in a clinical trial, while the Alzheimer Disease Cooperative Study-PACC required two to three times as many participants. CONCLUSIONS: Analyses of cognition with the Knight-PACC and our domain-specific composites offer researchers flexibility by providing validated outcome assessments that can equate across test versions to answer a wide range of questions regarding cognitive decline in normal aging and neurodegenerative disease. (PsycInfo Database Record (c) 2024 APA, all rights reserved).
Asunto(s)
Enfermedad de Alzheimer , Pruebas Neuropsicológicas , Humanos , Enfermedad de Alzheimer/psicología , Femenino , Masculino , Anciano , Anciano de 80 o más Años , Atención/fisiología , Persona de Mediana Edad , Memoria Episódica , Memoria a Corto Plazo/fisiología , Cognición/fisiología , Disfunción Cognitiva/diagnósticoRESUMEN
The use of biomarkers for the early detection of Alzheimer's disease (AD) is crucial for developing potential therapeutic treatments. Positron Emission Tomography (PET) is a well-established tool used to detect ß-amyloid (Aß) plaques in the brain. Previous studies have shown that cross-sectional biomarkers can predict cognitive decline (Schindler et al.,2021). However, it is still unclear whether longitudinal Aß-PET may have additional value for predicting time to cognitive impairment in AD. The current study aims to evaluate the ability of baseline- versus longitudinal rate of change in-11C-Pittsburgh compound B (PiB) Aß-PET to predict cognitive decline. A cohort of 153 participants who previously underwent PiB-PET scans and comprehensive clinical assessments were used in this study. Our analyses revealed that baseline Aß is significantly associated with the rate of change in cognitive composite scores, with cognition declining more rapidly when baseline PiB Aß levels were higher. In contrast, no signification association was identified between the rate of change in PiB-PET Aß and cognitive decline. Additionally, the ability of the rate of change in the PiB-PET measures to predict cognitive decline was significantly influenced by APOE ε4 carrier status. These results suggest that a single PiB-PET scan is sufficient to predict cognitive decline and that longitudinal measures of Aß accumulation do not improve the prediction of cognitive decline once someone is amyloid positive.