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Recent longitudinal PET imaging studies have established methods to estimate the age at which amyloid becomes abnormal at the level of the individual. Here we recontextualized amyloid levels into the temporal domain to better understand the downstream Alzheimer's disease processes of tau neurofibrillary tangle (NFT) accumulation and cognitive decline. This cohort study included a total of 601 individuals from the Wisconsin Registry for Alzheimer's Prevention and Wisconsin Alzheimer's Disease Research Center that underwent amyloid and tau PET, longitudinal neuropsychological assessments and met clinical criteria for three clinical diagnosis groups: cognitively unimpaired (n = 537); mild cognitive impairment (n = 48); or dementia (n = 16). Cortical 11C-Pittsburgh compound B (PiB) distribution volume ratio (DVR) and sampled iterative local approximation were used to estimate amyloid positive (A+; global PiB DVR > 1.16 equivalent to 17.1 centiloids) onset age and years of A+ duration at tau PET (i.e. amyloid chronicity). Tau PET burden was quantified using 18F-MK-6240 standardized uptake value ratios (70-90â min, inferior cerebellar grey matter reference region). Whole-brain and region-specific approaches were used to examine tau PET binding along the amyloid timeline and across the Alzheimer's disease clinical continuum. Voxel-wise 18F-MK-6240 analyses revealed that with each decade of A+, the spatial extent of measurable tau spread (i.e. progressed) from regions associated with early to late NFT tau stages. Regional analyses indicated that tau burden in the entorhinal cortex was detectable, on average, within 10 years of A+ onset. Additionally, the entorhinal cortex was the region most sensitive to early amyloid pathology and clinical impairment in this predominantly preclinical sample. Among initially cognitively unimpaired (n = 472) individuals with longitudinal cognitive follow-up, mixed effects models showed significant linear and non-linear interactions of A+ duration and entorhinal tau on cognitive decline, suggesting a synergistic effect whereby greater A+ duration, together with a higher entorhinal tau burden, increases the likelihood of cognitive decline beyond their separable effects. Overall, the amyloid time framework enabled a spatiotemporal characterization of tau deposition patterns across the Alzheimer's disease continuum. This approach, which examined cross-sectional tau PET data along the amyloid timeline to make longitudinal disease course inferences, demonstrated that A+ duration explains a considerable amount of variability in the magnitude and topography of tau spread, which largely recapitulated NFT staging observed in human neuropathological studies. By anchoring disease progression to the onset of amyloid, this study provides a temporal disease context, which may help inform disease prognosis and timing windows for anti-amyloid therapies.
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Enfermedad de Alzheimer , Encéfalo , Disfunción Cognitiva , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Enfermedad de Alzheimer/metabolismo , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/patología , Anciano , Masculino , Femenino , Proteínas tau/metabolismo , Tomografía de Emisión de Positrones/métodos , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/patología , Encéfalo/metabolismo , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Anciano de 80 o más Años , Ovillos Neurofibrilares/patología , Ovillos Neurofibrilares/metabolismo , Progresión de la Enfermedad , Compuestos de Anilina , Estudios de Cohortes , Péptidos beta-Amiloides/metabolismo , Persona de Mediana Edad , Estudios Longitudinales , Tiazoles , Pruebas Neuropsicológicas , Amiloide/metabolismoRESUMEN
BACKGROUND: The sensitivity of amyloid to pre-analytic factors complicates cerebrospinal fluid (CSF) diagnostics for Alzheimer disease. We report reliability and validity evidence for automated immunoassays from frozen and fresh CSF samples in an ongoing, single-site research program. METHODS: CSF samples were obtained from 2 Wisconsin cohorts (1256 measurements; 727 participants). Levels of amyloid beta 1-42 (Aß42), phosphorylated tau 181 (pTau181), and total tau (tTau) were obtained using an Elecsys cobas e 601 platform. Repeatability and fixed effects of storage tube type, extraction method, and freezing were assessed via mixed models. Concordance with amyloid positron emission tomography (PET) was investigated with 238 participants having a temporally proximal PET scan. RESULTS: Repeatability was high with intraclass correlation (ICC) ≥0.9, but tube type strongly affected measurements. Discriminative accuracy for PET amyloid positivity was strong across tube types (area under the curve [AUC]: Aß42, 0.87; pTau181Aß42 , 0.96), although optimal thresholds differed. CONCLUSIONS: Under real-world conditions, the Elecsys platform had high repeatability. However, strong effects of pre-analytic factors suggest caution in drawing longitudinal inferences.
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Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Reproducibilidad de los Resultados , Proteínas tau/líquido cefalorraquídeo , Tomografía de Emisión de Positrones , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
INTRODUCTION: Published norms are typically cross-sectional and often are not sensitive to preclinical cognitive changes due to dementia. We developed and validated demographically adjusted cross-sectional and longitudinal normative standards using harmonized outcomes from two Alzheimer's disease (AD) risk-enriched cohorts. METHODS: Data from the Wisconsin Registry for Alzheimer's Prevention and the Wisconsin Alzheimer's Disease Research Center were combined. Quantile regression was used to develop unconditional (cross-sectional) and conditional (longitudinal) normative standards for 18 outcomes using data from cognitively unimpaired participants (N = 1390; mean follow-up = 9.25 years). Validity analyses (N = 2456) examined relationships between percentile scores (centiles), consensus-based cognitive statuses, and AD biomarker levels. RESULTS: Unconditional and conditional centiles were lower in those with consensus-based impairment or biomarker positivity. Similarly, quantitative biomarker levels were higher in those whose centiles suggested decline. DISCUSSION: This study presents normative standards for cognitive measures sensitive to pre-clinical changes. Future directions will investigate potential clinical applications of longitudinal normative standards. HIGHLIGHTS: Quantile regression was used to construct longitudinal norms for cognitive tests. Poorer percentile scores were related to concurrent diagnosis and Alzheimer's disease biomarkers. A ShinyApp was built to display test scores and norms and flag low performance.
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Enfermedad de Alzheimer , Biomarcadores , Pruebas Neuropsicológicas , Humanos , Enfermedad de Alzheimer/diagnóstico , Masculino , Anciano , Femenino , Pruebas Neuropsicológicas/normas , Pruebas Neuropsicológicas/estadística & datos numéricos , Estudios Longitudinales , Wisconsin , Estudios Transversales , Disfunción Cognitiva/diagnóstico , Estudios de Cohortes , Cognición/fisiología , Anciano de 80 o más Años , Persona de Mediana EdadRESUMEN
INTRODUCTION: Understanding longitudinal change in key plasma biomarkers will aid in detecting presymptomatic Alzheimer's disease (AD). METHODS: Serial plasma samples from 424 Wisconsin Registry for Alzheimer's Prevention participants were analyzed for phosphorylated-tau217 (p-tau217; ALZpath) and other AD biomarkers, to study longitudinal trajectories in relation to disease, health factors, and cognitive decline. Of the participants, 18.6% with known amyloid status were amyloid positive (A+); 97.2% were cognitively unimpaired (CU). RESULTS: In the CU, amyloid-negative (A-) subset, plasma p-tau217 levels increased modestly with age but were unaffected by body mass index and kidney function. In the whole sample, average p-tau217 change rates were higher in those who were A+ (e.g., simple slopes(se) for A+ and A- at age 60 were 0.232(0.028) and 0.038(0.013))). High baseline p-tau217 levels predicted faster preclinical cognitive decline. DISCUSSION: p-tau217 stands out among markers for its strong association with disease and cognitive decline, indicating its potential for early AD detection and monitoring progression. HIGHLIGHTS: Phosphorylated-tau217 (p-tau217) trajectories were significantly different in people who were known to be amyloid positive. Subtle age-related trajectories were seen for all the plasma markers in amyloid-negative cognitively unimpaired. Kidney function and body mass index were not associated with plasma p-tau217 trajectories. Higher plasma p-tau217 was associated with faster preclinical cognitive decline.
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Objective: The current study examined the longitudinal relationship between cognitive reserve (CR), depression, and executive function (EF) in a cohort of older adults. Methods: 416 participants were selected from the Wisconsin Registry for Alzheimer's Prevention. They were native English speakers, aged ≥50+, and cognitively unimpaired at baseline, with no history of neurological or other psychiatric disorders aside from depression. Depression was assessed with the 20-item Center for Epidemiologic Studies Depression Scale (CES-D). A composite score, based on the premorbid IQ (WRAT-3 Reading subtest) and years of education was used to estimate CR. Another composite score from four cognitive tests was used to estimate EF. A moderation analysis was performed to evaluate the effects of CR and Depression on EF at follow-up after controlling for age, gender, and APOE risk score. Moreover, a multinomial logistic regression was used to predict conversion to Mild Cognitive Impairment (MCI) from the healthy baseline. Results: The negative relationship between depression and EF was stronger in individuals with higher CR levels, suggesting a possible floor effect at lower CR levels. In the multinomial regression, the interaction between CR and depression predicted conversion to MCI status, indicating that lower CR paired with more severe depression at baseline was associated with a higher risk of subsequent impairment. Conclusions: This study sheds light on the intricate relationship between depression and EF over time, suggesting that the association may be influenced by varying levels of CR. Further studies may replicate these findings in clinical populations.
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Objective: Process-based scores of episodic memory tests, such as the recency ratio (Rr), have been found to compare favourably to, or to be better than, most conventional or "traditional" scores employed to estimate memory ability in older individuals (Bock et al., 2021; Bruno et al., 2019). We explored the relationship between process-based scores and hippocampal volume in older adults, while comparing process-based to traditional story recall-derived scores, to examine potential differences in their predictive abilities. Methods: We analysed data from 355 participants extracted from the WRAP and WADRC databases, who were classified as cognitively unimpaired, or exhibited mild cognitive impairment (MCI) or dementia. Story Recall was measured with the Logical Memory Test (LMT) from the Weschler Memory Scale Revised, collected within twelve months of the magnetic resonance imaging scan. Linear regression analyses were conducted with left or right hippocampal volume (HV) as outcomes separately, and with Rr, Total ratio, Immediate LMT, or Delayed LMT scores as predictors, along with covariates. Results: Higher Rr and Tr scores significantly predicted lower left and right HV, while Tr showed the best model fit of all, as indicated by AIC. Traditional scores, Immediate LMT and Delayed LMT, were significantly associated with left and right HV, but were outperformed by both process-based scores for left HV, and by Tr for right HV. Conclusions: Current findings show the direct relationship between hippocampal volume and all the LMT scores examined here, and that process-based scores outperform traditional scores as markers of hippocampal volume.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Anciano , Pruebas Neuropsicológicas , Disfunción Cognitiva/patología , Hipocampo/patología , Memoria a Corto Plazo , Análisis de Regresión , Imagen por Resonancia Magnética , Enfermedad de Alzheimer/psicologíaRESUMEN
Objective: Neighborhood disadvantage is associated with worse health and cognitive outcomes. Morphological similarity network (MSN) is a promising approach to elucidate cortical network patterns underlying complex cognitive functions. We hypothesized that MSNs could capture intricate changes in cortical patterns related to neighborhood disadvantage and cognitive function, potentially explaining some of the risk for later life cognitive impairment among individuals who live in disadvantaged contexts. Methods: This cross-sectional study included cognitively unimpaired participants (n=524, age=62.96±8.377, gender (M:F)=181:343, ADI(L:H) =450,74) from the Wisconsin Alzheimer's Disease Research Center or Wisconsin Registry for Alzheimer's Prevention. Neighborhood disadvantage status was obtained using the Area Deprivation Index (ADI). Cognitive performance was assessed through six tests evaluating memory, executive functioning, and the modified preclinical Alzheimer's cognitive composite (mPACC). Morphological Similarity Networks (MSN) were constructed for each participant based on the similarity in distribution of cortical thickness of brain regions, followed by computation of local and global network features. We used linear regression to examine ADI associations with cognitive scores and MSN features. The mediating effect of MSN features on the relationship between ADI and cognitive performance was statistically assessed. Results: Neighborhood disadvantage showed negative association with category fluency, implicit learning speed, story recall and mPACC scores, indicating worse cognitive function among those living in more disadvantaged neighborhoods. Local network features of frontal and temporal brain regions differed based on ADI status. Centrality of left lateral orbitofrontal region showed a partial mediating effect between association of neighborhood disadvantage and story recall performance. Conclusion: Our findings suggest differences in local cortical organization by neighborhood disadvantage, which also partially mediated the relationship between ADI and cognitive performance, providing a possible network-based mechanism to, in-part, explain the risk for poor cognitive functioning associated with disadvantaged neighborhoods. Future work will examine the exposure to neighborhood disadvantage on structural organization of the brain.
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Neurovascular 4D-Flow MRI enables non-invasive evaluation of cerebral hemodynamics including measures of cerebral blood flow (CBF), vessel pulsatility index (PI), and cerebral pulse wave velocity (PWV). 4D-Flow measures have been linked to various neurovascular disorders including small vessel disease and Alzheimer's disease; however, physiological and technical sources of variability are not well established. Here, we characterized sources of diurnal physiological and technical variability in cerebral hemodynamics using 4D-Flow in a retrospective study of cognitively unimpaired older adults (N = 750) and a prospective study of younger adults (N = 10). Younger participants underwent repeated MRI sessions at 7am, 4 pm, and 10 pm. In the older cohort, having an MRI earlier on the day was significantly associated with higher CBF and lower PI. In prospective experiments, time of day significantly explained variability in CBF and PI; however, not in PWV. Test-retest experiments showed high CBF intra-session repeatability (repeatability coefficient (RPC) =7.2%), compared to lower diurnal repeatability (RPC = 40%). PI and PWV displayed similar intra-session and diurnal variability (PI intra-session RPC = 22%, RPC = 24% 7am vs 4 pm; PWV intra-session RPC = 17%, RPC = 21% 7am vs 4 pm). Overall, CBF measures showed low technical variability, supporting diurnal variability is from physiology. PI and PWV showed higher technical variability but less diurnal variability.
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Circulación Cerebrovascular , Ritmo Circadiano , Hemodinámica , Imagen por Resonancia Magnética , Humanos , Circulación Cerebrovascular/fisiología , Masculino , Femenino , Anciano , Imagen por Resonancia Magnética/métodos , Ritmo Circadiano/fisiología , Hemodinámica/fisiología , Adulto , Estudios Retrospectivos , Estudios Prospectivos , Análisis de la Onda del Pulso/métodos , Adulto Joven , Persona de Mediana Edad , Velocidad del Flujo Sanguíneo/fisiología , Anciano de 80 o más Años , Encéfalo/diagnóstico por imagen , Encéfalo/irrigación sanguínea , Encéfalo/fisiología , Flujo Pulsátil/fisiologíaRESUMEN
BACKGROUND: Early detection of Alzheimer's disease (AD) is one of the critical components of the global response to the growing dementia crisis. Analysis of serial position performance in story recall tests has yielded sensitive metrics for the prediction of AD at low cost. In this study, we examined whether serial position markers in two story recall tests (the logical memory test, LMT, and the Craft Story 21 test, CST) were sensitive to cross-sectional biomarker-based assessment of in vivo neuropathology. METHODS: Participants were selected from the Wisconsin Registry of Alzheimer's Prevention (n = 288; WRAP) and the Alzheimer's Disease Research Center (n = 156; ADRC), both from the University of Wisconsin-Madison. Average age at PET was 68.9 (6.7) and 67.0 (8.0), respectively. Data included tau and PiB PET, and LMT for WRAP participants and CST for ADRC participants. Two sets of Bayesian analyses (logistic regressions and ANCOVAs) were conducted within each cohort, separately. RESULTS: Results indicated that the A+T+ classification was best predicted, cross-sectionally, by the recency ratio (Rr), indexing how much of the end of the story was forgotten between initial learning and delayed assessment. Rr outperformed traditional scores and discriminated between A+T+ and A+T-/A-T-, in both cohorts. CONCLUSIONS: Overall, this study confirms that serial position analysis of LMT and CST data, and particularly Rr as an index of recency loss, is a valuable tool for the identification of in vivo tau pathology in individuals free of dementia. Diagnostic considerations are discussed.
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Enfermedad de Alzheimer , Recuerdo Mental , Tomografía de Emisión de Positrones , Humanos , Masculino , Femenino , Enfermedad de Alzheimer/diagnóstico por imagen , Anciano , Tomografía de Emisión de Positrones/métodos , Recuerdo Mental/fisiología , Persona de Mediana Edad , Estudios Transversales , Pruebas Neuropsicológicas , Proteínas tau/metabolismo , Encéfalo/diagnóstico por imagenRESUMEN
Reduced brain volumes and more prominent white matter hyperintensities on MRI scans are commonly observed among older adults without cognitive impairment. However, it remains unclear whether rates of change in these measures among cognitively normal adults differ as a function of genetic risk for late-onset Alzheimer's disease, including APOE-É4, APOE-É2 and Alzheimer's disease polygenic risk scores (AD-PRS), and whether these relationships are influenced by other variables. This longitudinal study examined the trajectories of regional brain volumes and white matter hyperintensities in relationship to APOE genotypes (N = 1541) and AD-PRS (N = 1093) in a harmonized dataset of middle-aged and older individuals with normal cognition at baseline (mean baseline age = 66 years, SD = 9.6) and an average of 5.3 years of MRI follow-up (max = 24 years). Atrophy on volumetric MRI scans was quantified in three ways: (i) a composite score of regions vulnerable to Alzheimer's disease (SPARE-AD); (ii) hippocampal volume; and (iii) a composite score of regions indexing advanced non-Alzheimer's disease-related brain aging (SPARE-BA). Global white matter hyperintensity volumes were derived from fluid attenuated inversion recovery (FLAIR) MRI. Using linear mixed effects models, there was an APOE-É4 gene-dose effect on atrophy in the SPARE-AD composite and hippocampus, with greatest atrophy among É4/É4 carriers, followed by É4 heterozygouts, and lowest among É3 homozygouts and É2/É2 and É2/É3 carriers, who did not differ from one another. The negative associations of APOE-É4 with atrophy were reduced among those with higher education (P < 0.04) and younger baseline ages (P < 0.03). Higher AD-PRS were also associated with greater atrophy in SPARE-AD (P = 0.035) and the hippocampus (P = 0.014), independent of APOE-É4 status. APOE-É2 status (É2/É2 and É2/É3 combined) was not related to baseline levels or atrophy in SPARE-AD, SPARE-BA or the hippocampus, but was related to greater increases in white matter hyperintensities (P = 0.014). Additionally, there was an APOE-É4 × AD-PRS interaction in relation to white matter hyperintensities (P = 0.038), with greater increases in white matter hyperintensities among APOE-É4 carriers with higher AD-PRS. APOE and AD-PRS associations with MRI measures did not differ by sex. These results suggest that APOE-É4 and AD-PRS independently and additively influence longitudinal declines in brain volumes sensitive to Alzheimer's disease and synergistically increase white matter hyperintensity accumulation among cognitively normal individuals. Conversely, APOE-É2 primarily influences white matter hyperintensity accumulation, not brain atrophy. Results are consistent with the view that genetic factors for Alzheimer's disease influence atrophy in a regionally specific manner, likely reflecting preclinical neurodegeneration, and that Alzheimer's disease risk genes contribute to white matter hyperintensity formation.
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Neuropsychological measures sensitive to decline in the preclinical phase of Alzheimer's disease are needed. We previously demonstrated that higher amyloid-beta (Aß) assessed by positron emission tomography in adults without cognitive impairment was associated with recall of fewer proper names in Logical Memory story recall. The current study investigated the association between proper names and cerebrospinal fluid biomarkers (Aß42/40, phosphorylated tau181 [pTau181], neurofilament light) in 223 participants from the Wisconsin Registry for Alzheimer's Prevention. We assessed associations between biomarkers and delayed Logical Memory total score and proper names using binary logistic regressions. Sensitivity analyses used multinomial logistic regression and stratified biomarker groups. Lower Logical Memory total score and proper names scores from the most recent visit were associated with biomarker positivity. Relatedly, there was a 27% decreased risk of being classified Aß42/40+/pTau181+ for each additional proper name recalled. A linear mixed effects model found that longitudinal change in proper names recall was predicted by biomarker status. These results demonstrate a novel relationship between proper names and Alzheimer's disease-cerebrospinal fluid pathology.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/patología , Proteínas tau/líquido cefalorraquídeo , Estudios Longitudinales , Progresión de la Enfermedad , Disfunción Cognitiva/psicología , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Fragmentos de Péptidos/líquido cefalorraquídeoRESUMEN
Importance: Phosphorylated tau (p-tau) is a specific blood biomarker for Alzheimer disease (AD) pathology, with p-tau217 considered to have the most utility. However, availability of p-tau217 tests for research and clinical use has been limited. Expanding access to this highly accurate AD biomarker is crucial for wider evaluation and implementation of AD blood tests. Objective: To determine the utility of a novel and commercially available immunoassay for plasma p-tau217 to detect AD pathology and evaluate reference ranges for abnormal amyloid ß (Aß) and longitudinal change across 3 selected cohorts. Design, Setting, and Participants: This cohort study examined data from 3 single-center observational cohorts: cross-sectional and longitudinal data from the Translational Biomarkers in Aging and Dementia (TRIAD) cohort (visits October 2017-August 2021) and Wisconsin Registry for Alzheimer's Prevention (WRAP) cohort (visits February 2007-November 2020) and cross-sectional data from the Sant Pau Initiative on Neurodegeneration (SPIN) cohort (baseline visits March 2009-November 2021). Participants included individuals with and without cognitive impairment grouped by amyloid and tau (AT) status using PET or CSF biomarkers. Data were analyzed from February to June 2023. Exposures: Magnetic resonance imaging, Aß positron emission tomography (PET), tau PET, cerebrospinal fluid (CSF) biomarkers (Aß42/40 and p-tau immunoassays), and plasma p-tau217 (ALZpath pTau217 assay). Main Outcomes and Measures: Accuracy of plasma p-tau217 in detecting abnormal amyloid and tau pathology, longitudinal p-tau217 change according to baseline pathology status. Results: The study included 786 participants (mean [SD] age, 66.3 [9.7] years; 504 females [64.1%] and 282 males [35.9%]). High accuracy was observed in identifying elevated Aß (area under the curve [AUC], 0.92-0.96; 95% CI, 0.89-0.99) and tau pathology (AUC, 0.93-0.97; 95% CI, 0.84-0.99) across all cohorts. These accuracies were comparable with CSF biomarkers in determining abnormal PET signal. The detection of abnormal Aß pathology using a 3-range reference yielded reproducible results and reduced confirmatory testing by approximately 80%. Longitudinally, plasma p-tau217 values showed an annual increase only in Aß-positive individuals, with the highest increase observed in those with tau positivity. Conclusions and Relevance: This study found that a commercially available plasma p-tau217 immunoassay accurately identified biological AD, comparable with results using CSF biomarkers, with reproducible cut-offs across cohorts. It detected longitudinal changes, including at the preclinical stage.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Anciano , Femenino , Humanos , Masculino , Enfermedad de Alzheimer/diagnóstico por imagen , Amiloide , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores , Estudios de Cohortes , Estudios Transversales , Inmunoensayo , Tomografía de Emisión de Positrones , Proteínas tau/líquido cefalorraquídeo , Estudios Observacionales como AsuntoRESUMEN
The association between depressive symptomatology and cognitive decline has been examined using the Centre for Epidemiologic Studies-Depression Scale (CES-D); however, concerns have been raised about this self-report measure. Here, we examined how the CES-D total score from the 14- and 10-item versions compared to the 20-item version in predicting progression to cognitive decline from a cognitively unimpaired baseline. Data from 1054 participants were analysed using ordinal logistic regression, alongside moderator and receiver-operating characteristics curve analyses. All baseline total scores significantly predicted progression to cognitive decline. The 14-item version was better than the 20-item version in predicting consensus diagnosis, as shown by their AICs, while also showing the highest accuracy when discriminating between participants by diagnosis at last visit. We did not find sex to moderate the relationship between CES-D score and cognitive decline. Current findings suggest the 10- and 14-item versions of the CES-D are comparable to the 20-item version, and that the 14-item version may be better at predicting longitudinal consensus diagnosis compared to the 20-item version.
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An accurate blood test for Alzheimer's disease that is sensitive to preclinical proteinopathy and cognitive decline has clear implications for early detection and secondary prevention. We assessed the performance of plasma phosphorylated tau 217 ( pTa u 217 ) against brain PET markers of amyloid [ [ 11 C ] -labelled Pittsburgh compound B (PiB)] and tau ( [ 18 F ] MK-6240) and its utility for predicting longitudinal cognition. Samples were analysed from a subset of participants with up to 8 years follow-up in the Wisconsin Registry for Alzheimer's Prevention (WRAP; 2001-present; plasma 2011-present), a longitudinal cohort study of adults from midlife, enriched for parental history of Alzheimer's disease. Participants were a convenience sample who volunteered for at least one PiB scan, had usable banked plasma and were cognitively unimpaired at first plasma collection. Study personnel who interacted with participants or samples were blind to amyloid status. We used mixed effects models and receiver-operator characteristic curves to assess concordance between plasma pTa u 217 and PET biomarkers of Alzheimer's disease and mixed effects models to understand the ability of plasma pTa u 217 to predict longitudinal performance on WRAP's preclinical Alzheimer's cognitive composite (PACC-3). The primary analysis included 165 people (108 women; mean age = 62.9 ± 6.06; 160 still enrolled; 2 deceased; 3 discontinued). Plasma pTa u 217 was strongly related to PET-based estimates of concurrent brain amyloid ( ß ^ = 0.83 (0.75, 0.90), P < 0.001). Concordance was high between plasma pTa u 217 and both amyloid PET (area under the curve = 0.91, specificity = 0.80, sensitivity = 0.85, positive predictive value = 0.58, negative predictive value = 0.94) and tau PET (area under the curve = 0.95, specificity = 1, sensitivity = 0.85, positive predictive value = 1, negative predictive value = 0.98). Higher baseline pTa u 217 levels were associated with worse cognitive trajectories ( ß ^ p T a u × a g e = -0.07 (-0.09, -0.06), P < 0.001). In a convenience sample of unimpaired adults, plasma pTa u 217 levels correlate well with concurrent brain Alzheimer's disease pathophysiology and with prospective cognitive performance. These data indicate that this marker can detect disease before clinical signs and thus may disambiguate presymptomatic Alzheimer's disease from normal cognitive ageing.
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Recency refers to the information learned at the end of a study list or task. Recency forgetting, as tracked by the ratio between recency recall in immediate and delayed conditions, i.e., the recency ratio (Rr), has been applied to list-learning tasks, demonstrating its efficacy in predicting cognitive decline, conversion to mild cognitive impairment (MCI), and cerebrospinal fluid (CSF) biomarkers of neurodegeneration. However, little is known as to whether Rr can be effectively applied to story recall tasks. To address this question, data were extracted from the database of the Alzheimer's Disease Research Center at the University of Wisconsin - Madison. A total of 212 participants were included in the study. CSF biomarkers were amyloid-beta (Aß) 40 and 42, phosphorylated (p) and total (t) tau, neurofilament light (NFL), neurogranin (Ng), and α-synuclein (a-syn). Story Recall was measured with the Logical Memory Test (LMT). We carried out Bayesian regression analyses with Rr, and other LMT scores as predictors; and CSF biomarkers (including the Aß42/40 and p-tau/Aß42 ratios) as outcomes. Results showed that models including Rr consistently provided best fits with the data, with few exceptions. These findings demonstrate the applicability of Rr to story recall and its sensitivity to CSF biomarkers of neurodegeneration, and encourage its inclusion when evaluating risk of neurodegeneration with story recall.
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Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/psicología , Péptidos beta-Amiloides , Teorema de Bayes , Biomarcadores , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/psicología , Proteínas tau , NeuronasRESUMEN
BACKGROUND: Wordlist and story recall tests are routinely employed in clinical practice for dementia diagnosis. In this study, our aim was to establish how well-standard clinical metrics compared to process scores derived from wordlist and story recall tests in predicting biomarker determined Alzheimer's disease, as defined by CSF ptau/Aß42 ratio. METHODS: Data from 295 participants (mean age = 65 ± 9.) were drawn from the University of Wisconsin - Madison Alzheimer's Disease Research Center (ADRC) and Wisconsin Registry for Alzheimer's Prevention (WRAP). Rey's Auditory Verbal Learning Test (AVLT; wordlist) and Logical Memory Test (LMT; story) data were used. Bayesian linear regression analyses were carried out with CSF ptau/Aß42 ratio as outcome. Sensitivity analyses were carried out with logistic regressions to assess diagnosticity. RESULTS: LMT generally outperformed AVLT. Notably, the best predictors were primacy ratio, a process score indexing loss of information learned early during test administration, and recency ratio, which tracks loss of recently learned information. Sensitivity analyses confirmed this conclusion. CONCLUSIONS: Our study shows that story recall tests may be better than wordlist tests for detection of dementia, especially when employing process scores alongside conventional clinical scores.
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Enfermedad de Alzheimer , Humanos , Persona de Mediana Edad , Anciano , Enfermedad de Alzheimer/diagnóstico , Teorema de Bayes , Biomarcadores , Aprendizaje , Recuerdo MentalRESUMEN
Importance: Knowledge is lacking on the prevalence and prognosis of individuals with a ß-amyloid-negative, tau-positive (A-T+) cerebrospinal fluid (CSF) biomarker profile. Objective: To estimate the prevalence of a CSF A-T+ biomarker profile and investigate its clinical implications. Design, Setting, and Participants: This was a retrospective cohort study of the cross-sectional multicenter University of Gothenburg (UGOT) cohort (November 2019-January 2021), the longitudinal multicenter Alzheimer Disease Neuroimaging Initiative (ADNI) cohort (individuals with mild cognitive impairment [MCI] and no cognitive impairment; September 2005-May 2022), and 2 Wisconsin cohorts, Wisconsin Alzheimer Disease Research Center and Wisconsin Registry for Alzheimer Prevention (WISC; individuals without cognitive impairment; February 2007-November 2020). This was a multicenter study, with data collected from referral centers in clinical routine (UGOT) and research settings (ADNI and WISC). Eligible individuals had 1 lumbar puncture (all cohorts), 2 or more cognitive assessments (ADNI and WISC), and imaging (ADNI only) performed on 2 separate occasions. Data were analyzed on August 2022 to April 2023. Exposures: Baseline CSF Aß42/40 and phosphorylated tau (p-tau)181; cognitive tests (ADNI: modified preclinical Alzheimer cognitive composite [mPACC]; WISC: modified 3-test PACC [PACC-3]). Exposures in the ADNI cohort included [18F]-florbetapir amyloid positron emission tomography (PET), magnetic resonance imaging (MRI), [18F]-fluorodeoxyglucose PET (FDG-PET), and cross-sectional tau-PET (ADNI: [18F]-flortaucipir, WISC: [18F]-MK6240). Main Outcomes and Measures: Primary outcomes were the prevalence of CSF AT biomarker profiles and continuous longitudinal global cognitive outcome and imaging biomarker trajectories in A-T+ vs A-T- groups. Secondary outcomes included cross-sectional tau-PET. Results: A total of 7679 individuals (mean [SD] age, 71.0 [8.4] years; 4101 male [53%]) were included in the UGOT cohort, 970 individuals (mean [SD] age, 73 [7.0] years; 526 male [54%]) were included in the ADNI cohort, and 519 individuals (mean [SD] age, 60 [7.3] years; 346 female [67%]) were included in the WISC cohort. The prevalence of an A-T+ profile in the UGOT cohort was 4.1% (95% CI, 3.7%-4.6%), being less common than the other patterns. Longitudinally, no significant differences in rates of worsening were observed between A-T+ and A-T- profiles for cognition or imaging biomarkers. Cross-sectionally, A-T+ had similar tau-PET uptake to individuals with an A-T- biomarker profile. Conclusion and Relevance: Results suggest that the CSF A-T+ biomarker profile was found in approximately 5% of lumbar punctures and was not associated with a higher rate of cognitive decline or biomarker signs of disease progression compared with biomarker-negative individuals.
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Importance: Alzheimer disease (AD) pathology starts with a prolonged phase of ß-amyloid (Aß) accumulation without symptoms. The duration of this phase differs greatly among individuals. While this disease phase has high relevance for clinical trial designs, it is currently unclear how to best predict the onset of clinical progression. Objective: To evaluate combinations of different plasma biomarkers for predicting cognitive decline in Aß-positive cognitively unimpaired (CU) individuals. Design, Setting, and Participants: This prospective population-based prognostic study evaluated data from 2 prospective longitudinal cohort studies (the Swedish BioFINDER-1 and the Wisconsin Registry for Alzheimer Prevention [WRAP]), with data collected from February 8, 2010, to October 21, 2020, for the BioFINDER-1 cohort and from August 11, 2011, to June 27, 2021, for the WRAP cohort. Participants were CU individuals recruited from memory clinics who had brain Aß pathology defined by cerebrospinal fluid (CSF) Aß42/40 in the BioFINDER-1 study and by Pittsburgh Compound B (PiB) positron emission tomography (PET) in the WRAP study. A total of 564 eligible Aß-positive and Aß-negative CU participants with available relevant data from the BioFINDER-1 and WRAP cohorts were included in the study; of those, 171 Aß-positive participants were included in the main analyses. Exposures: Baseline P-tau181, P-tau217, P-tau231, glial fibrillary filament protein, and neurofilament light measured in plasma; CSF biomarkers in the BioFINDER-1 cohort, and PiB PET uptake in the WRAP cohort. Main Outcomes and Measures: The primary outcome was longitudinal measures of cognition (using the Mini-Mental State Examination [MMSE] and the modified Preclinical Alzheimer Cognitive Composite [mPACC]) over a median of 6 years (range, 2-10 years). The secondary outcome was conversion to AD dementia. Baseline biomarkers were used in linear regression models to predict rates of longitudinal cognitive change (calculated separately). Models were adjusted for age, sex, years of education, apolipoprotein E ε4 allele status, and baseline cognition. Multivariable models were compared based on model R2 coefficients and corrected Akaike information criterion. Results: Among 171 Aß-positive CU participants included in the main analyses, 119 (mean [SD] age, 73.0 [5.4] years; 60.5% female) were from the BioFINDER-1 study, and 52 (mean [SD] age, 64.4 [4.6] years; 65.4% female) were from the WRAP study. In the BioFINDER-1 cohort, plasma P-tau217 was the best marker to predict cognitive decline in the mPACC (model R2 = 0.41) and the MMSE (model R2 = 0.34) and was superior to the covariates-only models (mPACC: R2 = 0.23; MMSE: R2 = 0.04; P < .001 for both comparisons). Results were validated in the WRAP cohort; for example, plasma P-tau217 was associated with mPACC slopes (R2 = 0.13 vs 0.01 in the covariates-only model; P = .01) and MMSE slopes (R2 = 0.29 vs 0.24 in the covariates-only model; P = .046). Sparse models were identified with plasma P-tau217 as a predictor of cognitive decline. Power calculations for enrichment in hypothetical clinical trials revealed large relative reductions in sample sizes when using plasma P-tau217 to enrich for CU individuals likely to experience cognitive decline over time. Conclusions and Relevance: In this study, plasma P-tau217 predicted cognitive decline in patients with preclinical AD. These findings suggest that plasma P-tau217 may be used as a complement to CSF or PET for participant selection in clinical trials of novel disease-modifying treatments.
Asunto(s)
Enfermedad de Alzheimer , Disfunción Cognitiva , Humanos , Femenino , Anciano , Persona de Mediana Edad , Masculino , Enfermedad de Alzheimer/líquido cefalorraquídeo , Estudios Longitudinales , Estudios Prospectivos , Péptidos beta-Amiloides/metabolismo , Tomografía de Emisión de Positrones , Biomarcadores , Proteínas tau/líquido cefalorraquídeoRESUMEN
Previous studies suggest associations between self-reported sleep problems and poorer health, cognition, Alzheimer's disease pathology and dementia-related outcomes. It is important to develop a deeper understanding of the relationship between these complications and sleep disturbance, a modifiable risk factor, in late midlife, a time when Alzheimer's disease pathology may be accruing. The objectives of this study included application of unsupervised machine learning procedures to identify distinct subgroups of persons with problematic sleep and the association of these subgroups with concurrent measures of mental and physical health, cognition and PET-identified amyloid. Dementia-free participants from the Wisconsin Registry for Alzheimer's Prevention (n = 619) completed sleep questionnaires including the Insomnia Severity Index, Epworth Sleepiness Scale and Medical Outcomes Study Sleep Scale. K-means clustering analysis identified discrete sleep problem groups who were then compared across concurrent health outcomes (e.g. depression, self-rated health and insulin resistance), cognitive composite indices including episodic memory and executive function and, in a subset, Pittsburgh Compound B PET imaging to assess amyloid burden. Significant omnibus tests (P < 0.05) were followed with pairwise comparisons. Mean (SD) sample baseline sleep assessment age was 62.6 (6.7). Cluster analysis identified three groups: healthy sleepers [n = 262 (42.3%)], intermediate sleepers [n = 229 (37.0%)] and poor sleepers [n = 128 (20.7%)]. All omnibus tests comparing demographics and health measures across sleep groups were significant except for age, sex and apolipoprotein E e4 carriers; the poor sleepers group was worse than one or both of the other groups on all other measures, including measures of depression, self-reported health and memory complaints. The poor sleepers group had higher average body mass index, waist-hip ratio and homeostatic model assessment of insulin resistance. After adjusting for covariates, the poor sleepers group also performed worse on all concurrent cognitive composites except working memory. There were no differences between sleep groups on PET-based measures of amyloid. Sensitivity analyses indicated that while different clustering approaches resulted in different group assignments for some (predominantly the intermediate group), between-group patterns in outcomes were consistent. In conclusion, distinct sleep characteristics groups were identified with a sizable minority (20.7%) exhibiting poor sleep characteristics, and this group also exhibited the poorest concurrent mental and physical health and cognition, indicating substantial multi-morbidity; sleep group was not associated with amyloid PET estimates. Precision-based management of sleep and related factors may provide an opportunity for early intervention that could serve to delay or prevent clinical impairment.
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Cognitive decline in Alzheimer's disease and other dementias typically begins long before clinical impairment. Identifying people experiencing subclinical decline may facilitate earlier intervention. This study developed cognitive trajectory clusters using longitudinally based random slope and change point parameter estimates from a Preclinical Alzheimer's disease Cognitive Composite and examined how baseline and most recently available clinical/health-related characteristics, cognitive statuses and biomarkers for Alzheimer's disease and vascular disease varied across these cognitive clusters. Data were drawn from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal cohort study of adults from late midlife, enriched for a parental history of Alzheimer's disease and without dementia at baseline. Participants who were cognitively unimpaired at the baseline visit with ≥3 cognitive visits were included in trajectory modelling (n = 1068). The following biomarker data were available for subsets: positron emission tomography amyloid (amyloid: n = 367; [11C]Pittsburgh compound B (PiB): global PiB distribution volume ratio); positron emission tomography tau (tau: n = 321; [18F]MK-6240: primary regions of interest meta-temporal composite); MRI neurodegeneration (neurodegeneration: n = 581; hippocampal volume and global brain atrophy); T2 fluid-attenuated inversion recovery MRI white matter ischaemic lesion volumes (vascular: white matter hyperintensities; n = 419); and plasma pTau217 (n = 165). Posterior median estimate person-level change points, slopes' pre- and post-change point and estimated outcome (intercepts) at change point for cognitive composite were extracted from Bayesian Bent-Line Regression modelling and used to characterize cognitive trajectory groups (K-means clustering). A common method was used to identify amyloid/tau/neurodegeneration/vascular biomarker thresholds. We compared demographics, last visit cognitive status, health-related factors and amyloid/tau/neurodegeneration/vascular biomarkers across the cognitive groups using ANOVA, Kruskal-Wallis, χ2, and Fisher's exact tests. Mean (standard deviation) baseline and last cognitive assessment ages were 58.4 (6.4) and 66.6 (6.6) years, respectively. Cluster analysis identified three cognitive trajectory groups representing steep, n = 77 (7.2%); intermediate, n = 446 (41.8%); and minimal, n = 545 (51.0%) cognitive decline. The steep decline group was older, had more females, APOE e4 carriers and mild cognitive impairment/dementia at last visit; it also showed worse self-reported general health-related and vascular risk factors and higher amyloid, tau, neurodegeneration and white matter hyperintensity positive proportions at last visit. Subtle cognitive decline was consistently evident in the steep decline group and was associated with generally worse health. In addition, cognitive trajectory groups differed on aetiology-informative biomarkers and risk factors, suggesting an intimate link between preclinical cognitive patterns and amyloid/tau/neurodegeneration/vascular biomarker differences in late middle-aged adults. The result explains some of the heterogeneity in cognitive performance within cognitively unimpaired late middle-aged adults.