Measuring Human Auditory Evoked Fields with a Flexible Multi-Channel OPM-Based MEG System.

BACKGROUND: Magnetoencephalography (MEG) is a non-invasive imaging technique for directly measuring the external magnetic field generated from synchronously activated pyramidal neurons in the brain. The optically pumped magnetometer (OPM) is known for its less expensive, non-cryogenic, movable and user-friendly custom-design provides the potential for a change in functional neuroimaging based on MEG. METHODS: An array of OPMs covering the opposite sides of a subject's head is placed inside a magnetically shielded room (MSR) and responses evoked from the auditory cortices are measured. RESULTS: High signal-to-noise ratio auditory evoked response fields (AEFs) were detected by a wearable OPM-MEG system in a MSR, for which a flexible helmet was specially designed to minimize the sensor-to-head distance, along with a set of bi-planar coils developed for background field and gradient nulling. Neuronal current sources activated in AEF experiments were localized and the auditory cortices showed the highest activities. Performance of the hybrid optically pumped magnetometer-magnetoencephalography/electroencephalography (OPM-MEG/EEG) system was also assessed. CONCLUSIONS: The multi-channel OPM-MEG system performs well in a custom built MSR equipped with bi-planar coils and detects human AEFs with a flexible helmet. Moreover, the similarities and differences of auditory evoked potentials (AEPs) and AEFs are discussed, while the operation of OPM-MEG sensors in conjunction with EEG electrodes provides an encouraging combination for the exploration of hybrid OPM-MEG/EEG systems.

Sleep duration and efficiency are associated with plasma amyloid-ß in non-demented older people.

STUDY OBJECTIVES: This study aims to investigate the extent to which sleep duration and efficiency are associated with plasma amyloid-ß (Aß) levels in non-demented older people. METHODS: This study is a cross-sectional analysis of 305 non-demented older people. Sleep duration and efficiency were assessed used the Pittsburgh Sleep Quality Index. Levels of plasma Aß were determined by sandwich enzyme-linked immunosorbent assay technique. Associations between sleep variables and plasma Aß levels were evaluated with multivariable linear regression analysis. RESULTS: Compared to those with sleep duration > 7 h, participants with sleep duration < 6 h had a higher plasma Aß42 level (ß = 0.495, 95% CI 0.077~0.913, p = 0.021) and Aß42/Aß40 ratio (ß = 0.101, 95% CI 0.058~0.144, p < 0.001). Compared to those with sleep efficiency ≥ 85%, participants with lower sleep efficiency (65~74%, <65%) had a higher level of plasma Aß42 (<65%: ß = 0.627, 95% CI 0.147~1.108, p = 0.011) and Aß42/Aß40 ratio (65~74%: ß = 0.052, 95% CI 0.007~0.097, p = 0.026; <65%: ß = 0.117, 95% CI 0.067~0.168, p < 0.001). CONCLUSIONS: These findings indicated that short sleep duration and low sleep efficiency were associated with a high level of Aß42. A better comprehending of the link between sleep and plasma Aß levels may lead to effective sleep-based intervention to reduce the risk of Alzheimer's disease.

The cost of Alzheimer's disease in China and re-estimation of costs worldwide.

INTRODUCTION: The socioeconomic costs of Alzheimer's disease (AD) in China and its impact on global economic burden remain uncertain. METHODS: We collected data from 3098 patients with AD in 81 representative centers across China and estimated AD costs for individual patient and total patients in China in 2015. Based on this data, we re-estimated the worldwide costs of AD. RESULTS: The annual socioeconomic cost per patient was US $19,144.36, and total costs were US $167.74 billion in 2015. The annual total costs are predicted to reach US $507.49 billion in 2030 and US $1.89 trillion in 2050. Based on our results, the global estimates of costs for dementia were US $957.56 billion in 2015, and will be US $2.54 trillion in 2030, and US $9.12 trillion in 2050, much more than the predictions by the World Alzheimer Report 2015. DISCUSSION: China bears a heavy burden of AD costs, which greatly change the estimates of AD cost worldwide.

Elevated Plasma Homocysteine Level Increased the Risk of Early Renal Impairment in Acute Ischemic Stroke Patients.

Renal insufficiency is associated with the prognosis of acute ischemic stroke (AIS) and homocysteine (Hcy) levels. This study investigated the association between plasma Hcy levels and renal insufficiency in patients with AIS. A total of 987 patients with AIS who had been treated at the First People's Hospital of Foshan between 2011 and 2014 were retrospectively studied. Based on their cystatin C (Cys C) levels, the patients were divided into the normal renal function group (Cys C ≤ 1.25 mg/L) or the renal impairment group (Cys C > 1.25 mg/L). Multivariate regression analysis was applied to reveal the association between hyperhomocysteinemia (HHcy) and renal impairment. The renal impairment group showed more advanced age of onset, higher percentage of prior stroke and hypertension, higher baseline National Institute of Health Stroke Scale score, lower high-density lipoprotein cholesterol levels, and higher Hcy levels compared with the normal renal function group. A multivariate analysis revealed a relationship between early renal impairment and Hcy levels: an increase of Hcy by 1 µmol/L was associated with an increase of 12-18% of the risk of renal impairment among patients with AIS and HHcy. Patients with AIS and HHcy had a 2.42-3.51 fold increase of the risk of renal impairment compared with patients with normal Hcy level (P < 0.001). In conclusion, patients with stroke and HHcy could be more prone to renal impairment.

A Multi-Modal Classification Method for Early Diagnosis of Mild Cognitive Impairment and Alzheimer's Disease Using Three Paradigms With Various Task Difficulties.

Alzheimer's Disease (AD) accounts for the majority of dementia, and Mild Cognitive Impairment (MCI) is the early stage of AD. Early and accurate diagnosis of dementia plays a vital role in more targeted treatments and effectively halting disease progression. However, the clinical diagnosis of dementia requires various examinations, which are expensive and require a high level of expertise from the doctor. In this paper, we proposed a classification method based on multi-modal data including Electroencephalogram (EEG), eye tracking and behavioral data for early diagnosis of AD and MCI. Paradigms with various task difficulties were used to identify different severity of dementia: eye movement task and resting-state EEG tasks were used to detect AD, while eye movement task and delayed match-to-sample task were used to detect MCI. Besides, the effects of different features were compared and suitable EEG channels were selected for the detection. Furthermore, we proposed a data augmentation method to enlarge the dataset, designed an extra ERPNet feature extract layer to extract multi-modal features and used domain-adversarial neural network to improve the performance of MCI diagnosis. We achieved an average accuracy of 88.81% for MCI diagnosis and 100% for AD diagnosis. The results of this paper suggest that our classification method can provide a feasible and affordable way to diagnose dementia.

Brain Activation During Working Memory Task in Amnestic Mild Cognitive Impairment Patients and Its Association with Memory and Attention.

BACKGROUND: Amnestic mild cognitive impairment (aMCI) is regarded as a transitional state of Alzheimer's disease, with working memory (WM) impairment. OBJECTIVE: To investigate the brain activity in aMCI patients during WM tasks with the functional near-infrared spectroscopy (fNIRS) technique, as well as explore the association between brain activity and cognitive function in multiple domains. METHODS: This study is a case-control study of 54 aMCI patients and 33 cognitively healthy elderly (NC). All participants underwent neuropsychological assessments. fNIRS was applied to examine the brain activation during the WM task. Multivariable linear regression analysis was applied to evaluate associations between brain activation and cognitive function in multiple domains. RESULTS: Compared to NC subjects, aMCI patients had lower activation in the bilateral prefrontal, parietal, and occipital cortex during the WM task. Additionally, activation in the left prefrontal, bilateral parietal, and occipital cortex during the encoding and maintenance phase was positively associated with memory function. During memory retrieval, higher activity in the left prefrontal, parietal, and occipital cortex were correlated with higher memory scores. Besides, a positive association also formed between attention function and the activation in the left prefrontal, parietal, and occipital cortex during the WM task. CONCLUSION: These findings demonstrated that reduced activation in the prefrontal, parietal and occipital cortex during WM might reflect the risk of cognitive impairment, especially memory and attention function in aMCI patients. Given the brain activation visualization, fNIRS may be a convenient and alternative tool for screening the risk of Alzheimer's disease.

Diagnostic accuracy of multi-component spatial-temporal gait parameters in older adults with amnestic mild cognitive impairment.

Objective: This study aimed to develop a diagnostic model of multi-kinematic parameters for patients with amnestic mild cognitive impairment (aMCI). Method: In this cross-sectional study, 94 older adults were included (33 cognitively normal, CN; and 61 aMCI). We conducted neuropsychological battery tests, such as global cognition and cognitive domains, and collected gait parameters by an inertial-sensor gait analysis system. Multivariable regression models were used to identify the potential diagnostic variables for aMCI. Receiver operating characteristic (ROC) curves were applied to assess the diagnostic accuracy of kinematic parameters in discriminating aMCI from healthy subjects. Results: Multivariable regression showed that multi-kinematic parameters were the potential diagnostic variables for aMCI. The multi-kinematic parameter model, developed using Timed Up and Go (TUG) time, stride length, toe-off/heel stride angles, one-leg standing (OLS) time, and braking force, showed areas under ROC (AUC), 0.96 [95% confidence interval (CI), 0.905-0.857]; sensitivity, 0.90; and specificity, 0.91. In contrast, a single kinematic parameter's sensitivity was 0.26-0.95 and specificity was 0.21-0.90. Notably, the separating capacity of multi-kinematic parameters was highly similar to Montreal Cognitive Assessment (MoCA; AUC: 0.96 vs. 0.95). Compared to cognitive domain tests, the separating ability was comparable to Auditory Verbal Learning Test (AVLT) and Boston Naming Test (BNT; AUC: 0.96 vs. 0.97; AUC: 0.96 vs. 0.94). Conclusion: We developed one diagnostic model of multi-kinematic parameters for patients with aMCI in Foshan.

High Fall Risk Associated With Memory Deficit and Brain Lobes Atrophy Among Elderly With Amnestic Mild Cognitive Impairment and Mild Alzheimer's Disease.

Objectives: This study aimed to primarily examine the association between memory deficit and increased fall risk, second, explore the underlying neuroanatomical linkage of this association in the elderly with aMCI and mild AD. Methods: In this cross-sectional study, a total of 103 older adults were included (55 cognitively normal, CN; 48 cognitive impairment, CI, elderly with aMCI, and mild AD). Memory was assessed by the Auditory Verbal Learning Test (AVLT). Fall risk was evaluated by the Timed Up and Go (TUG) Test, heel strike angles, and stride speed, which were collected by an inertial-sensor-based wearable instrument (the JiBuEn™ gait analysis system). Brain volumes were full-automatic segmented and quantified using AccuBrain® v1.2 from three-dimensional T1-weighted (3D T1W) MR images. Multivariable regression analysis was used to examine the extent of the association between memory deficit and fall risk, the association of brain volumes with memory, and fall risk. Age, sex, education, BMI, and HAMD scores were adjusted. Sensitivity analysis was conducted. Results: Compared to CN, participants with aMCI and mild AD had poorer cognitive performance (p < 0.001), longer TUG time (p = 0.018), and smaller hippocampus and medial temporal volumes (p = 0.037 and 0.029). In the CI group, compared to good short delayed memory (SDM) performance (AVLT > 5), the elderly with bad SDM performance (AVLT ≤ 3) had longer TUG time, smaller heel strike angles, and slower stride speed. Multivariable regression analysis showed that elderly with poor memory had higher fall risk than relative good memory performance among cognitive impairment elderly. The TUG time increased by 2.1 s, 95% CI, 0.54∼3.67; left heel strike angle reduced by 3.22°, 95% CI, -6.05 to -0.39; and stride speed reduced by 0.09 m/s, 95% CI, -0.19 to -0.00 for the poor memory elderly among the CI group, but not found the association in CN group. In addition, serious medial temporal atrophy (MTA), small volumes of the frontal lobe and occipital lobe were associated with long TUG time and small heel strike angles; small volumes of the temporal lobe, frontal lobe, and parietal lobe were associated with slow stride speed. Conclusion: Our findings suggested that memory deficit was associated with increased fall risk in the elderly with aMCI and mild AD. The association might be mediated by the atrophy of medial temporal, frontal, and parietal lobes. Additionally, increased fall risk, tested by TUG time, heel stride angles, and stride speed, might be objective and convenient kinematics markers for dynamic monitoring of both memory function and fall risk.

Identifying and characterizing trajectories of cognitive change in older persons with mild cognitive impairment.

BACKGROUND: Mild cognitive impairment (MCI) represents a state of high risk for dementia but is heterogeneous in its course. To date, the trajectories reflecting distinct developmental courses of cognition among patients with MCI have not been well defined. AIM: To identify the developmental trajectory of groups with distinct cognitive change patterns among a cohort of MCI patients. METHODS: 187 MCI patients from 2 geriatric outpatient clinics were evaluated serially with the Mini-Mental State Examination (MMSE) for up to 3.5 years. Group-based trajectory analysis was applied to identify distinct trajectories. Estimates of decline for each group were compared with the mean rate of decline obtained from mixed modeling of the entire sample. RESULTS: 5 trajectories were identified and labeled based on their baseline MMSE score and course: (1) 29/stable (6.5%); (2) 27/stable (53.9%); (3) 25/slow decline (23.8%); (4) 24/slow decline (11.6%); (5) 25/rapid decline (4.2%). Annual rate of change in the MMSE score for these 5 groups was 0.09, -0.43, -1.23, -1.84, and -4.6 points, respectively. None corresponded to the mean rate of -0.82 points estimated for the group as a whole. A majority of MCI patients (60.4%) follow stable cognitive trajectories over time. Within the 3 groups with declining trajectories, cognitive decline occurs slowly in a vast majority of MCI patients (98.5%). CONCLUSIONS: Results provide direct evidence for the heterogeneous course of cognitive decline that has been suggested by the variable prognosis for patients with MCI.

Predictors of future cognitive decline in persons with mild cognitive impairment.

This study sought first to identify individual items of the Mini-Mental State Examination (MMSE) and demographic variables at baseline that predicted the trajectories of cognitive change among patients with mild cognitive impairment (MCI), and second to quantify the risk of cognitive decline in such patients based on their pattern of failure of MMSE items. 187 MCI patients were evaluated serially with the MMSE for up to 3.5 years. Patients who followed a declining cognitive trajectory differed from the stable reference group in their baseline profile of MMSE test performance. Patient age and performance on delayed recall, constructional praxis, attention, and orientation to time and floor predicted future cognitive decline with good accuracy (79.9%) and specificity (86.4%), and moderate sensitivity (67.2%). These results are presented in the form of a simple clinical tool for quantifying risk of future cognitive decline in MCI.

Improving precision in the quantification of cognition using the Montreal Cognitive Assessment and the Mini-Mental State Examination.

BACKGROUND: The Montreal Cognitive Assessment (MoCA) can be used to quantify cognitive ability in older persons undergoing screening for cognitive impairment. Although highly sensitive in detecting mild cognitive impairment, its measurement precision is weakest among persons with milder forms of impairment. We sought to overcome this limitation by integrating information from the Mini-Mental State Examination (MMSE) into the calculation of cognitive ability. METHODS: Data from 185 geriatric outpatients screened for cognitive impairment with the MoCA and the MMSE were Rasch analyzed to evaluate the extent to which the MMSE items improved measurement precision in the upper ability ranges of the population. RESULTS: Adding information from the MMSE resulted in a 13.8% (13.3-14.3%) reduction in measurement error, with significant improvements in all quartiles of patient ability. The addition of three-word repetition and recall, copy pentagons, repeat sentence, and write sentence improved measurement of cognition in the upper levels of ability. CONCLUSIONS: The algorithm presented here maximizes the yield of available clinical data while improving measurement of cognitive ability, which is particularly important for tracking changes over time in patients with milder levels of impairment.

Development of a method for quantifying cognitive ability in the elderly through adaptive test administration.

BACKGROUND: The field of geriatric medicine has identified a need for an evaluative tool that can rapidly quantify global cognitive ability and accurately monitor change over time in patients with a wide range of impairments. We hypothesized that the development of an adaptive test approach to cognitive measurement would help to meet that need. This study aimed to provide evidence for the interpretability of scores obtained from a novel, adaptive approach to cognitive assessment, called the Geriatric Rapid Adaptive Cognitive Estimate (GRACE) method. METHODS: An adaptive method for cognitive assessment was developed using data from 185 patients referred for geriatric cognitive assessment, and pilot tested in an additional 137 patients. Correlations between test scores and between rank orders of patients were computed to examine the reliability and validity of cognitive ability scores obtained by (1) administering test questions out of their usual order, (2) administering only a subset of questions, and (3) administering questions adaptively using simplified selection rules based on the most difficult question passed. RESULTS: Cognitive ability scores obtained with the GRACE method correlated highly with the Montreal Cognitive Assessment (MoCA) scores (r = 0.93) and ranked patients similarly in order of ability (r > 0.87). A simplified adaptive testing algorithm for pencil-and-paper assessment demonstrated moderately high correlations with scores obtained from administering the full set of MMSE and MoCA items as well as the MoCA items alone. CONCLUSIONS: Scores from the GRACE method can be obtained easily in 5-10 minutes, reducing test burden. The resulting numeric score quantifies cognitive ability, allowing clinicians to compare patients and monitor change in global cognition over time. The adaptive nature of this method allows for evaluation of persons across a broader range of cognitive ability levels than currently available tests.

French-English cross-linguistic comparison and diagnostic impact of the AD-8 dementia screening questionnaire in a geriatric assessment clinic.

The AD-8 dementia screening questionnaire is a novel tool that allows clinicians to assess changes in cognitive function. This study examined psychometric properties of the test in French-speaking and English-speaking patients, and its impact on diagnostic practice in the geriatric assessment clinics of a university health centre. Data were extracted from the clinical database for all new patients screened for cognitive impairment 15 months before (historic control group) and 15 months after the introduction of the test (AD-8 group and concurrent control group). Analysis of differential item functioning revealed formal equivalence of the French- and English-language items, supporting the validity of the French version. Respondent type significantly influenced the total score on the AD-8. Concurrent validity with other cognitive screening tests was moderately high. Finally, among patients who did not present with pre-existing dementia, a higher proportion of dementia diagnoses was made in those administered the AD-8 relative to the concurrent control group. Implications for clinical use of the AD-8 are discussed.

Subjective Sleep Quality in Amnestic Mild Cognitive Impairment Elderly and Its Possible Relationship With Plasma Amyloid-ß.

STUDY OBJECTIVES: To investigate the extent to which sleep quality associated with plasma Aß levels in amnestic mild cognitive impairment (aMCI) elderly. METHODS: A total of 172 cognitively normal (NC) elderly and 133 aMCI elderly were included in this study. For the evaluation of sleep quality, the Pittsburgh Sleep Quality Index (PSQI) was used. Levels of plasma Aß were determined by the sandwich enzyme-linked immunosorbent assay technique. Multivariable linear regression analysis was applied to evaluate associations between sleep quality and plasma Aß levels after adjusting potential confounders. RESULTS: Compared to NC subjects, participants with aMCI had a higher global PSQI score (8.72 ± 3.87 vs. 7.10 ± 3.07, p < 0.001). The global PSQI score was positively associated with plasma Aß42 level in the aMCI group (ß = 0.063, 95% CI 0.001-0.125, and p = 0.049) but not in the NC group (p > 0.05). Additionally, a higher global PSQI score was associated with a higher plasma Aß42/Aß40 ratio in both NC (ß = 0.010, 95% CI 0.003-0.016, and p = 0.003) and aMCI groups (ß = 0.012, 95% CI 0.005-0.018, and p < 0.001). The association between global PSQI score and plasma Aß42/Aß40 ratio was stronger in individuals with aMCI relative to the NC subjects (ß = 0.076 vs. 0.030, p for interaction = 0.023). CONCLUSION: Poor sleep quality was associated with plasma Aß42 and Aß42/Aß40 ratio, with a stronger effect among individuals with aMCI. A better understanding of the role of sleep in plasma Aß levels in aMCI patients could lead to effective sleep-based intervention against the risk of Alzheimer's disease.

Measuring cognition in a geriatric outpatient clinic: Rasch analysis of the Montreal Cognitive Assessment.

OBJECTIVE: To evaluate the psychometric properties of the Montreal Cognitive Assessment as a quantitative measure of cognitive ability. DATA ANALYZED: A total of 222 cases extracted from a clinical database (57-91 years) of patients screened for cognitive impairment in outpatient geriatric assessment clinics. DATA COLLECTED: Demographic information and individual item responses to Montreal Cognitive Assessment. RESULTS: Comparison of the data with a unidimensional Rasch model indicated that the total score obtained by summing across all items yields a reliable (0.75) quantitative estimate of global cognitive ability. All items fit the model and together spanned a range of difficulty from -3.75 to +2.88 logits. Items were assessed for differential item functioning across such patient characteristics as age, education, and language spoken. We provide a table for converting Montreal Cognitive Assessment total scores onto a linearly scaled score, with guidelines for interpreting changes in Montreal Cognitive Assessment score in terms of their statistical significance. CONCLUSIONS: The Montreal Cognitive Assessment can provide a reliable and valid quantitative estimate of cognitive ability in a geriatric cognitive disorders clinic setting.

Wearable Sensor-Based Daily Life Walking Assessment of Gait for Distinguishing Individuals With Amnestic Mild Cognitive Impairment.

Objectives: To characterize gait disorders in patients with amnestic mild cognitive impairment (aMCIs) and determine the association between the performance of the gait function and cognition. Methodology: In this study, we enrolled 38 patients with aMCI and 30 cognitively normal individuals normal controls (NC). Neuropsychological assessments included tests of memory, executive function, language, and attention. Using an inertial-sensor-based wearable instrument, we collected the gait data dynamically for at least 1 h/day for 2 weeks. The gait parameters included walking velocity, stride length, stride time, cadence, and stride time variability. Results: The aMCI patients had reduced walking velocity and stride length and increased stride time variability compared with the NCs. The total number of steps, stride time, and cadence did not differ between the two groups. For all the subjects, walking velocity and stride length was positively associated with memory and executive function. Stride time variability was negatively correlated with the cognitive domains including memory, executive function and attention. Conclusion: This study suggested that cognitive impairment-related gait disorders occur (reduced gait speed, gait length, and gait stability) in daily life walking among the aMCI patients. A sensor-based wearable device for gait measurement may be an alternative and convenient tool for screening cognitive impairment.

Is hyperhomocysteinemia associated with the structural changes of the substantia nigra in Parkinson's disease? A two-year follow-up study.

OBJECTIVE: It was recently found that structural changes in the substantia nigra (SN) and motor symptoms become more prominent in Parkinson's disease (PD) patients with striatal silent lacunar infarction (SSLI) than in those without SSLI. Hyperhomocysteinemia (HHCY) was an independent risk factor for SSLI in PD patients. In this follow-up study, we investigated the relationship between HHCY and structural changes of the SN in PD patients. METHODS: A total of 72 untreated early PD patients without SSLI, divided into control and HHCY groups, were enrolled in this study. All participants underwent conventional MRI and diffusion kurtosis imaging (DKI) twice; at baseline and at the 2-year visit. The differences of the following variables between the two groups were analyzed: mean kurtosis (MK) values of the SN, the severity of disease, daily dosage of levodopa, and the variation of these indexes from baseline to 2-year visit. Logistic regression analysis was used to identify the relationship between HHCY and structural changes of the SN in PD patients. RESULTS: 1.All variables mentioned above showed significant differences between the two groups. 2. The variation in MK values of the SN were positively correlated with the variation in the severity of disease. 3. HHCY was an independent risk factor for the variation in MK values of the SN in PD patients. CONCLUSION: HHCY is associated with the structural changes of the SN in PD patients. As PD progresses, motor symptoms become aggravated with increased structural changes to the SN, especially in patients with HHCY.

Corrigendum: Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

[This corrects the article DOI: 10.3389/fnagi.2019.00222.].

Age-Dependent Relationship Between Plasma Aß40 and Aß42 and Total Tau Levels in Cognitively Normal Subjects.

Both amyloid plaques and neurofibrillary tangles are pathological hallmarks in the brains of patients with Alzheimer's disease (AD). However, the constituents of these hallmarks, amyloid beta (Aß) 40, Aß42, and total Tau (t-Tau), have been detected in the blood of cognitively normal subjects by using an immunomagnetic reduction (IMR) assay. Whether these levels are age-dependent is not known, and their interrelation remains undefined. We determined the levels of these biomarkers in cognitively normal subjects of different age groups. A total of 391 cognitively normal subjects aged 23-91 were enrolled from hospitals in Asia, Europe, and North America. Healthy cognition was evaluated by NIA-AA guidelines to exclude subjects with mild cognitive impairment (MCI) and AD and by cognitive assessment using the Mini Mental State Examination and Clinical Dementia Rating (CDR). We examined the effect of age on plasma levels of Aß40, Aß42, and t-Tau and the relationship between these biomarkers during aging. Additionally, we explored age-related reference intervals for each biomarker. Plasma t-Tau and Aß42 levels had modest but significant correlations with chronological age (r = 0.127, p = 0.0120 for t-Tau; r = -0.126, p = 0.0128 for Aß42), ranging from ages 23 to 91. Significant positive correlations were detected between Aß42 and t-Tau in the groups aged 50 years and older, with Rho values ranging from 0.249 to 0.474. Significant negative correlations were detected between Aß40 and t-Tau from age 40 to 91 (r ranged from -0.293 to -0.582) and between Aß40 and Aß42 in the age groups of 30-39 (r = -0.562, p = 0.0235), 50-59 (r = -0.261, p = 0.0142), 60-69 (r = -0.303, p = 0.0004), and 80-91 (r = 0.459, p = 0.0083). We also provided age-related reference intervals for each biomarker. In this multicenter study, age had weak but significant effects on the levels of Aß42 and t-Tau in plasma. However, the age group defined by decade revealed the emergence of a relationship between Aß40, Aß42, and t-Tau in the 6th and 7th decades. Validation of our findings in a large-scale and longitudinal study is warranted.