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Background: Precisely defining the delay in onset of dementia is a particular challenge for early diagnosis. Brain [18F] fluoro-2-deoxy-2-D-glucose (18F-FDG) Positron Emission Tomography (PET) is a particularly interesting tool for the early diagnosis of neurodegenerative diseases, through the measurement of the cerebral glucose metabolic rate. There is currently a lack of longitudinal studies under real-life conditions, with sufficient patients, to accurately evaluate the predictive values of brain 18F-FDG PET scans. Here, we aimed to estimate the value of brain 18F-FDG PET for predicting the risk of dementia conversion and the risk of occurrence of a neurodegenerative pathology. Methods: Longitudinal data for a cohort of patients with no diagnosis of dementia at the time of recruitment referred by a tertiary memory clinic for brain 18F-FDG PET were matched with (Prince M, Wimo A, Guerchet Maëlenn, Ali G-C, Wu Y-T et al. World Alzheimer Report 2015. The Global Impact of Dementia: An analysis of prevalence, incidence, cost and trends. [Research Report] Alzheimer's Disease International. 2015. 2015.) data from the French National Health Data System (NHDS), (Jack CR, Bennett DA, Blennow K, Carrillo MC, Dunn B, Haeberlein SB, et al. NIA-AA Research Framework: Toward a biological definition of Alzheimer's disease. Alzheimers Dement. 2018;14(4):535–62.) data from the National Alzheimer Bank (NAB), and (Davis M, O'Connell T, Johnson S, Cline S, Merikle E, Martenyi F, et al. Estimating Alzheimer's Disease Progression Rates from Normal Cognition Through Mild Cognitive Impairment and Stages of Dementia. CAR. 2018;15(8):777–88.) lumbar puncture (LP) biomarker data. The criteria for dementia conversion were the designation, within the three years after the brain 18F-FDG PET scan, of a long-term condition for dementia in the NHDS and a dementia stage of cognitive impairment in the NAB. The criterion for the identification of a neurodegenerative disease in the medical records was the determination of LP biomarker levels. Results: Among the 403 patients (69.9 ± 11.4 years old, 177 women) from the initial cohort with data matched with the NHDS data, 137 were matched with the NAB data, and 61 were matched with LP biomarker data. Within three years of the scan, a 18F-FDG PET had negative predictive values of 85% for dementia conversion (according to the NHDS and NAB datasets) and 95% for the presence of LP neurodegeneration biomarkers. Conclusion: A normal brain 18F-FDG PET scan can help rule out the risk of dementia conversion and the presence of cerebrospinal fluid (CSF) biomarker of neurodegeneration early with high certainty, allowing modifications to patient management regimens in the short term. Trial registration: Clinical Trials database (NCT04804722). March 18, 2021. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Background: Cerebrospinal fluid (CSF) or blood biomarkers like phosphorylated tau proteins (p-tau) are used to detect Alzheimer's disease (AD) early. Increasing studies on cognitive function and blood or CSF p-tau levels are controversial. Objective: Our study examined the potential of p-tau as a biomarker of cognitive status in normal control (NC), mild cognitive impairment (MCI), and AD patients. Methods: We searched PubMed, Cochrane, Embase, and Web of Science for relevant material through 12 January 2023. 5,017 participants from 20 studies—1,033 AD, 2,077 MCI, and 1,907 NC—were evaluated. Quantitative analysis provided continuous outcomes as SMDs with 95% CIs. Begg tested publication bias. Results: MCI patients had lower CSF p-tau181 levels than AD patients (SMD =−0.60, 95% CI (−0.85, −0.36)) but higher than healthy controls (SMD = 0.67). AD/MCI patients had greater plasma p-tau181 levels than healthy people (SMD =−0.73, 95% CI (−1.04, −0.43)). MCI patients had significantly lower p-tau231 levels than AD patients in plasma and CSF (SMD =−0.90, 95% CI (−0.82, −0.45)). MCI patients showed greater CSF and plasma p-tau231 than healthy controls (SMD = 1.34, 95% CI (0.89, 1.79) and 0.43, (0.23, 0.64)). Plasma p-tau181/231 levels also distinguished the three categories. MCI patients had higher levels than healthy people, while AD patients had higher levels than MCI patients. Conclusions: CSF p-tau181 and p-tau231 biomarkers distinguished AD, MCI, and healthy populations. Plasma-based p-tau181 and p-tau231 biomarkers for AD and MCI need further study. [ABSTRACT FROM AUTHOR]

Background: The Free and Cued Selective Reminding Test (FCSRT), assessing verbal episodic memory with controlled learning and semantic cueing, has been recommended for detecting the genuine encoding and storage deficits characterizing AD-related memory disorders. Objective: The present study aims at investigating the ability of FCSRT in predicting cerebrospinal fluid (CSF) evidence of amyloid-β positivity in subjects with amnestic mild cognitive impairment (aMCI) and exploring its associations with amyloidopathy, tauopathy and neurodegeneration biomarkers. Methods: 120 aMCI subjects underwent comprehensive neurological and neuropsychological examinations, including the FCSRT assessment, and CSF collection; CSF Aβ42/40 ratio, p-tau181, and total-tau quantification were conducted by an automated CLEIA method on Lumipulse G1200. Based on the Aβ42/40 ratio value, subjects were classified as either A+ or A–. Results: All FCSRT subitem scores were significantly lower in A+ group and significantly predicted the amyloid-β status, with Immediate Total Recall (ITR) being the best predictor. No significant correlations were found between FCSRT and CSF biomarkers in the A– aMCI group, while in the A+ aMCI group, all FCSRT subitem scores were negatively correlated with CSF p-tau181 and total-tau, but not with the Aβ42/40 ratio. Conclusions: FCSRT confirms its validity as a tool for the diagnosis of AD, being able to predict the presence of amyloid-β deposition with high specificity. The associations between FCSRT subitem scores and CSF p-tau-181 and total-tau levels in aMCI due to AD could further encourage the clinical use of this simple and cost-effective test in the evaluation of individuals with aMCI. [ABSTRACT FROM AUTHOR]

Background/Aim: Detection of cerebrospinal fluid (CSF) biomarker deviations improve prediction of progression from mild cognitive impairment (MCI) to dementia. However, it is not settled whether the same pattern exists in patients progressing from very mild to more pronounced MCI. Given that neurodegenerative processes occur very early in the disease course, we also expected to find biomarker deviations in these patients. Methods: A total of 246 memory clinic patients with non-progressive (n = 161), progressive (n = 19), or converting (n = 66) MCI, 67 with stable dementia, and 80 controls were followed for 24 months. At baseline, CSF total tau (T-tau), β-amyloid 1-42 (Aβ42) and the light subunit of neurofilament protein (NFL) were determined. Results: Patients with converting MCI and stable dementia had lower CSF Aβ42 concentrations and higher T-tau concentrations and NFL in comparison with controls and non-progressive/progressive MCI (p < 0.0005). No differences were found between progressive and non-progressive MCI. Conclusion: As expected, biomarker deviations predicted progression from MCI to dementia. Contrary to our hypothesis, progression from very mild MCI to more pronounced MCI was not reflected by biomarker deviations. The results suggest that the measured biomarkers are not early disease markers, or alternatively Alzheimer or vascular pathology is not the underlying cause in this patient group. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Winblad B, Palmer K, Kivipelto M, Jelic V, Fratiglioni L, Wahlund L-O, Nordberg A, Bäckman L, Albert M, Almkvist O, Arai H, Basun H, Blennow K, de Leon M, DeCarli C, Erkinjuntti T, Giacobini E, Graff C, Hardy J, Jack C, Jorm A, Ritchie K, van Duijn C, Visser P, Petersen RC (Karolinska Institutet, Stockholm, Sweden; John Hopkins University School of Medicine, Baltimore, MD, USA; Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan; Uppsala University, Sweden; Gothenburg University, Sweden; New York University School of Medicine, New York, NY, USA; University of California at Davis, Sacramento, CA, USA; Helsinki University Hospital, Helsinki, Finland; University of Geneva Medical School, Switzerland; National Institute on Aging/National Institute of Health, Bethesda, MD, USA; Mayo Clinic, Rochester, MN, USA; Australian National University, Canberra, Australia; French National Institute of Medical Research (INSERM), Montpellier, France; Erasmus Medical Center, Rotterdam, The Netherlands; University of Maastricht, The Netherlands). Mild cognitive impairment – beyond controversies, towards a consensus: report of the International Working Group on Mild Cognitive Impairment (Key Symposium). J Intern Med 2004; 256: 240–246. The First Key Symposium was held in Stockholm, Sweden, 2–5 September 2003. The aim of the symposium was to integrate clinical and epidemiological perspectives on the topic of Mild Cognitive Impairment (MCI). A multidisciplinary, international group of experts discussed the current status and future directions of MCI, with regard to clinical presentation, cognitive and functional assessment, and the role of neuroimaging, biomarkers and genetics. Agreement on new perspectives, as well as recommendations for management and future research were discussed by the international working group. The specific recommendations for the general MCI criteria include the following: (i) the person is neither normal nor demented; (ii) there is evidence of cognitive deterioration shown by either objectively measured decline over time and/or subjective report of decline by self and/or informant in conjunction with objective cognitive deficits; and (iii) activities of daily living are preserved and complex instrumental functions are either intact or minimally impaired. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a rapidly growing disease that affects millions of people worldwide, therefore there is an urgent need for its early diagnosis and treatment. A huge amount of research studies are performed on possible accurate and reliable diagnostic biomarkers of AD. Due to its direct contact with extracellular space of the brain, cerebrospinal fluid (CSF) is the most useful biological fluid reflecting molecular events in the brain. Proteins and molecules that reflect the pathogenesis of the disease, e.g., neurodegeneration, accumulation of Abeta, hyperphosphorylation of tau protein and apoptosis may be used as biomarkers. The aim of the current manuscript is to present the most commonly used CSF biomarkers for AD as well as novel biomarkers. Three CSF biomarkers, namely total tau, phospho-tau and Abeta42, are believed to have the highest diagnostic accuracy for early AD diagnosis and the ability to predict AD development in mild cognitive impairment (MCI) patients. Moreover, other biomarkers such as soluble amyloid precursor protein (APP), apoptotic proteins, secretases and inflammatory and oxidation markers are believed to have increased future prospects. [ABSTRACT FROM AUTHOR]

Background: The National Institute on Aging-Alzheimer's Association Research Framework proposes defining Alzheimer's disease by grouping imaging and fluid biomarkers by their respective pathologic processes. The AT(N) structure proposes several neurodegenerative fluid biomarkers (N) including total tau (t-tau), neurogranin (Ng), and neurofilament light chain (NfL). However, pathologic drivers influencing each biomarker remain unclear. Objective: To determine whether cerebrospinal fluid (CSF)-neurodegenerative biomarkers (N) map differentially to Alzheimer's disease pathology measured by Aβ42 (an indicator of amyloidosis, [A]), p-tau (an indicator of tau deposition, [T]), and MRI vascular pathology indicators (measured by white-matter integrity, infarcts, and microbleeds [V]). Methods: Participants were from Mayo Clinic Study of Aging (MCSA) with CSF measures of NfL, Ng, t-tau, Aβ42, and p-tau and available MRI brain imaging. Linear models assessed associations between CSF neurodegeneration (N) markers, amyloid markers (A), tau (T), and vascular pathology (V). Results: Participants (n = 408) had a mean age of 69.2±10.7; male, 217 (53.2%); cognitively unimpaired, 359 (88%). All three neurodegeneration biomarkers correlated with age (p < 0.001 for NfL and t-tau, p = 0.018 for Ng). Men had higher CSF-NfL levels; women had higher Ng (p < 0.001). NfL and t-tau levels correlated with infarcts (p = 0.009, p = 0.034 respectively); no biomarkers correlated with white-matter integrity. N biomarkers correlated with p-tau levels (T, p < 0.001). Higher Aβ42 levels associated with higher N-biomarker levels but only among cognitively unimpaired (A, p < 0.001). Conclusion: The influence of vascular pathology in the general population on CSF (N) biomarkers is modest, with greater influence of infarcts than white-matter disruption. Neurodegeneration markers more closely correlated with tau than amyloid markers. [ABSTRACT FROM AUTHOR]

Background: Blood-based biomarkers (BBMs) are of growing interest in the field of Alzheimer's disease (AD) and related dementias. Objective: This study aimed to assess the ability of plasma biomarkers to 1) predict disease progression from mild cognitive impairment (MCI) to dementia and 2) improve the predictive ability of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) measures when combined. Methods: We used data from the Alzheimer's Disease Neuroimaging Initiative. Machine learning models were trained using the data from participants who remained cognitively stable (CN-s) and with Dementia diagnosis at 2-year follow-up visit. The models were used to predict progression to dementia in MCI individuals. We assessed the performance of models with plasma biomarkers against those with CSF and MRI measures, and also in combination with them. Results: Our models with plasma biomarkers classified CN-s individuals from AD with an AUC of 0.75±0.03 and could predict conversion to dementia in MCI individuals with an AUC of 0.64±0.03 (17.1% BP, base prevalence). Models with plasma biomarkers performed better when combined with CSF and MRI measures (CN versus AD: AUC of 0.89±0.02; MCI-to-AD: AUC of 0.76±0.03, 21.5% BP). Conclusions: Our results highlight the potential of plasma biomarkers in predicting conversion to dementia in MCI individuals. While plasma biomarkers could improve the predictive ability of CSF and MRI measures when combined, they also show the potential to predict non-progression to AD when considered alone. The predictive ability of plasma biomarkers is crucially linked to reducing the costly and effortful collection of CSF and MRI measures. [ABSTRACT FROM AUTHOR]

Background: Mild cognitive impairment (MCI) is a heterogeneous condition, and the prognosis differs within the group. Recent findings suggest that hippocampal volumetry and CSF biomarkers can be used to predict which MCI patients have an underlying neurodegenerative disorder. Objective: To examine the combined predictive value of hippocampal volume and CSF levels of total tau (T-tau) and β-amyloid42 (Aβ42) in stable and converting MCI patients. The participants (n = 68) included patients with MCI at baseline and who converted to dementia by the time of the 2-year follow-up (n = 21), stable MCI patients (n = 21) and healthy controls (n = 26). Methods: The Göteborg MCI study is a clinically based longitudinal study with biannual clinical assessments. Hippocampal volumetry was performed manually, based on data from the 0.5-tesla MRI investigations at baseline. Baseline CSF levels of T-tau and Aβ42 were measured using commercially available, enzyme-linked immunosorbent assays. Results: The converting MCI group had significantly smaller left hippocampi, lower CSF Aβ42 and higher T-tau compared to both the stable MCI group and the healthy controls. Multivariate analysis revealed that a combination of the variables outperformed the prognostic ability of the separate variables. Conclusions: Hippocampal volumes supplement the prognostic accuracy of CSF Aβ42 and T-tau in MCI. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Identifying individuals at high risk of developing Alzheimer’s disease (AD) is important for future therapeutic strategies, and there is a clinical need for diagnostic biomarkers to identify incipient AD. Objective: The aim of the present study was to investigate if the AD-associated Aβ peptide pattern recently found in cerebrospinal fluid (CSF) could discriminate between patients with incipient AD and those with stable mild cognitive impairment (MCI) by analyzing CSF from patients with MCI at baseline. Methods: The levels of Aβ1-37, -38, -39, -40, -42 were analyzed by Aβ-SDS-PAGE/immunoblot in CSF from 19 healthy controls, 25 patients with stable MCI and from 25 patients with MCI who later developed AD during 4- to 6-year follow-up. Results: All healthy controls and 20 out of 22 patients who developed AD were correctly classified by their baseline Aβ peptide pattern. In 9 out of 25 stable MCI patients, the pattern indicated incipient AD in spite of clinical nonconversion. Interestingly, these individuals had apolipoprotein E genotypes and CSF levels of tau and phospho-tau that are known to be associated with high risk of AD. Conclusion: Altogether, our study reveals the novel finding that the Aβ peptide pattern is able to predict AD in patients with MCI with a sensitivity of 91% and specificity of 64%. The specificity would increase to 94% if the high-risk patients in the stable MCI cohort developed AD during extended follow-up. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives Cognitive decline is common in Parkinson's disease ( PD), but the underlying mechanisms for this complication are incompletely understood. Genotypes affecting dopamine transmission may be of importance. This study investigates whether genotypes associated with reduced prefrontal dopaminergic tone and/or reduced dopamine D2-receptor availability (Catechol-O-methyltransferase [ COMT] Val158Met genotype and DRD2 C957T genotype) affect the development of cognitive deficits in PD. Materials and methods One hundred and 34 patients with idiopathic PD, participating in a regional, population-based study of incident parkinsonism, underwent genotyping. After extensive baseline investigations (including imaging and biomarker analyses), the patients were followed prospectively during 6-10 years with neuropsychological evaluations, covering six cognitive domains. Cognitive decline (defined as the incidence of either Parkinson's disease mild cognitive impairment [ PD- MCI] or dementia [ PDD], diagnosed according to published criteria and blinded to genotype) was studied as the primary outcome. Results Both genotypes affected cognition, as shown by Cox proportional hazards models. While the COMT 158Val/Val genotype conferred an increased risk of mild cognitive impairment in patients with normal cognition at baseline (hazard ratio: 2.13, P = .023), the DRD2 957T/T genotype conferred an overall increased risk of PD dementia (hazard ratio: 3.22, P < .001). The poorer cognitive performance in DRD2 957T/T carriers with PD occurred mainly in episodic memory and attention. Conclusions The results favor the hypothesis that dopamine deficiency in PD not only relate to mild cognitive deficits in frontostriatal functions, but also to a decline in memory and attention. This could indicate that dopamine deficiency impairs a wide network of brain areas. [ABSTRACT FROM AUTHOR]

Background: Although cerebrospinal fluid (CSF) amyloid-β42 peptide (Aβ42) and phosphorylated tau (p-tau) and blood p-tau are valuable for differential diagnosis of Alzheimer's disease (AD) from cognitively normal (CN) there is a lack of validated biomarkers for mild cognitive impairment (MCI). Objective: This study sought to determine how plasma and CSF protein markers compared in the characterization of MCI and AD status. Methods: This cohort study included Alzheimer's Disease Neuroimaging Initiative (ADNI) participants who had baseline levels of 75 proteins measured commonly in plasma and CSF (257 total, 46 CN, 143 MCI, and 68 AD). Logistic regression, least absolute shrinkage and selection operator (LASSO) and Random Forest (RF) methods were used to identify the protein candidates for the disease classification. Results: We observed that six plasma proteins panel (APOE, AMBP, C3, IL16, IGFBP2, APOD) outperformed the seven CSF proteins panel (VEGFA, HGF, PRL, FABP3, FGF4, CD40, RETN) as well as AD markers (CSF p-tau and Aβ42) to distinguish the MCI from AD [area under the curve (AUC) = 0.75 (plasma proteins), AUC = 0.60 (CSF proteins) and AUC = 0.56 (CSF p-tau and Aβ42)]. Also, these six plasma proteins performed better than the CSF proteins and were in line with CSF p-tau and Aβ42 in differentiating CN versus MCI subjects [AUC = 0.89 (plasma proteins), AUC = 0.85 (CSF proteins) and AUC = 0.89 (CSF p-tau and Aβ42)]. These results were adjusted for age, sex, education, and APOEϵ4 genotype. Conclusions: This study suggests that the combination of 6 plasma proteins can serve as an effective marker for differentiating MCI from AD and CN. [ABSTRACT FROM AUTHOR]

Background: Plasma biomarkers have emerged as a promising approach for characterizing pathophysiology in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Objective: We aimed to characterize plasma biomarkers for AD and neurodegeneration across the AD clinical continuum, and to assess their ability to differentiate between AD, MCI, and normal cognition. Methods: This population-based study engaged 1,446 rural-dwelling older adults (age ≥60 years, 61.0% women) derived from MIND-China; of these, 402 were defined with MCI and 142 with AD. Plasma amyloid-β (Aβ), total tau (t-tau), and neurofilament light chain (NfL) concentrations were analyzed using the Simoa platform. Data were analyzed using linear and logistic regression models, and receiver operating characteristic (ROC) analysis. Results: Across the AD clinical spectrum, plasma Aβ40 and NfL increased, whereas Aβ42/Aβ40 ratio decreased. Plasma t-tau was higher in people with AD dementia than those with MCI or normal cognition. Plasma NfL outperformed other biomarkers in differentiating AD from normal cognition (area under the ROC curve [AUC] = 0.75), but all plasma biomarkers performed poorly to distinguish MCI from normal cognition (AUC <0.60). Plasma NfL in combination with age, sex, education, and APOE genotype yielded the AUC of 0.87 for differentiating between AD and normal cognition, 0.79 between AD and MCI, and 0.64 between MCI and normal cognition. Conclusions: In this Chinese population, AD plasma biomarkers vary by age, sex, and APOE genotype. Plasma Aβ, t-tau, and NfL differ across the AD clinical spectrum, and plasma NfL appears to be superior to plasma Aβ and t-tau for defining the clinical spectrum. [ABSTRACT FROM AUTHOR]

Background: Elevated tau phosphorylation has been linked to the Apolipoprotein E (APOE) ɛ4 allele, which is considered one of the most significant genes related to Alzheimer's disease (AD). However, it is uncertain whether the impact of increased plasma tau phosphorylated at threonine 181 (p-tau181) on memory and executive function decline would be greater among APOEɛ4 carriers. Objective: To investigate the effects of plasma p-tau181 and APOEɛ4 on memory and executive function. Methods: The longitudinal analysis included 608 older adults without dementia (aged 72±7 years; 47% female; follow-up period of 1.59±1.47 years) from the ADNI dataset, including 180 individuals with normal cognition and 429 individuals with mild cognitive impairment. Linear mixed-effects models were utilized to assess the contributions of APOEɛ4 status and plasma p-tau181 to longitudinal changes in memory composite score and executive function composite score. Results: At baseline, the APOEɛ4+/Tau+ group exhibited poorer performance in memory composite score and executive function composite score, and an elevated load of cerebrospinal fluid Aβ and tau pathologies. To further understand longitudinal changes, we compared groups directly based on plasma p-tau181 and APOEɛ4 status (four groups: APOEɛ4–/Tau–, APOEɛ4–/Tau+, APOEɛ4+/Tau–, APOEɛ4+/Tau+). Both the memory composite score and executive function composite score showed a significantly greater decline in the APOEɛ4+/Tau+ group than in all other groups. Conclusions: Our findings indicate that there is an interaction between plasma p-tau181 levels and APOEɛ4 status, which contributes to the longitudinal changes of memory and executive function in older adults without dementia. [ABSTRACT FROM AUTHOR]

Serum light-chain neurofilaments (sNfL) have been investigated as a potential minimally invasive biomarker that could help in the diagnosis of patients with cognitive symptoms. We assessed the correlation between sNfL and cerebrospinal fluid (CSF) biomarkers (sNfL versus CSF NfL, ρ= 0.70, p < 0.001), the performance of sNfL in distinguishing controls from patients (controls versus frontotemporal dementia, area under curve 0.86), and sNfL differences in mild cognitive impairment according to amyloid-β (Aβ) deposition (Aβ versus non-Aβ, p = 0.017). Our results support the role of this biomarker in the screening and risk stratification of patients followed in a neurological consultation of a tertiary center. [ABSTRACT FROM AUTHOR]

An accurate and early diagnosis of Alzheimer's disease (AD) is important to select optimal patient care and is critical in current clinical trials targeting core AD neuropathological features. The past decades, much progress has been made in the development and validation of cerebrospinal fluid (CSF) biomarkers for the biochemical diagnosis of AD, including standardization and harmonization of (pre-) analytical procedures. This has resulted in three core CSF biomarkers for AD diagnostics, namely the 42 amino acid long amyloid-beta peptide (Aβ1-42), total tau protein (T-tau), and tau phosphorylated at threonine 181 (P-tau181). These biomarkers have been incorporated into research diagnostic criteria for AD and have an added value in the (differential) diagnosis of AD and related disorders, including mixed pathologies, atypical presentations, and in case of ambiguous clinical dementia diagnoses. The implementation of the CSF Aβ1-42/Aβ1-40 ratio in the core biomarker panel will improve the biomarker analytical variability, and will also improve early and differential AD diagnosis through a more accurate reflection of pathology. Numerous biomarkers are being investigated for their added value to the core AD biomarkers, aiming at the AD core pathological features like the amyloid mismetabolism, tau pathology, or synaptic or neuronal degeneration. Others aim at non-AD neurodegenerative, vascular or inflammatory hallmarks. Biomarkers are essential for an accurate identification of preclinical AD in the context of clinical trials with potentially disease-modifying drugs. Therefore, a biomarker-based early diagnosis of AD offers great opportunities for preventive treatment development in the near future. [ABSTRACT FROM AUTHOR]

Cerebrospinal fluid (CSF) phosphorylated tau231 (P‐tau231) is associated with neuropathological outcomes of Alzheimer's disease (AD). The invasive access of cerebrospinal fluid has greatly stimulated interest in the identification of blood‐based P‐tau231, and the recent advent of single‐molecule array assay for the quantification of plasma P‐tau231 may provide a turning point to evaluate the usefulness of P‐tau231 as an AD‐related biomarker. Yet, in the plasma P‐tau231 literature, findings with regard to its diagnostic utility have been inconsistent, and thus, we aimed to statistically investigate the potential of plasma P‐tau231 in the context of AD via meta‐analysis. Publications on plasma P‐tau231 were systematically retrieved from PubMed, EMBASE, the Cochrane library and Web of Science databases. A total of 10 studies covering 2007 participants were included, and we conducted random‐effect or fixed‐effect meta‐analysis, sensitivity analysis and publication bias analysis using the STATA SE 14.0 software. According to our quantitative integration, plasma P‐tau231 increased from cognitively unimpaired (CU) populations to mild cognitive impairment to AD and showed significant changes in pairwise comparisons of AD, mild cognitive impairment and CU. Plasma P‐tau231 level was significantly higher in CU controls with positive amyloid‐β (Aβ) status compared with Aβ‐negative CU group. Additionally, the excellent diagnostic accuracy of plasma P‐tau231 for asymptomatic Aβ pathology was verified by the pooled value of area under the receiver operating characteristic curves (standard mean difference [95% confidence interval]:.75 [.69,.81], P < 0.00001). Overall, the increased plasma P‐tau231 concentrations were found in relation to the early development and progression of AD. [ABSTRACT FROM AUTHOR]

Background: Previous studies showed conflicting results regarding soluble triggering receptor expressed on myeloid cells 2 (sTREM2) level alteration in body fluid in Alzheimer's disease (AD) and Parkinson's disease (PD). Methods: We applied the STATA 12.0 software to compute standard mean difference (SMD) and 95% confidence interval (CI). Results: The study showed elevated sTREM2 level in cerebrospinal fluid (CSF) in AD, mild cognitive impairment (MCI), and preclinical AD (pre-AD) patients, compared to healthy controls (HCs) with random effects models (AD: SMD 0.28, 95% CI 0.12 to 0.44, I2 = 77.6%, p < 0.001; MCI: SMD 0.29, 95% CI 0.09 to 0.48, I2 = 89.7%, p < 0.001; pre-AD: SMD 0.24, 95% CI 0.00 to 0.48, I2 = 80.8%, p < 0.001). The study showed no significant difference in sTREM2 level in plasma between AD patients and HCs with a random effects model (SMD 0.06, 95% CI − 0.16 to 0.28, I2 = 65.6%, p = 0.008). The study showed no significant difference in sTREM2 level in CSF or plasma between PD patients and HCs with random effects models (CSF: SMD 0.33, 95% CI − 0.02 to 0.67, I2 = 85.6%, p < 0.001; plasma: SMD 0.37, 95% CI − 0.17 to 0.92, I2 = 77.8%, p = 0.011). Conclusions: In conclusion, the study highlighted the CSF sTREM2 as a promising biomarker in the different clinical stages of AD. More studies were essential to explore the CSF and plasmatic concentrations of sTREM2 alteration in PD. [ABSTRACT FROM AUTHOR]

Background: Accessible measurements for the early detection of mild cognitive impairment (MCI) due to Alzheimer's disease (AD) are urgently needed to address the increasing prevalence of AD. Objective: To determine the benefits of a composite MemTrax Memory Test and AD-related blood biomarker assessment for the early detection of MCI-AD in non-specialty clinics. Methods: The MemTrax Memory Test and Montreal Cognitive Assessment were administered to 99 healthy seniors with normal cognitive function and 101 patients with MCI-AD; clinical manifestation and peripheral blood samples were collected. We evaluated correlations between the MemTrax Memory Test and blood biomarkers using Spearman's rank correlation analyses and then built discrimination models using various machine learning approaches that combined the MemTrax Memory Test and blood biomarker results. The models' performances were assessed according to the areas under the receiver operating characteristic curve. Results: The MemTrax Memory Test and Montreal Cognitive Assessment areas under the curve for differentiating patients with MCI-AD from the healthy controls were similar. The MemTrax Memory Test strongly correlated with phosphorylated tau 181 and amyloid-β42/40. The area under the curve for the best composite MemTrax Memory Test and blood biomarker model was 0.975 (95% confidence interval: 0.950–0.999). Conclusion: Combining MemTrax Memory Test and blood biomarker results is a promising new technique for the early detection of MCI-AD. [ABSTRACT FROM AUTHOR]

Background: Evidence for the universal presence of IgG autoantibodies in blood and their potential utility for the diagnosis of Alzheimer's disease (AD) and other neurodegenerative diseases has been extensively demonstrated by our laboratory. The fact that AD-related neuropathological changes in the brain can begin more than a decade before tell-tale symptoms emerge has made it difficult to develop diagnostic tests useful for detecting the earliest stages of AD pathogenesis. Objective: To determine the utility of a panel of autoantibodies for detecting the presence of AD-related pathology along the early AD continuum, including at pre-symptomatic [an average of 4 years before the transition to mild cognitive impairment (MCI)/AD)], prodromal AD (MCI), and mild-moderate AD stages. Methods: A total of 328 serum samples from multiple cohorts, including ADNI subjects with confirmed pre-symptomatic, prodromal, and mild-moderate AD, were screened using Luminex xMAP® technology to predict the probability of the presence of AD-related pathology. A panel of eight autoantibodies with age as a covariate was evaluated using randomForest and receiver operating characteristic (ROC) curves. Results: Autoantibody biomarkers alone predicted the probability of the presence of AD-related pathology with 81.0% accuracy and an area under the curve (AUC) of 0.84 (95% CI = 0.78–0.91). Inclusion of age as a parameter to the model improved the AUC (0.96; 95% CI = 0.93–0.99) and overall accuracy (93.0%). Conclusion: Blood-based autoantibodies can be used as an accurate, non-invasive, inexpensive, and widely accessible diagnostic screener for detecting AD-related pathology at pre-symptomatic and prodromal AD stages that could aid clinicians in diagnosing AD. [ABSTRACT FROM AUTHOR]

Background: The primary manifestations of Alzheimer's disease (AD) include cognitive decline and brain gray matter volume (GMV) atrophy. Recent studies have found that plasma phosphorylated-tau (p-tau) concentrations perform better in diagnosing, differentiating, and monitoring the progression of AD. However, the correlation between plasma p-tau, GMV, and cognition remains unclear. Objective: To investigate whether GMV plays a mediating role in the association between plasma p-tau concentrations and cognition. Methods: In total, 99 participants (47 patients with AD and 52 cognitively unimpaired [CU] individuals) were included. All participants underwent neuropsychological assessments, laboratory examinations, and magnetic resonance imaging scans. Plasma p-tau217 and p-tau181 concentrations were measured using an enzyme-linked immunosorbent assay kit. Voxel-based morphometry was performed to assess participants' brain GMV. Partial correlation and mediation analyses were conducted in AD group. Results: Plasma p-tau concentrations were significantly higher in the AD group than in the CU group. Patients with AD had significant brain GMV atrophy in the right hippocampus, bilateral middle temporal gyrus, and right inferior temporal gyrus. In the AD group, there were significant correlations between plasma p-tau217 concentrations, GMV, and Mini-Mental State Examination (MMSE) scores. Brain GMV of the right hippocampus mediated the association between plasma p-tau217 concentrations and MMSE scores. A significant correlation between plasma p-tau181 and MMSE scores was not identified. Conclusion: The findings indicate that p-tau217 is a promising biomarker for central processes affecting brain GMV and cognitive function. This may provide potential targets for future intervention and treatment of tau-targeting therapies in the early stages of AD. [ABSTRACT FROM AUTHOR]

Background: YKL-40 and neurogranin are promising additional cerebrospinal fluid (CSF) biomarkers for Alzheimer's disease (AD) which reflect different underlying disease mechanisms.Objective: To compare the levels of CSF YKL-40 and neurogranin between asymptomatic carriers of familial AD (FAD) mutations (MC) and non-carriers (NC) from the same families. Another objective was to assess changes in YKL-40 and neurogranin, from the presymptomatic to clinical phase of FAD.Methods: YKL-40 and neurogranin, as well as Aβ42, total tau-protein, and phospho-tau, were measured in the CSF of 14 individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G), and PSEN1 (p.H163Y), as well as in 17 NC from the same families. Five of the MC developed mild cognitive impairment (MCI) during follow-up.Results: In this pilot study, there was no difference in either CSF YKL-40 or neurogranin when comparing the presymptomatic MC to the NC. YKL-40 correlated positively with expected years to symptom onset and to age in both the MC and the NC, while neurogranin had no correlation to either variable in either of the groups. A subgroup of the participants underwent more than one CSF sampling in which half of the MC developed MCI during follow-up. The longitudinal data showed an increase in YKL-40 levels in the MC as the expected symptom onset approached. Neurogranin remained stable over time in both the MC and the NC.Conclusion: These findings support a positive correlation between progression from presymptomatic to symptomatic AD and levels of CSF YKL-40, but not neurogranin. [ABSTRACT FROM AUTHOR]

Background. According to recent studies, amyloid-β (Aβ) isoforms as cerebrospinal fluid (CSF) biomarkers have remarkable predictive value for cognitive decline in the early stages of Alzheimer's disease (AD). Herein, we aimed to investigate the correlations between several targeted proteomics in CSF samples with Aβ ratios and cognitive scores in patients in AD spectrum to search for potential early diagnostic utility. Methods. A total of 719 participants were found eligible for inclusion. Patients were then categorized into cognitively normal (CN), mild cognitive impairment (MCI), and AD and underwent an assessment of Aβ and proteomics. Clinical Dementia Rating (CDR), Alzheimer's Disease Assessment Scale (ADAS), and Mini Mental State Exam (MMSE) were used for further cognitive assessment. The Aβ42, Aβ42/Aβ40, and Aβ42/38 ratios were considered as means of comparison to identify those peptides corresponding significantly to these established biomarkers and cognitive scores. The diagnostic utility of the IASNTQSR, VAELEDEK, VVSSIEQK, GDSVVYGLR, EPVAGDAVPGPK, and QETLPSK was assessed. Results. All investigated peptides corresponded significantly to Aβ42 in controls. In those with MCI, VAELEDEK and EPVAGDAVPGPK were significantly correlated with Aβ42 (p value < 0.001). Additionally, IASNTQSR, VVSSIEQK, GDSVVYGLR, and QETLPSK were significantly correlated with Aβ42/Aβ40 and Aβ42/38 (p value < 0.001) in this group. This group of peptides similarly corresponded to Aβ ratios in those with AD. Eventually, IASNTQSR, VAELEDEK, and VVSSIEQK were significantly associated with CDR, ADAS-11, and ADAS-13, particularly in MCI group. Conclusion. Our research suggests potential early diagnostic and prognostic utilities for certain peptides extracted from CSF-targeted proteomics research. The ethical approval of ADNI is available at ClinicalTrials.gov with Identifier: NCT00106899. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) dementia is the most frequent cause of neurodegenerative dementia. The cognitive and behavioral symptoms associated with this disorder often have overlapping characteristics, potentially resulting in delayed diagnosis or misdiagnosis. This study aimed to assess the level of peripheral blood neurofilament light chain (NfL) and total tau (t-tau) protein in AD patients and investigate their relationship with cognitive impairment. The study included 80 participants of both sexes between the ages of 60 to 85 years. The participants were divided into two groups, consisting of 40 individuals in the control group (mean age 75±6.6 years) who had no cognitive or functional impairments and 40 AD patients (mean age 74.98±5.03 years). This study utilized the DSM-5 diagnostic criteria for major or mild neurocognitive disorder attributed to Alzheimer's disease (AD). The clinical and biochemical features of all participants were documented, and the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-cog) scores were evaluated. Sandwich ELISA was employed to determine serum NfL and t-tau protein levels. The median serum NfL and t-tau protein levels in AD patients were significantly higher than those of the controls (47.84 pg/ml versus 17.66 pg/ml and 12.05 pg/ml versus 11.13 pg/ml, respectively). Age was positively correlated with NfL, t-tau levels, and ADAS-cog. Although elevated NfL and t-tau protein levels may play a role in disease progression, their diagnostic value for AD was limited. [ABSTRACT FROM AUTHOR]

Background: Imbalance between the production and clearance of amyloid-β (Aβ) promotes the development of Alzheimer's disease (AD). Presenilin-1 (PS1) is the catalytic subunit of γ-secretase, which is involved in the process of Aβ production. The profiles of autoantibodies are dysregulated in AD patients. Objective: This study aims to investigate the relative levels and clinical relevance of naturally occurring antibodies to PS1 (NAbs-PS1) in AD. Methods: A total of 55 subjects with AD (including both dementia and mild cognitive impairment due to AD), 28 subjects with cognitive impairment (including both dementia and mild cognitive impairment) not due to AD (non-AD CI), and 70 cognitively normal (CN) subjects were recruited. One-site ELISA was utilized to determine the relative levels of NAbs-PS1 in plasma. Results: AD subjects had lower plasma levels of NAbs-PS1 than CN and non-AD CI subjects. Plasma NAbs-PS1 were negatively associated with the brain Aβ load, as reflected by PET-PiB SUVR, and were positively associated with cognitive functions of participants. Plasma NAbs-PS1 discriminated AD patients from CN with an area under the curve (AUC) of 0.730, a sensitivity of 69.09%, and a specificity of 67.14%, and they discriminated AD patients from non-AD CI subjects with an AUC of 0.750, a specificity of 70.91%, and a sensitivity of 71.43%. Conclusion: This study found an aberrant immunological phenotype in AD patients. Further investigations are needed to determine the pathophysiological functions of NAbs-PS1 in AD. [ABSTRACT FROM AUTHOR]

Cellular senescence, a hallmark of aging, plays an important role in age-related conditions among older adults. Targeting senescent cells and its phenotype may provide a promising strategy to delay the onset or progression of Alzheimer's disease (AD). In this review article, we investigated efficacy and safety of nutrition senotherapy in AD, with a focus on the role of polyphenols as current and potential nutrition senotherapeutic agents, as well as relevant dietary patterns. Promising results with neuroprotective effects of senotherapeutic agents such as quercetin, resveratrol, Epigallocatechin-gallate, curcumin and fisetin were reported from preclinical studies. However, in-human trials remain limited, and findings were inconclusive. In future, nutrition senotherapeutic agents should be studied both individually and within dietary patterns, through the perspective of cellular senescence and AD. Further studies are warranted to investigate bioavailability, dosing regimen, long term effects of nutrition senotherapy and provide better understanding of the underlying mechanisms. Collaboration between researchers needs to be established, and methodological limitations of current studies should be addressed. [ABSTRACT FROM AUTHOR]

Background: Epidemiology cohorts reveal associations between levels or intake of omega-3 polyunsaturated fatty acids (n-3 PUFA) and a lower risk of Alzheimer's disease (AD). However, the results of randomized clinical trials have been inconsistent. Objective: A systematic review was performed to understand the effects of n-3 PUFA supplementation on cognition in adults. The objective was to present suggestions for new study designs to translate epidemiological findings into effective clinical trials. Methods: A database search was conducted on PubMed (MEDLINE) and Web of Science to retrieve articles published between 2000 and 2023 that evaluated the effects of n-3 PUFA supplementation on cognitive function. Subsequently, the search results were filtered to collect randomized controlled trials with 100 or more participants, n-3 PUFA supplementation was one of the interventions, cognition was an outcome of interest, and participants were at least 18 years of age. Results: A total of 24 articles met the inclusion criteria. In 5 of the 24 studies reviewed, supplementation with n-3 PUFAs improved cognition. All four trials in persons with AD reported null outcomes. Most of the n-3 PUFA studies in cognitively normal individuals or participants with mild cognitive impairment were null, not powered to detect small effect sizes, or selected participants without dementia risk factors. Conclusions: We recommend that newer n-3 PUFA supplement trials targeting AD prevention be personalized. For the general population, the null hypothesis appears to be correct, and future interventions are needed to identify and test dietary patterns that include PUFA-rich food rather than supplements. [ABSTRACT FROM AUTHOR]

Hippocampal dysfunction is associated with early clinical signs of Alzheimer's disease (AD). Due to the limited availability or invasiveness of current biomarkers, the AD diagnosis is usually based on cognitive assessment and structural brain imaging. The recent study by Lalive and colleagues examined the specificity of brain morphometry for the AD diagnosis in a memory clinic cohort with hippocampal-type amnestic syndrome. The results indicate that memory deficits and hippocampal atrophy are similar in AD and non-AD patients, highlighting their low diagnostic specificity. These findings challenge the traditional AD diagnosis and underscore the need for biomarkers to differentiate specific neuropathological entities. [ABSTRACT FROM AUTHOR]

Background: Early detection of amyloid-β (Aβ) positivity is essential for an accurate diagnosis and treatment of Alzheimer's disease (AD), but it is currently costly and/or invasive. Objective: We aimed to classify Aβ positivity (Aβ+) using morphometric features from magnetic resonance imaging (MRI), a more accessible and non-invasive technique, in two clinical population scenarios: one containing AD, mild cognitive impairment (MCI) and cognitively normal (CN) subjects, and another only cognitively impaired subjects (AD and MCI). Methods: Demographic, cognitive (Mini-Mental State Examination [MMSE] scores), regional morphometry MRI (volumes, areas, and thicknesses), and derived morphometric graph theory (GT) features from all subjects (302 Aβ+, age: 73.3±7.2, 150 male; 246 Aβ–, age: 71.1±7.1, 131 male) were combined in different feature sets. We implemented a machine learning workflow to find the best Aβ+ classification model. Results: In an AD+MCI+CN population scenario, the best-performing model selected 120 features (107 GT features, 12 regional morphometric features and the MMSE total score) and achieved a negative predictive value (NPVadj) of 68.4%, and a balanced accuracy (BAC) of 66.9%. In a AD+MCI scenario, the best model obtained NPVadj of 71.6%, and BAC of 70.7%, using 180 regional morphometric features (98 volumes, 52 areas and 29 thicknesses from temporal, parietal, and frontal brain regions). Conclusions: Although with currently limited clinical applicability, regional MRI morphometric features have clinical usefulness potential for detecting Aβ status, which may be augmented by a combination with cognitive data when cognitively normal subjects make up a substantial part of the population presenting for diagnosis. [ABSTRACT FROM AUTHOR]

Background: Tau-PET is a diagnostic tool with high sensitivity and specificity for discriminating Alzheimer's disease (AD) dementia from other neurodegenerative disorders in well-controlled research environments. The role of tau-PET in real-world clinical practice, however, remains to be established. The aim of the TAP-TAU study is therefore to investigate the impact of tau-PET in clinical practice. Methods: TAP-TAU is a prospective, longitudinal multi-center study in 300 patients (≥ 50 years old) with mild cognitive impairment or mild dementia across five Dutch memory clinics. Patients are eligible if diagnostic certainty is < 85% after routine dementia screening and if the differential diagnosis includes AD. More specifically, we will include patients who (i) are suspected of having mixed pathology (e.g., AD and vascular pathology), (ii) have an atypical clinical presentation, and/or (iii) show conflicting or inconclusive outcomes on other tests (e.g., magnetic resonance imaging or cerebrospinal fluid). Participants will undergo a [18F]flortaucipir tau-PET scan, blood-based biomarker sampling, and fill out questionnaires on patient reported outcomes and experiences. The primary outcomes are change (pre- versus post- tau-PET) in diagnosis, diagnostic certainty, patient management and patient anxiety and uncertainty. Secondary outcome measures are head-to-head comparisons between tau-PET and less invasive and lower cost diagnostic tools such as novel blood-based biomarkers and artificial intelligence-based classifiers. Results: TAP-TAU has been approved by the Medical Ethics Committee of the Amsterdam UMC. The first participant is expected to be included in October 2024. Conclusions: In TAP-TAU, we will investigate the added clinical value of tau-PET in a real-world clinical setting, including memory clinic patients with diagnostic uncertainty after routine work-up. Findings of our study may contribute to recommendations regarding which patients would benefit most from assessment with tau-PET. This study is timely in the dawning era of disease modifying treatments as an accurate etiological diagnosis becomes increasingly important. Trial registration: This trial is registered and authorized on December 21st, 2023 in EU Clinical Trials with registration number 2023-505430-10-00. [ABSTRACT FROM AUTHOR]

The Bio-Hermes Study was a cross-sectional observational study designed to develop a database of blood-based and digital biomarkers to improve detection of Alzheimer's disease (AD) and mild cognitive impairment (MCI). We examined the ability of Cognivue Clarity to (a) detect MCI and AD in clinical diagnostics groups, (b) determine the presence of amyloid, and (c) distinguish between biomarker-confirmed groups. Bio-Hermes enrolled 887 participants who completed both Cognivue Clarity and amyloid PET scans (388 Cognitively Normal, 282 MCI, 217 Probable AD). Cognivue Clarity differentiated between Cognitively Normal, MCI, and probable AD in clinical cohorts, amyloid positive from amyloid negative individuals, and True Controls from MCI due to AD and AD in biomarker-confirmed cohorts (all p < 0.001) with large effect sizes. Cognivue Clarity correlated with amyloid PET and plasma amyloid and pTau (all p < 0.001). In biomarker confirmed groups, Cognivue Clarity had a positive likelihood ratio of 2.17, a negative likelihood ratio of 0.29, and a diagnostic odds ratio of 7.48. Cognivue Clarity detected cognitive impairment and differentiated between both clinically and biomarker defined MCI and AD groups. The use of Cognivue Clarity could assist with identification of MCI-AD or AD for inclusion into current treatment protocols or for enriching recruitment into clinical trials. Trial registration ClinicalTrials.gov (NCT04733989). [ABSTRACT FROM AUTHOR]

Objectives: The aim was to develop and validate the Communities Geriatric Mild Cognitive Impairment Risk Calculator (CGMCI-Risk), aiding community healthcare workers in the early identification of individuals at high risk of mild cognitive impairment (MCI). Methods: Based on nationally representative community survey data, backward stepwise regression was employed to screen the variables, and logistic regression was utilized to construct the CGMCI-Risk. Internal validation was conducted using bootstrap resampling, while external validation was performed using temporal validation. The area under the receiver operating characteristic curve (AUROC), calibration curve, and decision curve analysis (DCA) were employed to evaluate the CGMCI-Risk in terms of discrimination, calibration, and net benefit, respectively. Results: The CGMCI-Risk model included variables such as age, educational level, sex, exercise, garden work, TV watching or radio listening, Instrumental Activity of Daily Living (IADL), hearing, and masticatory function. The AUROC was 0.781 (95% CI = 0.766 to 0.796). The calibration curve showed strong agreement, and the DCA suggested substantial clinical utility. In external validation, the CGMCI-Risk model maintained a similar performance with an AUROC of 0.782 (95% CI = 0.763 to 0.801). Conclusions: CGMCI-Risk is an effective tool for assessing cognitive function risk within the community. It uses readily predictor variables, allowing community healthcare workers to identify the risk of MCI in older adults over a three-year span. [ABSTRACT FROM AUTHOR]

Background: In Alzheimer's disease (AD), the associations between tau pathology and brain atrophy and cognitive decline are well established, but imperfect. We investigate whether cerebrospinal fluid (CSF) biomarkers of biological processes (vascular, synaptic, and axonal integrity, neuroinflammation, neurotrophic factors) explain the disconnection between tau pathology and brain atrophy (brain resilience), and tau pathology and cognitive decline (cognitive resilience). Methods: We included 428 amyloid positive participants (134 cognitively unimpaired (CU), 128 with mild cognitive impairment (MCI), 166 with AD dementia) from the BioFINDER-2 study. At baseline, participants underwent tau positron emission tomography (tau-PET), magnetic resonance imaging (MRI), cognitive testing, and lumbar puncture. Longitudinal data were available for MRI (mean (standard deviation) follow-up 26.4 (10.7) months) and cognition (25.2 (11.4) months). We analysed 18 pre-selected CSF proteins, reflecting vascular, synaptic, and axonal integrity, neuroinflammation, and neurotrophic factors. Stratifying by cognitive status, we performed linear mixed-effects models with cortical thickness (brain resilience) and global cognition (cognitive resilience) as dependent variables to assess whether the CSF biomarkers interacted with tau-PET levels in its effect on cortical atrophy and cognitive decline. Results: Regarding brain resilience, interaction effects were observed in AD dementia, with vascular integrity biomarkers (VEGF-A (βinteraction = -0.009, pFDR = 0.047) and VEGF-B (βinteraction = -0.010, pFDR = 0.037)) negatively moderating the association between tau-PET signal and atrophy. In MCI, higher NfL levels were associated with more longitudinal cortical atrophy (β = -0.109, pFDR = 0.033) and lower baseline cortical thickness (β = -0.708, pFDR = 0.033) controlling for tau-PET signal. Cognitive resilience analyses in CU revealed interactions with tau-PET signal for inflammatory (GFAP, IL-15; βinteraction -0.073–-0.069, pFDR 0.001–0.045), vascular (VEGF-A, VEGF-D, PGF; βinteraction -0.099–-0.063, pFDR < 0.001–0.046), synaptic (14–3-3ζ/δ; βinteraction = -0.092, pFDR = 0.041), axonal (NfL; βinteraction = -0.079, pFDR < 0.001), and neurotrophic (NGF; βinteraction = 0.091, pFDR < 0.001) biomarkers. In MCI higher NfL levels (βmain = -0.690, pFDR = 0.025) were associated with faster cognitive decline independent of tau-PET signal. Conclusions: Biomarkers of co-existing pathological processes, in particular vascular pathology and axonal degeneration, interact with levels of tau pathology on its association with the downstream effects of AD pathology (i.e. brain atrophy and cognitive decline). This indicates that vascular pathology and axonal degeneration could impact brain and cognitive resilience. [ABSTRACT FROM AUTHOR]

Background: Early detection of Alzheimer's disease (AD) is essential for timely management and consideration of therapeutic options; therefore, detecting the risk of conversion from mild cognitive impairment (MCI) to AD is crucial during neurodegenerative progression. Existing neuroimaging studies have mostly focused on group differences between individuals with MCI (or AD) and cognitively normal (CN), discarding the temporal information of conversion time. Here, we aimed to develop a prognostic model for AD conversion using functional connectivity (FC) and Cox regression suitable for conversion event modeling. Methods: We developed a prognostic model using a large-scale Alzheimer's Disease Neuroimaging Initiative dataset, and it was validated using external data obtained from the Open Access Series of Imaging Studies. We considered individuals who were initially CN or had MCI but progressed to AD and those with MCI with no progression to AD during the five-year follow-up period. As the exact conversion time to AD is unknown, we inferred this information using imputation approaches. We generated cortex-wide principal FC gradients using manifold learning techniques and computed subcortical-weighted manifold degrees from baseline functional magnetic resonance imaging data. A penalized Cox regression model with an elastic net penalty was adopted to define a risk score predicting the risk of conversion to AD, using FC gradients and clinical factors as regressors. Results: Our prognostic model predicted the conversion risk and confirmed the role of imaging-derived manifolds in the conversion risk. The brain regions that largely contributed to predicting AD conversion were the heteromodal association and visual cortices, as well as the caudate and hippocampus. Our risk score based on Cox regression was consistent with the expected disease trajectories and correlated with positron emission tomography tracer uptake and symptom severity, reinforcing its clinical usefulness. Our findings were validated using an independent dataset. The cross-sectional application of our model showed a higher risk for AD than that for MCI, which correlated with symptom severity scores in the validation dataset. Conclusion: We proposed a prognostic model predicting the risk of conversion to AD. The associated risk score may provide insights for early intervention in individuals at risk of AD conversion. [ABSTRACT FROM AUTHOR]

The prevalence of dementia, a condition associated with high social costs, is rising alongside the aging population. Early diagnosis of mild cognitive impairment (MCI), a precursor to dementia, is essential for effective intervention. Recent research has focused on diagnosing cognitive function in the elderly by analyzing behavioral data, such as gait and hand movements. Compared to traditional neuropsychological assessment methods, behavioral data-based assessments offer advantages, including reduced fatigue for patients and examiners, faster testing procedures, and more objective evaluation of results. This study reviews 15 research projects from the past five years (2018–2023) that have utilized behavioral data to assess cognitive function. It examines the specific gait and hand movement variables used, the technologies implemented, and user experiences reported in these studies. As these types of assessments require new technologies or environments, we analyzed usability issues that should be considered for accurate cognitive assessment. Based on this analysis, the paper proposes future directions for research in the field of behavioral data-based cognitive function assessment. [ABSTRACT FROM AUTHOR]

The co-occurrence of Alzheimer's disease (AD) and cardiovascular diseases (CVDs) in older adults highlights the necessity for the exploration of potential shared risk factors. A total of 566 adults were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database, including 111 individuals with AD, 383 with mild cognitive impairment (MCI), and 410 with CVD. The multivariable linear mixed model (LMM) was used to investigate the associations of AD and CVD with longitudinal changes in 146 plasma proteomic biomarkers (measured at baseline and the 12-month follow-up). The LMM showed that 48 biomarkers were linked to AD and 46 to CVD (p < 0.05). Both AD and CVD were associated with longitudinal changes in 14 biomarkers (α1Micro, ApoH, β2M, BNP, complement C3, cystatin C, KIM1, NGAL, PPP, TIM1, THP, TFF3, TM, and VEGF), and both MCI and CVD were associated with 12 biomarkers (ApoD, AXL, BNP, Calcitonin, CD40, C-peptide, pM, PPP, THP, TNFR2, TTR, and VEGF), suggesting intricate connections between cognitive decline and cardiovascular health. Among these, the Tamm Horsfall Protein (THP) was associated with AD, MCI, CVD, and APOE-ε4. This study provides valuable insights into shared and distinct biological markers and mechanisms underlying AD and CVD. [ABSTRACT FROM AUTHOR]

This cohort study investigates the risk of mild cognitive impairment, Alzheimer disease, and all-cause dementia associated with subjective cognitive decline using the subjective cognitive decline–plus criteria among cognitively normal adults in the community. Key Points: Question: Among cognitively normal adults in the community, what is the risk from subjective cognitive decline (SCD), using SCD-plus (SCD+) criteria and assessed longitudinally, associated with mild cognitive impairment (MCI), Alzheimer disease (AD), and all-cause dementia? Findings: In this cohort study using longitudinal data from the Framingham Heart Study including 3585 participants, SCD+ was significantly associated with survival time to MCI, AD, and all-cause dementia. Associations were independent of APOE status and an AD polygenic risk score. Meaning: In a community setting, SCD+ was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. Importance: Subjective cognitive decline (SCD) is recognized to be in the Alzheimer disease (AD) cognitive continuum. The SCD Initiative International Working Group recently proposed SCD-plus (SCD+) features that increase risk for future objective cognitive decline but that have not been assessed in a large community-based setting. Objective: To assess SCD risk for mild cognitive impairment (MCI), AD, and all-cause dementia, using SCD+ criteria among cognitively normal adults. Design, Setting, and Participants: The Framingham Heart Study, a community-based prospective cohort study, assessed SCD between 2005 and 2019, with up to 12 years of follow-up. Participants 60 years and older with normal cognition at analytic baseline were included. Cox proportional hazards (CPH) models were adjusted for baseline age, sex, education, APOE ε4 status, and tertiles of AD polygenic risk score (PRS), excluding the APOE region. Data were analyzed from May 2021 to November 2023. Exposure: SCD was assessed longitudinally using a single question and considered present if endorsed at the last cognitively normal visit. It was treated as a time-varying variable, beginning at the first of consecutive, cognitively normal visits, including the last, at which it was endorsed. Main Outcomes and Measures: Consensus-diagnosed MCI, AD, and all-cause dementia. Results: This study included 3585 participants (mean [SD] baseline age, 68.0 [7.7] years; 1975 female [55.1%]). A total of 1596 participants (44.5%) had SCD, and 770 (21.5%) were carriers of APOE ε4. APOE ε4 and tertiles of AD PRS status did not significantly differ between the SCD and non-SCD groups. MCI, AD, and all-cause dementia were diagnosed in 236 participants (6.6%), 73 participants (2.0%), and 89 participants (2.5%), respectively, during follow-up. On average, SCD preceded MCI by 4.4 years, AD by 6.8 years, and all-cause dementia by 6.9 years. SCD was significantly associated with survival time to MCI (hazard ratio [HR], 1.57; 95% CI, 1.22-2.03; P <.001), AD (HR, 2.98; 95% CI, 1.89-4.70; P <.001), and all-cause dementia (HR, 2.14; 95% CI, 1.44-3.18; P <.001). After adjustment for APOE and AD PRS, the hazards of SCD were largely unchanged. Conclusions and Relevance: Results of this cohort study suggest that in a community setting, SCD reflecting SCD+ features was associated with an increased risk of future MCI, AD, and all-cause dementia with similar hazards estimated in clinic-based settings. SCD may be an independent risk factor for AD and other dementias beyond the risk incurred by APOE ε4 and AD PRS. [ABSTRACT FROM AUTHOR]

Background: Apolipoprotein E (APOE) genotypes have been suggested to influence cognitive impairment and clinical onset in presenilin-1 (PSEN1) E280A carriers for autosomal dominant Alzheimer's disease (ADAD). Less is known about their impact on the trajectory of biomarker changes. Neurofilament light chain (NfL), a marker of neurodegeneration, begins to accumulate in plasma about 20 years prior to the clinical onset of ADAD. In this study we investigated the impact of APOE ε4 and ε2 variants on age-related plasma NfL increases and cognition in PSEN1 E280A mutation carriers. Methods: We analyzed cross-sectional data from PSEN1 E280A mutation carriers and non-carriers recruited from the Alzheimer's Prevention Initiative Registry of ADAD. All participants over 18 years with available APOE genotype, plasma NfL, and neuropsychological evaluation were included in this study. APOE genotypes and plasma NfL concentrations were characterized for each participant. Cubic spline models using a Hamiltonian Markov chain Monte Carlo method were used to characterize the respective impact of at least one APOE ε4 or ε2 allele on age-related log-transformed plasma NfL increases. Linear regression models were estimated to explore the impact of APOE ε4 and ε2 variants and plasma NfL on a composite cognitive test score in the ADAD mutation carrier and non-carrier groups. Results: Analyses included 788 PSEN1 E280A mutation carriers (169 APOE ε4 + , 114 ε2 +) and 650 mutation non-carriers (165 APOE ε4 + , 80 ε2 +), aged 18–75 years. APOE ε4 allele carriers were distinguished from ε4 non-carriers by greater age-related NfL elevations in the ADAD mutation carrier group, beginning about three years after the mutation carriers' estimated median age at mild cognitive impairment onset. APOE ε2 allele carriers had lower plasma NfL concentrations than ε2 non-carriers in both the ADAD mutation carrier and non-carrier groups, unrelated to age, and an attenuated relationship between higher NfL levels on cognitive decline in the ADAD mutation carrier group. Conclusions: APOE ε4 accelerates age-related plasma NfL increases and APOE ε2 attenuates the relationship between higher plasma NfL levels and cognitive decline in ADAD. NfL may be a useful biomarker to assess clinical efficacy of APOE-modifying drugs with the potential to help in the treatment and prevention of ADAD. [ABSTRACT FROM AUTHOR]

Biomarkers that accurately identify mild cognitive impairment (MCI) are of greater importance for Alzheimer's disease (AD) management and treatment. On the other hand, blood-based biomarkers are not only more practical but also less invasive than the common cerebrospinal fluid biomarkers. In their report in the Journal of Alzheimer's Disease, Wang and collaborators identified 67 upregulated and 220 downregulated long noncoding RNAs (lncRNAs). They further demonstrated that 4 of these lncRNAs could discriminate MCI from cognitively healthy individuals. Apart from their significance as potential biomarkers for MCI diagnosis, these lncRNAs can offer additional information on the cellular mechanisms of AD pathology. [ABSTRACT FROM AUTHOR]

Introduction: The prediction of progression from mild cognitive impairment (MCI) to Alzheimer's disease (AD) is an important clinical challenge. This study aimed to identify the independent risk factors and develop a nomogram model that can predict progression from MCI to AD. Methods: Data of 141 patients with MCI were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. We set a follow-up time of 72 months and defined patients as stable MCI (sMCI) or progressive MCI (pMCI) according to whether or not the progression of MCI to AD occurred. We identified and screened independent risk factors by utilizing weighted gene co-expression network analysis (WGCNA), where we obtained 14,893 genes after data preprocessing and selected the soft threshold b = 7 at an R² of 0.85 to achieve a scale-free network. A total of 14 modules were discovered, with the midnightblue module having a strong association with the prognosis of MCI. Using machine learning strategies, which included the least absolute selection and shrinkage operator and support vector machine-recursive feature elimination; and the Cox proportional-hazardsmodel, which included univariate and multivariable analyses, we identified and screened independent risk factors. Subsequently, we developed a nomogram model for predicting the progression from MCI to AD. The performance of our nomogram was evaluated by the C-index, calibration curve, and decision curve analysis (DCA). Bioinformatics analysis and immune infiltration analysis were conducted to clarify the function of early B cell factor 1 (EBF1). Results: First, the results showed that 40 differentially expressed genes (DEGs) related to the prognosis of MCI were generated by weighted gene co-expression network analysis. Second, five hub variables were obtained through the abovementioned machine learning strategies. Third, a low Montreal Cognitive Assessment (MoCA) score [hazard ratio (HR): 4.258, 95% confidence interval (CI): 1.994-9.091] and low EBF1 expression (hazard ratio: 3.454, 95% confidence interval: 1.813-6.579) were identified as the independent risk factors through the Cox proportional-hazards regression analysis. Finally, we developed a nomogrammodel including the MoCA score, EBF1, and potential confounders (age and gender). By evaluating our nomogram model and validating it in both internal and external validation sets, we demonstrated that our nomogrammodel exhibits excellent predictive performance. Through the Gene Ontology (GO) enrichment analysis, Kyoto Encyclopedia of Genes Genomes (KEGG) functional enrichment analysis, and immune infiltration analysis, we found that the role of EBF1 in MCI was closely related to B cells. Conclusion: EBF1, as a B cell-specific transcription factor, may be a key target for predicting progression from MCI to AD. Our nomogram model was able to provide personalized risk factors for the progression from MCI to AD after evaluation and validation. [ABSTRACT FROM AUTHOR]

Background: The relationship between white matter hyperintensities (WMH) and the core features of Alzheimer's disease (AD) remains controversial. Further, due to the prevalence of co-pathologies, the precise role of WMH in cognition and neurodegeneration also remains uncertain. Methods: Herein, we analyzed 1803 participants with available WMH volume data, extracted from the ADNI database, including 756 cognitively normal controls, 783 patients with mild cognitive impairment (MCI), and 264 patients with dementia. Participants were grouped according to cerebrospinal fluid (CSF) pathology (A/T profile) severity. Linear regression analysis was applied to evaluate the factors associated with WMH volume. Modeled by linear mixedeffects, the increase rates (Δ) of the WMH volume, cognition, and typical neurodegenerative markers were assessed. The predictive effectiveness of WMH volume was subsequently tested using Cox regression analysis, and the relationship between WMH/ΔWMH and other indicators such as cognition was explored through linear regression analyses. Furthermore, we explored the interrelationship among amyloid-ß deposition, cognition, and WMH using mediation analysis. Results: Higher WMH volume was associated with older age, lower CSF amyloid-ß levels, hypertension, and smoking history (all p = 0.001), as well as cognitive status (MCI, p < 0.001; dementia, p = 0.008), but not with CSF tau levels. These results were further verified in any clinical stage, except hypertension and smoking history in the dementia stage. Although WMH could not predict dementia conversion, its increased levels at baseline were associated with a worse cognitive performance and a more rapid memory decline. Longitudinal analyses showed that baseline dementia and positive amyloid-ß status were associated with a greater accrual of WMH volume, and a higher ΔWMH was also correlated with a faster cognitive decline. In contrast, except entorhinal cortex thickness, the WMH volume was not found to be associated with any other neurodegenerative markers. To a lesser extent, WMH mediates the relationship between amyloid-ß and cognition. Conclusion: WMH are non-specific lesions that are associated with amyloid-ß deposition, cognitive status, and a variety of vascular risk factors. Despite evidence indicating only a weak relationship with neurodegeneration, early intervention to reduce WMH lesions remains a high priority for preserving cognitive function in the elderly. [ABSTRACT FROM AUTHOR]

Background: Effective interventions for overall healthy subjects with mild cognitive impairment are currently limited. Choline alphoscerate (alpha glyceryl phosphorylcholine, αGPC) is a choline-containing phospholipid used to treat cognitive function impairments in specific neurological conditions. This study aimed to investigate the efficacy and safety of αGPC in individuals diagnosed with mild cognitive impairment. Methods: In this multicenter, randomized, placebo-controlled trial, 100 study subjects with mild cognitive impairment underwent a double-blind SHCog™ soft capsule (600 mg αGPC) or placebo treatment for 12 weeks. The primary efficacy outcome included changes from baseline on the Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS-cog). Safety assessments included regular monitoring of adverse events, and clinical laboratory tests were conducted at baseline and the end of the trial. Results: After 12 weeks of αGPC treatment, the ADAS-cog score decreased by 2.34 points, which was significantly greater than the change observed in the placebo group. No serious AEs were reported, and no study subjects discontinued the intervention because of AEs. There was no significant difference in incidence rate of AEs between the αGPC group and the placebo group. Conclusion: This study suggests that αGPC is a safe and effective intervention for improving cognitive function in study subjects with mild cognitive impairment. Trial registration: Clinical Research Information Service; Osong (Chungcheongbuk-do): Korea Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); KCT0008797; A 12-week, multicenter, randomized, double-blind, placebo-controlled human application study to evaluate the efficacy and safety of SH_CAPK08 on cognitive function improvement in mild cognitive decline. [ABSTRACT FROM AUTHOR]

The progressive aging of the global population and the high impact of neurodegenerative diseases, such as Alzheimer's disease (AD), underscore the urgent need for innovative diagnostic and therapeutic strategies. AD, the most prevalent neurodegenerative disorder among the elderly, is expected to affect 75 million people in developing countries by 2030. Despite extensive research, the precise etiology of AD remains elusive due to its heterogeneity and complexity. The key pathological features of AD, including amyloid-beta plaques and hyperphosphorylated tau protein, are established years before clinical symptoms appear. Recent studies highlight the pivotal role of neuroinflammation in AD pathogenesis, with the chronic activation of the brain's immune system contributing to the disease's progression. Pro-inflammatory cytokines, such as TNF- α , IL-1 β , and IL-6, are elevated in AD and mild cognitive impairment (MCI) patients, suggesting a strong link between peripheral inflammation and CNS degeneration. There is a pressing need for minimally invasive, cost-effective diagnostic methods. Buccal mucosa cells and saliva, which share an embryological origin with the CNS, show promise for AD diagnosis and prognosis. This study integrates cellular observations with advanced data processing and machine learning to identify significant biomarkers and patterns, aiming to enhance the early diagnosis and prevention strategies for AD. [ABSTRACT FROM AUTHOR]

Objectives: This review aims to summarize the common physiological mechanisms associated with both mild cognitive impairment (MCI) and musculoskeletal aging while also examining the relevant literature on how exercise regulation influences the levels of shared myokines in these conditions. Methods: The literature search was conducted via databases such as PubMed (including MEDLINE), EMBASE, and the Cochrane Library of Systematic Reviews. The searches were limited to full-text articles published in English, with the most recent search conducted on 16 July 2024. The inclusion criteria for this review focused on the role of exercise and myokines in delaying musculoskeletal aging and enhancing cognitive health. The Newcastle--Ottawa Scale (NOS) was utilized to assess the quality of nonrandomized studies, and only those studies with moderate to high quality scores, as per these criteria, were included in the final analysis. Data analysis was performed through narrative synthesis. Results: The primary outcome of this study was the evaluation of myokine expression, which included IL-6, IGF-1, BDNF, CTSB, irisin, and LIF. A total of 16 studies involving 633 older adults met the inclusion criteria. The current exercise modalities utilized in these studies primarily consisted of resistance training and moderate-to high-intensity cardiovascular exercise. The types of interventions included treadmill training, elastic band training, aquatic training, and Nordic walking training. The results indicated that both cardiovascular exercise and resistance exercise could delay musculoskeletal aging and enhance the cognitive functions of the brain. Additionally, different types and intensities of exercise exhibited varying effects on myokine expression. Conclusion: Current evidence suggests that exercise mediates the secretion of specific myokines, including IL-6, IGF-1, BDNF, CTSB, irisin, and LIF, which establish self-regulatory circuits between the brain and muscle. This interaction enhances cognitive function in the brain and improves skeletal muscle function. Future research should focus on elucidating the exact mechanisms that govern the release of myokines, the correlation between the intensity of exercise and the secretion of these myokines, and the distinct processes by which myokines influence the interaction between muscle and the brain. [ABSTRACT FROM AUTHOR]

In vivo proton (1H) magnetic resonance spectroscopy (MRS) is a powerful non-invasive method that can measure Alzheimer's disease (AD)-related neuropathological alterations at the molecular level. AD biomarkers include amyloid-beta (Aβ) plaques and hyperphosphorylated tau neurofibrillary tangles. These biomarkers can be detected via postmortem analysis but also in living individuals through positron emission tomography (PET) or biofluid biomarkers of Aβ and tau. This review offers an overview of biochemical abnormalities detected by 1H MRS within the biologically defined AD spectrum. It includes a summary of earlier studies that explored the association of 1H MRS metabolites with biofluid, PET, and postmortem AD biomarkers and examined how apolipoprotein e4 allele carrier status influences brain biochemistry. Studying these associations is crucial for understanding how AD pathology affects brain homeostasis throughout the AD continuum and may eventually facilitate the development of potential novel therapeutic approaches. [ABSTRACT FROM AUTHOR]