Cerebrospinal Fluid Aβ42 Levels Research Articles

Cerebral Amyloidosis in Individuals with Subjective Cognitive Decline: From Genetic Predisposition to Actual Cerebrospinal Fluid Measurements

The possible relationship between Subjective Cognitive Decline (SCD) and dementia needs further investigation. In the present study, we explored the association between specific biomarkers of Alzheimer’s Disease (AD), amyloid-beta 42 (Aβ42) and Tau with the odds of SCD using data from two ongoing studies. In total, 849 cognitively normal (CN) individuals were included in our analyses. Among the participants, 107 had available results regarding cerebrospinal fluid (CSF) Aβ42 and Tau, while 742 had available genetic data to construct polygenic risk scores (PRSs) reflecting their genetic predisposition for CSF Aβ42 and plasma total Tau levels. The associations between AD biomarkers and SCD were tested using logistic regression models adjusted for possible confounders such as age, sex, education, depression, and baseline cognitive test scores. Abnormal values of CSF Aβ42 were related to 2.5-fold higher odds of SCD, while higher polygenic loading for Aβ42 was associated with 1.6-fold higher odds of SCD. CSF Tau, as well as polygenic loading for total Tau, were not associated with SCD. Thus, only cerebral amyloidosis appears to be related to SCD status, either in the form of polygenic risk or actual CSF measurements. The temporal sequence of amyloidosis being followed by tauopathy may partially explain our findings.

Serum and cerebrospinal fluid neurofilament light chain and glial fibrillary acid protein levels in early and advanced stages of cerebral amyloid Angiopathy

BackgroundNeurofilament light chain (NFL) is a biomarker for neuroaxonal damage and glial fibrillary acidic protein (GFAP) for reactive astrocytosis. Both processes occur in cerebral amyloid angiopathy (CAA), but studies investigating the potential of NFL and GFAP as markers for CAA are lacking.We aimed to investigate NFL and GFAP as biomarkers for neuroaxonal damage and astrocytosis in CAA.MethodsFor this cross-sectional study serum and cerebrospinal fluid (CSF) samples were collected between 2010 and 2020 from controls, (pre)symptomatic Dutch-type hereditary (D-CAA) mutation-carriers and participants with sporadic CAA (sCAA) from two prospective CAA studies at two University hospitals in the Netherlands. NFL and GFAP levels were measured with Simoa-assays. The association between NFL and GFAP levels and age, cognitive performance (MoCA), CAA-related MRI markers (CAA-CSVD-burden) and Aβ40 and Aβ42 levels in CSF were assessed with linear regression adjusted for confounders. The control group was divided in age < 55 and ≥55 years to match the specific groups.ResultsWe included 187 participants: 28 presymptomatic D-CAA mutation-carriers (mean age 40 years), 29 symptomatic D-CAA participants (mean age 58 years), 59 sCAA participants (mean age 72 years), 33 controls < 55 years (mean age 42 years) and 38 controls ≥ 55 years (mean age 65 years).In presymptomatic D-CAA, only GFAP in CSF (7.7*103pg/mL vs. 4.4*103pg/mL in controls; P<.001) was increased compared to controls. In symptomatic D-CAA, both serum (NFL:26.2pg/mL vs. 12.5pg/mL; P=0.008, GFAP:130.8pg/mL vs. 123.4pg/mL; P=0.027) and CSF (NFL:16.8*102pg/mL vs. 7.8*102pg/mL; P=0.01 and GFAP:11.4*103pg/mL vs. 7.5*103pg/mL; P<.001) levels were higher than in controls and serum levels (NFL:26.2pg/mL vs. 6.7pg/mL; P=0.05 and GFAP:130.8pg/mL vs. 66.0pg/mL; P=0.004) were higher than in pre-symptomatic D-CAA. In sCAA, only NFL levels were increased compared to controls in both serum (25.6pg/mL vs. 12.5pg/mL; P=0.005) and CSF (20.0*102pg/mL vs 7.8*102pg/mL; P=0.008). All levels correlated with age. Serum NFL correlated with MoCA (P=0.008) and CAA-CSVD score (P<.001). NFL and GFAP in CSF correlated with Aβ42 levels (P=0.01/0.02).ConclusionsGFAP level in CSF is an early biomarker for CAA and is increased years before symptom onset. NFL and GFAP levels in serum and CSF are biomarkers for advanced CAA.

Associations between multidomain modifiable dementia risk factors with AD biomarkers and cognition in middle-aged and older adults

This study aimed to determine associations between modifiable dementia risk factors (MDRF), across domains mood symptomatology, lifestyle behaviors, cardiovascular conditions, cognitive/social engagement, sleep disorders/symptomatology, with cognition, beta-amyloid (Aβ) and tau, and brain volume. Middle-aged/older adults (n=82) enrolled in a sub-study of the Healthy Brain Project completed self-report questionnaires and a neuropsychological battery. Cerebrospinal fluid levels of Aβ 1–42, total tau (t-tau), and phosphorylated tau (p-tau181) (Roche Elecsys), and MRI markers of hippocampal volume and total brain volume were obtained. Participants were classified as no/single domain risk (≤1 domains) or multidomain risk (≥2 domains). Compared to the no/single domain risk group, the multidomain risk group performed worse on the Preclinical Alzheimer’s Cognitive Composite (d=0.63, p=.005), and Executive Function (d=0.50, p=.016), and had increased p-tau181 (d=0.47, p=.042) and t-tau (d=0.54, p=.021). In middle-aged/older adults, multidomain MDRFs were related to increases in tau and worse cognition, but not Aβ or brain volume. Findings suggest that increases in AD biomarkers are apparent in midlife, particularly for individuals with greater burden, or variety of MDRFs.

Amyloid and Tau as cerebrospinal fluid biomarkers in anti-N-Methyl-D-aspartate receptor encephalitis.

Neuroinfection is associated with the deposition of amyloid-beta (Aβ) peptides, and subsequent decrease in cerebrospinal fluid (CSF) amyloid levels. However, whether autoimmune encephalitis involves extracellular deposition of Aβ peptides in the brain is unreported. We examined CSF amyloid and tau values in adults with anti-N-methyl-D-aspartate receptor encephalitis (NMDAR-E). Forty-two patients with NMDAR-E, 35 patients with viral and bacterial neuroinfections, and 16 controls were included. We measured CSF Aβ1-42 (cAβ1-42), Aβ1-40 (cAβ1-40), t-Tau (ct-Tau), and p-Tau181 (cp-Tau181) levels and assessed their efficacies regarding differential diagnosis and predicting prognosis. NMDAR-E patients had lower cAβ1-42 levels; however, they were higher than those of patients with bacterial meningitis. ct-Tau levels in NMDAR-E patients were lower than those in patients with neuroinfections. No changes were observed in controls. cAβ1-42 and ct-Tau were combined as an excellent marker to distinguish NMDAR-E from neuroinfections. cAβ1-42 levels in NMDAR-E patients were positively correlated with Montreal Cognitive Assessment scores. We observed an inverse relationship between cAβ1-42 levels and modified Rankin Scale scores. Patients with poor outcomes exhibited low cAβ1-42 levels and high levels of several blood parameters. cAβ1-42 was the highest quality biomarker for assessing NMDAR-E prognosis. Correlations were found between cAβ1-42 and some inflammatory indicators. cAβ1-42 was decreased in NMDAR-E patients. cAβ1-42 levels indicated NMDAR-E severity and acted as a biomarker for its prognosis. Combining cAβ1-42 and ct-Tau levels could serve as a novel differential diagnostic marker for NMDAR-E.

CRISPR-Powered Aptasensor for Diagnostics of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause of dementia, characterized by the accumulation of amyloid beta (Aβ) peptides in the brain. Here, we present a simple, rapid, and affordable CRISPR-powered aptasensor for the quantitative detection of Aβ40 and Aβ42 biomarkers in cerebrospinal fluid (CSF) samples, enabling early and accurate diagnostics of AD patients. The aptasensor couples the high specificity of aptamers for Aβ biomarkers with CRISPR-Cas12a-based fluorescence detection. The CRISPR-powered aptasensor enables us to detect Aβ40 and Aβ42 in CSF samples within 60 min, achieving a detection sensitivity of 1 pg/mL and 0.1 pg/mL, respectively. To validate its clinical utility, we quantitatively detected Aβ40 and Aβ42 biomarkers in clinical CSF samples. Furthermore, by combining CSF Aβ42 levels with the c(Aβ42)/c(Aβ40) ratio, we achieved an accurate diagnostic classification of AD patients and healthy individuals, showing superior performance over the conventional ELISA method. We believe that our innovative aptasensor approach holds promise for the early diagnostic classification of AD patients.

Biomarker Profiling for Alzheimer‐like Dementia in Aged Non‐human Primates

AbstractBackgroundAlzheimer’s disease (AD) places increasingly burdens on global healthcare. Non‐human primates (NHPs) have been used in preclinical pharmacology for AD drug discovery and they were mainly based on induction by amyloid plaque. However, previous strategies focused on clearance and prevention of amyloid plaques and neurofibrillary inclusions have mostly yielded discouraging results in clinical trials for AD. More fitting NHP models reflective of natural ageing of brain with an AD‐related clinical profile would be most desirable for translational pharmacology. To address this, the pilot study herein profiled a group of aged NHPs for biomarkers characteristic of AD‐like dementia, including cognitive behavior, diagnostic neuroimaging, EEG, and amyloid beta 42 (Aβ42) in cerebrospinal fluid (CSF).MethodTwo groups of male Macaca fascicularis (adult: 9‐11 years, n = 4; aged: 20‐25 years, n = 10) were trained to perform a delayed response task (DRT) to assess their short term memory. Meanwhile, their CSF levels of Aβ42 were determined. EEG signals at rest were captured with Neuroscan EEG System and data processed with customized Matlab code. The volume of hippocampus in eight selected animals were analyzed through a 3‐D reconstruction with MRI imaging.ResultSix (6) out of 10 aged animals showed lower DRT performance (successful rate &lt; 80%) than the remaining 4 and those in the adult group. The overall DRT performance was positively correlated with the CSF levels of Aβ42 in all animals. Moreover, we observed the slowing of EEG activity (increased δ &amp; θ activity and decreased β activity) in the frontal lobe and smaller average volume of hippocampus in the low DRT performers vis‐à‐vis the rest of the animals.ConclusionWe identified a group of aged NHPs with spontaneous dementia, with cognitive, electrophysiological and brain structural characteristic of mild cognitive impairment in the humans. Their CSF levels of Aβ42 inversely correlated with the memory function. Most notably, EEG and neuroimaging showed promising potential as non‐invasive approaches for the evaluation of aging‐related dementia of NHP in the longitudinal studies. The translational value of such animals could provide important insight to the disease progress and the therapeutic efficacy of AD treatment in the preclinical stages.

Associations of self‐reported psychological stress with memory and cerebrospinal fluid biomarkers of Alzheimer’s disease in middle‐aged adults

AbstractBackgroundSelf‐reported psychological stress is associated with an increased risk of cognitive decline and dementia. However, it remains unclear whether stress is related to key biomarkers of Alzheimer’s disease (AD). This cross‐sectional study examined the relationship of psychological stress with memory and cerebrospinal fluid (CSF) biomarkers of AD in middle‐aged adults without dementia.MethodThe Healthy Brain Project (HBP) is a prospective web‐based study of adults aged between 40 and 70 years. A total of 2208 participants (76% female) completed the Depression, Anxiety, and Stress Scale (DASS) and Paired Associates Learning subtest of the CANTAB unsupervised on the HBP web platform. Additionally, a sub‐group of participants (n = 67; 41% APOE e4 carriers) attended an in‐person assessment where CSF samples were obtained to measure levels of amyloid‐beta (Aβ42), total tau (t‐tau), phosphorylated tau 181 (p‐tau), and neurofilament light chain (NFL). Separate linear regression analyses investigated associations of the DASS‐Stress score with memory performance and AD biomarkers. All analyses were adjusted for age, sex, education, and race.ResultIn the web‐based cohort, higher levels of self‐reported psychological stress were significantly associated with poorer memory (unstandardised β = ‐0.014, standard error [SE] = 0.004, p &lt;.001). However, there were no significant associations between psychological stress and CSF levels of Aβ42, t‐tau, p‐tau, and NFL (all p &gt; .05), with small effect sizes (Cohen’s f2 ≤ 0.05).ConclusionHigher levels of self‐reported psychological stress were associated with poorer memory in a large middle‐aged cohort but were not associated with AD biomarkers in a subset of participants with available CSF. One potential explanation is that non‐AD pathologies may underlie the relationship between stress and poorer memory; for example, poor coping strategies (e.g., smoking, overeating, and physical activity) might increase the risk of vascular cognitive impairment. However, it is also likely that the small sample size of the in‐clinic cohort was insufficient to detect any subtle relationships between stress and AD pathologies. Further research is needed to determine the associations between stress and the development of the clinical and biological manifestations of AD.

Predictive analysis between cytokine profile and Aβ42, p‐Tau, and p‐Tau/Aβ42 levels in the cerebrospinal fluid of older adults with and without cognitive impairment

AbstractBackgroundThe immune system activation observed in Alzheimer’s disease (AD) pathology contributes to its pathogenesis. It is proposed that ongoing interactions between β‐amyloid plaques, Tau protein, and neuroinflammatory mediators such as cytokines contribute to the maintenance of the inflammatory state in the brain. The aim was to evaluate whether cytokine profiles can predict variations in Aβ42, pTau, and pTau/Aβ42 cerebrospinal fluid (CSF) levels in older adults with and without objective cognitive impairment.MethodsEighty older adults were recruited, with a clinical diagnosis of AD dementia (36), with Mild Cognitive Impairment (MCI) (24), and without objective cognitive impairment (20). CSF levels of Aβ42, pTau, and 27 cytokines were assessed by the Luminex xMAP technique. Significant associations between Aβ42, p‐Tau, and p‐Tau/Aβ42 CSF levels and cytokines were explored in multiple linear regression analyses adjusted for age, education, and APOE ε4 carrier status.ResultsWe found that Granulocyte and Macrophage colony‐stimulating factors (GM‐CSF) (β = ‐.375; p = .010) and IL‐6 (β = ‐.370; p = .014) had a negative significant association with Aβ42, while IL‐8 (β = .452; p = .002) and IL‐4 (β = .488; p = .001) had positive significant association and higher magnitude of effect on Aβ42. For pTau, age (β = .240; p = .029), IL‐2 (β = .314; p = .012) and ε4 allele (β = 0.349; p = .002) had a positive significant association. The variable with the greatest magnitude of the effect was the presence of the ε4 allele. For the p‐Tau/Aβ42 ratio, G‐CSF (β = .423; p = .003) and GM‐CSF (β = .317; p = .019) had a significant positive association, while for IL‐8 (β = ‐.554; p = .001) and IL‐12 (β = ‐.334; p = .019) the association was significantly negative. IL‐8 had the greatest magnitude of effect on p‐Tau/Aβ42 ratio values.ConclusionThe higher levels of IL‐4 and the IL‐8 associated to a higher Aβ42 suggest their role at the beginning of the disease. On the other hand, the lower level of IL‐8 associated with a higher p‐Tau/Aβ42 suggests its inactivation as the disease progresses. Conversely, the higher levels of GM‐CSF associated with higher p‐Tau/Aβ42 suggests a more robust recruitment of the immune cell system at later stages.Reference: Aksnes, M., et al., (2021). Associations of cerebrospinal fluid amyloidogenic nanoplaques with cytokines in Alzheimer’s disease. Translational Neurodegeneration.

Spatial navigation, physical activity, and Alzheimer disease biomarkers

AbstractBackgroundElevated levels of amyloid are associated with worse performance on cognitive mapping (CM), a spatial navigation task reliant on the hippocampus. Prior animal work found that exercise is associated with better learning in CM tasks. Hence, the first goal of the study was to examine whether physical activity moderates the relationship between amyloid deposition and CM. In addition, spatial navigation ability predicts Alzheimer disease (AD) clinical progression but there is a need to examine whether it also predicts subsequent levels of amyloid and tau. Hence, the second goal was to examine whether CM predicts later levels of PET‐Tau and longitudinal trajectories of PET‐Amyloid.MethodCognitively normal individuals (n = 65; age range 50‐84 years) were administered a CM task in a virtual environment and a self‐report measure of physical activity. For cross‐sectional analyses, amyloid deposition was estimated via cerebrospinal fluid levels of Aβ42. One assessment of PET‐Tau (n = 49) and repeated assessments of PET‐Amyloid (n = 59) were obtained following the CM session.ResultConcurrent amyloid deposition was associated with reduced learning (p = 0.002) and retention of the environment (p = 0.002) while greater physical activity was associated with better learning (p = 0.004). There was no moderation by physical activity (all p’s &gt; 0.156). CM performance was not associated with longitudinal trajectories of PET‐Amyloid (all p’s &gt; 0.330) or the subsequent levels of PET‐Tau (all p’s &gt; 0.572).ConclusionThese results suggest that both current physical activity and levels of amyloid can be important predictors of spatial navigation skills. However, CM might be a limited predictor of AD biomarker accumulation. Future studies should use a larger sample size and greater number of assessments to examine these questions.

Alzheimer´s Disease initial cognitive profile in an Argentinian cohort of individuals with Down Syndrome

AbstractBackgroundDown Syndrome [DS] is the most frequent cause of genetic developmental and intellectual disability. The lifetime risk of Alzheimer’s Disease [AD] in people with DS is more than 90%, with an earlier age of onset than the general population. There is ongoing debate whether there are significant differences in dementia presentation in the specific context of DS, with some studies suggesting a predominantly frontal phenotype with behavioural symptoms and others suggesting a more frequent amnestic presentation.The aim of this study was to characterize the initial cognitive profile of AD in a cohort of Argentinian adults with DS.MethodAdults with DS and prodromal or established AD dementia who were part of the IASDA (Argentinian initiative for the study of DS and AD) cohort or spontaneusly attended our Memory Clinic were included. Initial cognitive profile was determined by a semi‐structured interview conducted by a cognitive neurologist with the subject, their family and caregivers.ResultSixteen adults with DS were included. Fifty‐six percent (n = 9) were males. Mean age was 51 yo (42‐59 yo). Sixty‐two percent (n = 10) had premorbid moderate intellectual disability [DI], 25% (n = 4) had severe DI and 13% (n = 2) had mild DI.Fifty‐six percent (n = 9) had a clinical diagnosis of prodromal AD, and the remaining individuals had clinically established AD dementia. Fifty percent (n = 8) had positive amiloid biomarkers (determined by cerebral PiB‐PET or cerebrospinal fluid levels of Aβ42, phosphorylated‐tau and total‐tau), while the remaining subjects did not undergo amiloid biomarker assessment. Due to cognitive impairment, premorbid language impairment and/or premorbid severe DI, only 25% (n = 4) of individuals completed neuropsychological testing (CAMDEX‐DS, Cued Recall Task).Initial cognitive profile was charactirized as amnestic (single‐domain amnestic or multiple‐domain amnestic) in 81% percent (n = 13) of the cohort. Only 13% (n = 2) of the subjects had initial non‐amnestic syndromes, and in one case (6%) the initial cognitive syndrome was uncertain.ConclusionAmnestic cognitive impariment was the most frequent presentation of AD in this small cohort of Latin American adults with DS.

Association between blood pressure and Alzheimer’s disease biomarkers in cognitively unimpaired adults

AbstractBackgroundHigh blood pressure is an established risk factor for dementia. However, the underlying mechanisms are not completely understood. We aimed to evaluate the association between blood pressure and Alzheimer’s disease (AD) biomarkers in cognitively unimpaired adults from the ALFA+ study.MethodWe analyzed data from 301 participants with available cross‐sectional blood pressure measures (acquired by trained staff with an oscillometric device after 5 minutes of rest) and cerebrospinal fluid (CSF) AD core biomarkers data (CSF p‐tau and t‐tau were measured with Elecsys® immunoassays and CSF Aβ42 and Aβ40 with the Roche NeuroToolKit, a panel of robust prototype assays, both from Roche Diagnostics International Ltd), and a subset of 278 participants with amyloid PET data, of whom 110 had a second follow‐up PET acquisition (3.4 years after in average). We used separate linear regression models to analyze the association of systolic blood pressure (SBP), diastolic blood pressure (DBP), and pulse pressure (PP = SBP‐DBP) with CSF and PET biomarkers at a cross‐sectional level, and their association with the annualized rate of change in amyloid PET [(follow‐up centiloids – baseline centiloids) / years between PET scan acquisition]. We adjusted all models by age, sex, APOE status, waist‐to‐hip ratio, dyslipidemia, diabetes, tobacco and alcohol consumption, physical activity, and antihypertensive treatment.ResultHigher baseline SBP (but not DBP or PP) was significantly associated with increased amyloid PET uptake over time (p = 0.043). In cross‐sectional analyses, DBP was negatively associated with Aβ42 (p = 0.013), Aβ40 (p = 0.026), and t‐tau (p = 0.045), and marginally associated with p‐tau (p = 0.069), but not with the Aβ42/40 ratio nor baseline amyloid PET uptake. Associations with Aβ42 and t‐tau were no longer significant after further adjustment by CSF Aβ40 levels. SBP and PP were not associated with CSF biomarkers or baseline amyloid PET uptake.ConclusionHigher SBP is associated with longitudinal brain amyloid accumulation, which reinforces the importance of blood pressure control in AD prevention. DBP is also associated at a cross‐sectional level with AD biomarker concentration in CSF, but the attenuation of this association after adjusting by Aβ40 suggests a non‐specific.

Sex‐specific CSF proteomic profiling of amyloid/tau positivity identifies distinctive sex‐specific alternation of multiple proteins involved in Alzheimer’s disease

AbstractBackgroundSporadic Alzheimer’s disease (AD) is a highly heterogeneous multifactorial disease in which females have a higher risk. Among 5.3 million senior Americans diagnosed with AD, over 60% are female. Despite the well‐established sex differences, sex‐specific molecular findings in AD are still limited. We therefore examined the role of sex in the proteomic alterations due to AD to elucidate potential protein markers of AD heterogeneity.MethodIn the discovery cohort, 599 preclinical AD and 435 controls underwent lumbar puncture. Over 7,000 proteins in cerebrospinal fluid (CSF) were measured using SomaLogic assay. Amyloid/tau positivity (AT classification) was determined using ELISA Aβ42 and pTau181 levels in CSF. Proteins with sex‐specific effects were identified through linear models focusing on the interaction term between AT classification and sex. Results were tested in the independent cohort (N = 732) using the identical approaches. We analyzed brain proteomics and transcriptomics data to validate the replicated sex‐specific proteins. We performed pathway enrichment, interaction network using ConsensusPathDB and drug‐target prediction.ResultWe identified 594 proteins with sex‐specific effects in discovery (P&lt;0.05 and permutation FDR &lt;0.05). Among them, 36 were validated in replication (P&lt;0.05 and consistent direction). These proteins were found to be involved in neurologic disorders and highly enriched in axon regeneration (fold enrichment = 9.38 and FDR = 2.8×10−4). Among the 36 proteins identified, 13 were classified as female‐specific and 23 as male‐specific. These 36 proteins strongly predicted amyloid/tau positivity (AUC = 0.926) for all individuals as well as 13 female‐specific proteins for females (AUC = 0.929). The interaction network identified CCN2 as a hub and contained 10 additional proteins including JAG1 and DLL4 of Notch signaling pathway and CTSB, an amyloid precursor protein secretase, among others. The results of 36 proteins in brain proteomics and transcriptomics confirmed the sex‐specific effect of CCN2 and others on AD in different tissues. Drug target prediction suggests minocycline and etoposide as potential treatments for females as well amitriptyline and verteporfin for males.ConclusionWe robustly identified 36 proteins that showed significant sex‐specific alterations by preclinical AD. Several proteins involved in AD and neurodegeneration were highlighted. Our findings facilitate mechanistic understanding of sex differences for AD risk and progression.

Time of the day at sampling affects amyloid‐beta levels in CSF and plasma

AbstractBackgroundStudies suggest that cerebrospinal fluid (CSF) levels of Alzheimer’s disease (AD) biomarkers, amyloid‐β (Aβ) and tau, follow a circadian rhythm. However sustained sampling of CSF with indwelling intrathecal catheter used in most of these studies might have affected the observed fluctuations in the biomarker levels.MethodsWe included 38 individuals with either normal (N = 18) or abnormal (N = 20) CSF Aβ42/40 status. CSF and plasma were collected, at the same occasion, at two different visits separated by an average of 53 days with lumbar punctures and venepunctures performed either in the morning or evening. At the first visit, collection was performed in the morning for 17 participants and the order was reversed (evening collection first) for the remaining 21 participants. CSF and plasma samples were analyzed for Aβ42, Aβ40, GFAP, NfL, p‐tau181, p‐tau217 and p‐tau231. CSF samples were also tested for a battery of synaptic and lysosomal proteins.ResultsCSF Aβ42 (mean difference [MD] = 0.208ng/ml; p = 0.043), CSF Aβ40 (MD = 1.85ng/ml; p&lt;0.001), plasma Aβ42 (MD = 1.65pg/ml; p = 0.002) and plasma Aβ40 (MD, 0.011ng/ml, p = 0.003) levels were increased in the evening samples compared with morning samples by 4.2%‐17.0% (Figures 1‐2). However, changes between morning and evening samples were not significant for either CSF or plasma Aβ42/40. Additional proteins in CSF, APP, STX1B, NPTXR and NPTX1, were also found increased in the evening samples (MDrange, 0.087–0.243; p&lt;0.048) by 4.7%‐12.15% (Figure 3). No significant differences were found between morning and evening levels for any of the other biomarkers, including p‐tau’s, NfL and GFAP. There were no significant interactions between time of day at sample collection and either Aβ status or order in which samples were obtained.ConclusionOur findings provide further evidence for diurnal fluctuations in Aβ peptides, which is observed in both CSF and plasma. Additionally, CSF levels of some synaptic proteins followed circadian rhythm. Importantly, CSF and plasma Aβ42/40 ratios remained unaltered, suggesting that increased production or decreased clearance of Aβ peptides during daytime similarly affect the CSF and plasma levels of both Aβ42 and Aβ40. Thus, these ratios are more suitable for implementation as biomarkers of AD as they are not influenced by diurnal fluctuations.

CSF Alzheimer’s Disease Biomarker Changes in Veterans with Mild Traumatic Brain Injury

AbstractBackgroundTraumatic brain injury (TBI) has been reported to increase risk of Alzheimer’s dementia (AD). It remains unknown whether mild TBI (mTBI) caused by blast in Veterans confers a similar increase of risk. This study investigated early AD changes defined by cerebrospinal fluid (CSF) AD biomarkers in Veterans with blast mTBI.MethodFifty‐one Veterans with mTBI, 34 non‐mTBI Veterans, and 51 non‐mTBI civilians were recruited from Seattle, Washington. Age‐matched Veteran and civilian non‐mTBI participants had no lifetime history of TBI. All blast‐mTBI Veterans had experienced at least one war zone blast or combined blast/impact exposure, with acute symptoms meeting VA/Department of Defense criteria for mTBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of CSF. CSF biomarkers were measured at the Clinical Neurochemistry Lab in Mölndal, Sweden, using Meso Scale Discovery (MSD) assays for Aβ40 and Aβ42, and Innotest ELISAs for phosphorylated Tau181 (pTau181) and total Tau (tTau).ResultDifferences in all 4 CSF AD biomarkers between participants with and without mTBI were highly age‐dependent and most pronounced in older ages (Figure 1). Both CSF Aβ40 and Aβ42 became lower as age increasing in the mTBI group starting around age 40‐45 years, while they increased with age in the non‐mTBI participants. In contrast, CSF tTau and pTau181 mean levels remained relatively constant with age in participants with mTBI, but increased after age 45 in the non‐mTBI participants. Consequently, for participants aged 50+ years, Veterans with mTBI had lower mean AD biomarkers than the non‐mTBI participants. Similarly, the differences in cognitive performance were age‐dependent, i.e., poorer performance in older Veterans with mTBI than in the non‐mTBI participants. Furthermore, the relationships between CSF Aβ42 and cognitive performance were also age‐dependent; specifically, in participants aged 45+ years, lower CSF Aβ42 level was associated with poorer performance on tests of verbal fluency and memory.ConclusionThe earliest AD biomarker, CSF Aβ42, started to decrease in middle‐aged Veterans with mTBI, more than a decade earlier than those without mTBI in our earlier study, suggesting mTBI may accelerate brain deposition of Aβ and increase risk for AD.

Associations between Alzheimer's disease biomarkers and postoperative delirium or cognitive dysfunction: A meta-analysis and trial sequential analysis of prospective clinical trials.

The relationship between Alzheimer's disease biomarkers and postoperative complications, such as postoperative delirium (POD) and postoperative cognitive dysfunction (POCD), remains a subject of ongoing debate. This meta-analysis aimed to determine whether there is an association between perioperative Alzheimer's disease biomarkers and postoperative complications. We conducted a meta-analysis of observational clinical studies that explored the correlation between Alzheimer's disease biomarkers and POD or POCD in patients who have undergone surgery, following PRISMA guidelines. The protocol was previously published (INPLASY: INPLASY202350001). A comprehensive search was conducted across PubMed, Embase, Web of Science, and Cochrane databases until March 2023. Surgical patients aged at least 18 years, studies focusing on POD or POCD, research involving Alzheimer's disease biomarkers, including Aβ or tau in blood or cerebrospinal fluid (CSF), and availability of the full text. Our meta-analysis included 15 studies: six focusing on POD and nine on POCD. The findings revealed a negative correlation between preoperative CSF β-amyloid 42 (Aβ42) levels and the onset of POD [mean difference -86.1, 95% confidence interval (CI), -114.15 to -58.05, I2 : 47%]; this association was strongly supported by trial sequential analysis (TSA). A similar negative correlation was discerned between preoperative CSF Aβ42 levels and the incidence of POCD (-165.01, 95% CI, -261.48 to -68.53, I2 : 95%). The TSA also provided robust evidence for this finding; however, the evidence remains insufficient to confirm a relationship between other Alzheimer's disease biomarkers [β-amyloid 40 (Aβ40), total tau (T-tau), phosphorylated tau (P-tau), and Aβ42/T-tau ratio] and POD or POCD. The study results indicate a negative correlation between preoperative CSF Aβ42 levels and the occurrence of both POD and POCD. Future investigations are warranted to identify the predictive cutoff value of preoperative CSF Aβ42 for POD and POCD.

Domain‐specific subtle cognitive decline associations with cerebrospinal fluid and plasma β‐amyloid and p‐tau Alzheimer’s disease biomarkers in cognitively unimpaired individuals

AbstractBackgroundPresence of Alzheimer’s disease (AD) core pathology, β‐amyloid (Aβ) and p‐tau, has been proven to impact cognitive function even in cognitively unimpaired (CU) individuals. Although the Aβ and p‐tau (AT) effect has been mainly associated with memory function, recent evidence (Tideman, P., 2022. Neurology) suggested that Aβ levels were associated independently of p‐tau with the cross‐sectional performance in executive functioning. The aim of the present study was to explore specific associations of cerebrospinal fluid (CSF) and plasma Aβ and p‐tau baseline levels with the longitudinal change in several cognitive domains in a sample of CU individuals at increased risk of AD.MethodWe analyzed the associations of baseline CSF Aβ42/40, and p‐tau181 as well as plasma Aβ42/40, and p‐tau231 levels, with domain‐specific cognitive changes 3 years after baseline in 337 CU participants from the ALFA+ study. We defined AT groups (A‐T‐, A+T‐, and A+T+) using CSF levels, and the A‐T‐ group’s baseline performance served as reference to compute z‐scores for Visual Processing, Semantic Fluency, Executive Functioning, Episodic Memory, and Attentional Processing. Delta scores were computed by subtracting baseline from follow‐up scores and then compared among AT groups by means of ANCOVAs. Multiple linear regressions were performed on the whole sample using CSF Aβ42/40, p‐tau181 and plasma Aβ42/40, p‐tau231 as predictors of change in cognitive function.ResultA+T+ individuals showed a significant decline in Executive Function (p = 0.005, Cohen’s d = 0.716), and Attentional Processing (p = 0.032, Cohen’s d = 0.563), but not in Episodic Memory (p = 0.334) when compared with A‐T‐ individuals. In the whole sample, CSF Aβ42/40 was associated independently of p‐tau181 with a decline in Semantic Fluency (β = 6.284, p = 0.013), Attentional Processing (β = 3.828, p = 0.020), and Episodic Memory (β = 3.513, p = 0.004). Plasma p‐tau231 levels were associated with a decline in Semantic Fluency (β = ‐0.413, p = 0.045). CSF p‐tau181 and plasma Aβ42/40 were not associated with cognitive changes.ConclusionExecutive Function and Attentional Processing were more sensitive than Episodic Memory in capturing the early subtle cognitive changes in CU individuals with underlying AD pathology. Attentional Processing was the only cognitive domain associated both with the status of AD biomarkers and with the effect of CSF Aβ levels independently of p‐tau.

Associations Between TREML2 Gene Variants and Alzheimer's Disease: Biomarkers, Neuroimage, and Cognition.

Recent genetic research identified a protective factor against late-onset Alzheimer's disease (AD) in Caucasians, a variant called rs3747742-C in the TREML2 gene. However, the roles of other TREML2 variants in AD have not been fully explored. We conducted a focused analysis of 16 TREML2 variants, examining their connection to AD by studying their correlation with cerebrospinal fluid (CSF) proteins, neuroimage, and cognition in the Alzheimer's Disease Neuroimaging Initiative database (ADNI). A multiple linear regression model was utilized to estimate potential associations between TREML2 genotypes and various endophenotypes in the entire ADNI sample at baseline, with age, gender, years of education, and APOE ɛ4 status included as covariates. To examine changes in clinical outcomes over time, linear mixed-effects models were employed. We found that the SNP rs17328707-A was associated with higher ADNI-VS scores, smaller ventricles, and larger middle temporal volume at baseline. The SNP rs6915083-G was linked to lower CSF t-tau and p-tau levels, and higher CSF Aβ levels. The SNP rs9394766-G was associated with a smaller hippocampus and larger ventricles at baseline. In longitudinal cohorts, the rs6915083-G SNP was associated with changes in ADNI-MEM and ADNI-EF scores, as well as the rate of hippocampal and middle temporal atrophy. Our findings reveal that TREML2 gene variants have different effects on AD. Two variants are protective, while one may be a risk factor. This enhances our understanding of AD genetics and could guide future research and personalized treatments.

A systematic review with meta-analysis to assess Alzheimer's disease biomarkers in adults with or without obstructive sleep apnoea

The aim was to design a meta-analysis evaluating the positron emission tomography (PET) uptake and cerebrospinal fluid (CSF), circulating levels of amyloid-β (Aβ), and tau proteins OSA group versus control group, as well as the association of these biomarkers with the severity of OSA. Four databases were searched until April 17, 2023, without any restrictions. The effect sizes were the standardized mean difference (SMD) along with a 95% confidence interval (CI). A total of 21 articles were entered into the meta-analysis. The pooled SMDs of the CSF levels in OSA adults compared to controls were: -0.82 (P=0.004) for Aβ42, -1.13 (P<0.001) for Aβ40, 0.17 (P=0.23) for p-tau, 0.04 (P=0.65) for t-tau, 0.08 (P=0.89) for Aβ42/Aβ40 ratio, and 0.81 (P=0.001) for t-tau/Aβ42 ratio. The pooled SMD for the PET uptake of Aβ burden in OSA adults compared to controls was 0.30 (P=0.03). The pooled SMDs of the circulating levels in OSA adults compared to controls were: 0.67 (P=0.002) for Aβ42, 0.11 (P=0.82) for Aβ40, 0.35 (P=0.06) for p-tau, and 1.41(P=0.005) for t-tau. The pooled SMDs for levels of Aβ42, Aβ40, total Aβ, p-tau, t-tau, and Aβ42/Aβ40 ratio in severe OSA adults compared to mild/moderate OSA adults were -0.15 (P=0.33), 0.25 (P=35), 0.04 (P=87), -2.53 (P=0.24), -0.24 (P=0.52), and -0.28 (P=0.30), respectively. The results indicated that CSF levels of Aβ42 and Aβ40 in OSA adults were significantly lower, but the CSF level of t-tau/Aβ42 ratio and PET Aβ burden uptake in OSA adults significantly were higher than in controls.

Cross-sectional associations of CSF tau levels with Rey's AVLT: A recency ratio study.

The preeminent in vivo cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease (AD) are amyloid β 1-42 (Aβ42), phosphorylated Tau (p-tau), and total Tau (t-tau). The goal of this study was to examine how well traditional (total and delayed recall) and process-based (recency ratio [Rr]) measures derived from Rey's Auditory Verbal Learning test (AVLT) were associated with these biomarkers. Data from 235 participants (Mage = 65.5, SD = 6.9), who ranged from cognitively unimpaired to mild cognitive impairment, and for whom CSF values were available, were extracted from the Wisconsin Registry for Alzheimer's Prevention. Bayesian regression analyses were carried out using CSF scores as outcomes, AVLT scores as predictors, and controlling for demographic data and diagnosis. We found moderate evidence that Rr was associated with both CSF p-tau (Bayesian factor [BFM] = 5.55) and t-tau (BFM = 7.28), above and beyond the control variables, while it did not correlate with CSF Aβ42 levels. In contrast, total and delayed recall scores were not linked with any of the AD biomarkers, in separate analyses. When comparing all memory predictors in a single regression, Rr remained the strongest predictor of CSF t-tau levels (BFM = 3.57). Our findings suggest that Rr may be a better cognitive measure than commonly used AVLT scores to assess CSF levels of p-tau and t-tau in nondemented individuals. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Different associations between amyloid-βeta 42, amyloid-βeta 40, and amyloid-βeta 42/40 with soluble phosphorylated-tau and disease burden in Alzheimer’s disease: a cerebrospinal fluid and fluorodeoxyglucose-positron emission tomography study

BackgroundDespite the high sensitivity of cerebrospinal fluid (CSF) amyloid beta (Aβ)42 to detect amyloid pathology, the Aβ42/Aβ40 ratio (amyR) better estimates amyloid load, with higher specificity for Alzheimer’s disease (AD). However, whether Aβ42 and amyR have different meanings and whether Aβ40 represents more than an Aβ42-corrective factor remain to be clarified. Our study aimed to compare the ability of Aβ42 and amyR to detect AD pathology in terms of p-tau/Aβ42 ratio and brain glucose metabolic patterns using fluorodeoxyglucose-positron emission tomography (FDG-PET).MethodsCSF biomarkers were analyzed with EUROIMMUN ELISA. We included 163 patients showing pathological CSF Aβ42 and normal p-tau (A + T −  = 98) or pathological p-tau levels (A + T +  = 65) and 36 control subjects (A − T −). A + T − patients were further stratified into those with normal (CSFAβ42 + /amyR −  = 46) and pathological amyR (CSFAβ42 + /amyR +  = 52). We used two distinct cut-offs to determine pathological values of p-tau/Aβ42: (1) ≥ 0.086 and (2) ≥ 0.122. FDG-PET patterns were evaluated in a subsample of patients (n = 46) and compared to 24 controls.ResultsCSF Aβ40 levels were the lowest in A − T − and in CSFAβ42 + /amyR − , higher in CSFAβ42 + /amyR + and highest in A + T + (F = 50.75; p < 0.001), resembling CSF levels of p-tau (F = 192; p < 0.001). We found a positive association between Aβ40 and p-tau in A − T − (β = 0.58; p < 0.001), CSFAβ42 + /amyR − (β = 0.47; p < 0.001), and CSFAβ42 + /amyR + patients (β = 0.48; p < 0.001) but not in A + T + . Investigating biomarker changes as a function of amyR, we observed a weak variation in CSF p-tau (+ 2 z-scores) and Aβ40 (+ 0.8 z-scores) in the normal amyR range, becoming steeper over the pathological threshold of amyR (p-tau: + 5 z-scores, Aβ40: + 4.5 z-score). CSFAβ42 + /amyR + patients showed a significantly higher probability of having pathological p-tau/Aβ42 than CSFAβ42 + /amyR − (cut-off ≥ 0.086: OR 23.3; cut-off ≥ 0.122: OR 8.8), which however still showed pathological values of p-tau/Aβ42 in some cases (cut-off ≥ 0.086: 35.7%; cut-off ≥ 0.122: 17.3%) unlike A − T − . Accordingly, we found reduced FDG metabolism in the temporoparietal regions of CSFAβ42 + /amyR − compared to controls, and further reduction in frontal areas in CSFAβ42 + /amyR + , like in A + T + .ConclusionsPathological p-tau/Aβ42 and FDG hypometabolism typical of AD can be found in patients with decreased CSF Aβ42 levels alone. AmyR positivity, associated with higher Aβ40 levels, is accompanied by higher CSF p-tau and widespread FDG hypometabolism.