Higher P-tau Research Articles

ALS plasma biomarkers reveal neurofilament and pTau correlate with disease onset and progression.

We performed a pilot screen to assess the utility of the NULISA™ (Nucleic-acid-Linked Immuno-Sandwich Assay) platform in the identification of amyotrophic lateral sclerosis (ALS) biomarkers. Plasma from 86 individuals (48 ALS, 18 asymptomatic C9orf72 repeat expansion carriers (AsymC9), and 20 healthy controls) was analyzed via a multiplexed NULISA™ assay that includes 120 neurodegeneration-associated proteins. Statistical analysis of NULISA™ results was performed to identify proteins differentially expressed in plasma and their correlation with disease-associated parameters. ALS plasma showed elevation of the established biomarkers, neurofilament light chain (NEFL) and neurofilament heavy chain (NEFH). Compared to controls and AsymC9, microtubule-associated protein tau (MAPT), phosphorylated tau 181 (pTau181), phosphorylated tau 217 (pTau217), phosphorylated tau 231 (pTau231), and phosphorylated TDP-43 (pTDP-43) were elevated in ALS. NEFL levels positively correlated with pTau181, pTau217, pTau231, and pTDP-43. MAPT and pTDP-43 were also correlated with pTau181, pTau217 and pTau231. Elevated pTau was negatively correlated with survival and ALSFRS-R. Spinal onset ALS was associated with higher pTau181, pTau217, and pTau231. We confirm previous reports showing elevated pTau181 in ALS plasma and show elevation of other phosphorylated tau forms, pTau217 and pTau231, typically observed in Alzheimer's disease. We provide preliminary data showing the detection and elevation of pTDP-43-409/410 in a subset of ALS samples compared to healthy controls. Neurofilament and tau levels are highly correlated suggesting their elevation may reflect a common pathology and disease state. Total and phosphorylated tau are correlated with multiple disease measures, such as ALS duration, ALSFRS-R, and site of onset.

Blood-Based Biomarkers and Risk of Onset of Mild Cognitive Impairment Over the Short and Long Term.

Blood-based biomarkers of amyloid and tau have been shown to predict Alzheimer disease (AD) dementia. Much less is known about their ability to predict risk of mild cognitive impairment (MCI), an earlier disease stage. This study examined whether levels of blood biomarkers of amyloid (Aβ42/Aβ40 ratio), tau (p-tau181), neurodegeneration (NfL), and glial activation and neuroinflammation (glial fibrillary acidic protein [GFAP], YKL40, soluble triggering receptor expressed on myeloid cells 2 [sTREM2]) collected when participants were cognitively normal are associated with the time to onset of MCI. Cognitively unimpaired participants from the longitudinal observational BIOCARD study provided blood plasma at their baseline evaluation ("baseline 1"). A second "baseline" specimen (collected using slightly different procedures) was evaluated for participants who were still cognitively normal approximately 7 years later. The plasma assays were based on the NeuroToolKit (cobas Elecsys assays, Roche Diagnostics). Cox regression models tested the association of biomarker levels with time to MCI symptom onset, separately for both baselines. Participants included 271 individuals at "baseline 1" (mean age = 57.5 years, 60.5% female, including 82 who progressed to MCI/dementia) and 202 individuals at "baseline 2" (mean age = 64.5 years, 62.4% female, including 31 progressors). The mean clinical follow-up was 15.5 years for "baseline 1" and 9.9 years for "baseline 2." For both baselines, lower plasma Aβ42/Aβ40 ratio (both hazard ratios, HRs ≤ 0.69, 95% CIs ≤ 0.55-0.87, p ≤ 0.034), higher GFAP (HRs ≥ 1.83, CIs ≥ 1.28-2.60, p < 0.002), and a higher ratio of p-tau181/(Aβ42/Aβ40) (HRs ≥ 1.64, CIs ≥ 1.25-2.13, p ≤ 0.001) were each associated with an earlier time to MCI symptom onset. For baseline 2, higher p-tau181 (HR = 2.07, CI = 1.12-3.83, p = 0.021) and higher NfL (HR = 1.75, CI = 0.99-3.10, p = 0.05) were also associated with earlier MCI symptom onset for progression within 7 years. When combining biomarkers, neither GFAP nor NFL was associated with MCI symptom onset after accounting for AD biomarker levels (e.g., p-tau181/(Aβ42/Aβ40)), which remained significant. YKL40 and sTREM2 were not associated with MCI onset. Results indicate that during preclinical AD, more abnormal blood biomarker levels of amyloid (Aβ42/Aβ40), p-tau181, neurodegeneration (NfL), and neuroinflammation (GFAP) individually are associated with progression from normal cognition to MCI, but the AD-nonspecific neurodegeneration and inflammation markers were not associated with symptom onset after accounting for amyloid and p-tau levels.

Differences of longitudinal plasma biomarkers between single memory domain and multidomain subject cognitive decline: Evidence from SILCODE.

Plasma biomarkers demonstrated potential in identifying amyloid pathology in early Alzheimer's disease. Different subtypes of subjective cognitive decline (SCD) may lead to different cognitive impairment conversion risks. To investigate the differences of plasma biomarkers in SCD subtypes individuals, which were unclear. The 347 individuals were involved, including 93 normal controls (NC), 76 single memory domain SCD (sd-SCD), 79 multidomain SCD (md-SCD), 55 mild cognitive impairment and 44 dementia. We investigated plasma biomarkers (Aβ42/40, p-tau181, p-tau217, NfL, and GFAP) and neuropsychological scales in the baseline and follow-up. The Kaplan-Meier survival analysis and Cox proportional hazards model were performed to investigate the risk of cognitive decline conversion. The t-test, Mann-Whitney U and multiple linear regression analysis were employed to evaluate the rate of change and correlation between PET-SUVR and plasma biomarker change. In cognitively normal subjects, md-SCD exhibited lower Aβ42/40 and higher p-tau181 and p-tau217 levels. Kaplan-Meier survival analysis revealed that md-SCD group exhibited a higher risk of cognitive decline conversion compared to NC and sd-SCD. Within SCD subgroups, those with positive GFAP status showed higher conversion risk than negative. In the Cox model, the risk of conversion in the md-SCD group was 2.77 times higher than sd-SCD. The md-SCD group demonstrated a faster rate of Aβ42/40 decline than sd-SCD. The study utilized plasma biomarkers to highlight the significance of staging in SCD. In cognitively normal subjects, md-SCD presents a higher risk of cognitive decline than sd-SCD, providing a valuable reference and convenient tool for early identification of individuals at risk for AD.

Interplay between oxidative stress, neuroinflammatory cytokines and melatonin in Alzheimer's disease: Insights from cerebrospinal fluid analysis.

Among neurodegenerative disorders Alzheimer's disease (AD) displays the highest prevalence and the projected increase in its incidence will require new advances in early diagnosis and treatment, particularly for distinguishing AD from other dementias. While beta-amyloid (Aβ) and tau biomarkers are currently used to discriminate AD from other tauopathies and dementias, additional indicators could enhance patient stratification for specific dementia types. The present study was designed to find potential associations among the classic neurologic markers, Aβ, total and phospho-tau (T-tau and P-tau), with other biomarkers including melatonin and its oxidative-derived metabolite, Formyl-N-acetyl-5-methoxykynurenamine (AFMK) levels, assayed in patients' cerebrospinal fluid (CSF) taken previously for diagnostic purposes. Other factors previously associated with the aetiology of AD, including redox indicators or proinflammatory biomarkers, were also included. The cross-sectional study included a cohort of 148 patients showing signs of dementia. A group of age-matched patients without neurological disorders were used as controls. CSF levels of Aβ, T-tau and P-tau were assayed, and patients were further classified according to threshold CSF levels of the three markers protein following the criteria of NIA-AA. Correlational and group analysis showed a positive association between oxidative stress and neuronal damage. TNF-α negatively correlated with CSF Aβ levels (amyloid plaques) while only RANTES/CCL5 correlated positively with T-tau and P-tau. Qualitative analysis of the proinflammatory cytokines assayed showed a higher detection level in Aβ-positive patients. Regarding melatonin in the CSF, indolamine levels did not correlate with its major oxidative-derived metabolite, i.e., AFMK. However, melatonin CSF levels were significantly reduced in AD patients but not in OT. On the contrary, AFMK showed the opposite pattern, with higher levels in samples from patients displaying high T-tau and P-tau levels. Neuroinflammation was associated with Aβ deposits (low concentration in CSF), while oxidative stress significantly correlated with high T-tau and P-tau levels. Finally, among all the parameters assayed in CSF samples from the cohort studied, P-tau, in combination with antioxidant capacity, offered the best ROC curve for the diagnostic capacity to discriminate between AD and OT, showing an 85% specificity. While oxidative stress is instead associated with high T- and P-tau levels, higher neuroinflammatory cytokines correlate with low CSF Aβ levels. An intriguing lack of correlation between neuroinflammation and melatonin found in this study could be as a result of sample size and requires further studies with a larger sample size. Even though indolamine levels in CSF drop significantly in AD, they do not correlate with AFMK, suggesting a different kynurenine synthesis source. None of them appear to discriminate between AD and OT. Finally, among all the parameters assayed in this study, P-tau in combination with antioxidant capacity, offered the best ROC curve for the diagnostic ability capacity to discriminate between AD and OT, showing an 85% specificity. This study holds the potential to significantly improve patient stratification and contribute to the early diagnosis and treatment of Alzheimer's disease.

Influence of APOE ε4 on performance of CSF biomarkers in differentiating clinical Alzheimer's disease.

Apolipoprotein E ε4 (APOE ε4) bring the higher risk of Alzheimer' Disease (AD). It is essential to evaluate whether the diagnostic performances and critical values of cerebrospinal fluid (CSF) biomarkers are influenced by APOE ε4, which has guiding significance for the clinical practical application. The differences in CSF biomarkers and their performances between APOE ε4 carriers and non-carriers in distinguishing AD, mild cognitive impairment (MCI) and preclinical AD from normal controls (NCs) were analyzed. The receiver operating characteristic (ROC) curves were generated to compare the area under the curve (AUC) between APOE ε4 carriers and non-carriers, as well as the critical values corresponding Youden Index. In a cross sectional convenience sample of 1610 participants, lower Aβ42 and Aβ42/Aβ40 and higher p-Tau 181/Aβ42 in CSF were observed among APOE ε4 carriers than non-carriers in NC, MCI, and AD groups (P< 0.05). The performance of CSF p-tau/Aβ42 in distinguishing MCI from NC among APOE ε4 carriers was superior to non-carriers [AUC: 0.714 (95%CI: 0.673- 0.752) vs 0.600 (95%CI: 0.564- 0.634), P< 0.001], although it was similar in distinguishing AD from NC between APOE ε4 carriers and non-carriers [AUC: 0.874 (95%CI: 0.835-0.906) vs 0.876 (95%CI: 0.843- 0.904)]. In the longitudinal cohort of 254 participants, the association of CSF Aβ42, Aβ42/Aβ40 and p-Tau181/Aβ42 with cognitive decline were stronger in APOE ε4 carriers compared to non-carriers (P< 0.05). Meanwhile, the critical values were different depending on APOE genotype. The CSF level of p-Tau181/Aβ42 was significantly different between APOE ε4 carriers and non-carriers at different stages of AD. The results indicate that the performances of CSF biomarkers are influenced by APOE ε4, which should be considered in the practical application.

Plasma phosphorylated tau and neuropsychiatric symptoms in dementia with Lewy bodies.

Neuropsychiatric symptoms (NPSs) are common in dementia with Lewy bodies (DLB) but their neurobiological mechanisms are poorly understood. NPSs and cognition were assessed annually in participants (DLB n=222; Alzheimer's disease [AD] n=125) from the European DLB (E-DLB) Consortium, and plasma phosphorylated tau-181 (p-tau181) and p-tau231 concentrations were measured at baseline. Hallucinations, delusions, and depression were more common in DLB than in AD and, in a subgroup with longitudinal follow-up, persistent hallucinations and NPSs were associated with lower p-tau181 and p-tau231 in DLB. In adjusted linear mixed-effects models, hallucinations at baseline were associated with greater longitudinal cognitive impairment in DLB, with a significant interaction with p-tau231. Higher p-tau181 and p-tau231 levels were associated with a lower longitudinal risk of NPSs and hallucinations in early-stage DLB. However, the interaction between hallucinations and p-tau231 suggests that when AD co-pathology and hallucinations do co-exist in DLB that they may synergistically exacerbate cognitive decline. Neuropsychiatric symptoms (NPSs) were more common in dementia with Lewy bodies (DLB) than in Alzheimer's disease (AD). Lower plasma phosphorylated tau-231 (p-tau231) and p-tau181 levels were associated with persistent hallucinations in DLB. Lower plasma p-tau231 and p-tau181 levels were associated with an increased risk of persistent NPSs in early DLB. Hallucinations at baseline were associated with greater cognitive dysfunction in DLB, and there was an interaction with p-tau231.

Plasma p‐tau181 is associated with brain amyloid deposition and predicts MCI conversion to AD

AbstractBackgroundPlasma phosphorated tau 181 (p‐tau181) was found to change in concordance with amyloid PET and well before tau PET, suggesting that the secretion of p‐tau181 may represent a physiologic reaction to β‐amyloid plaques. Our study aimed to evaluate the relationship between amyloid PET plasma p‐tau181 and whether p‐tau181 predicts amnestic MCI to AD conversion.MethodWe included 98 participants (43 demented and 55 nondemented) who underwent florbetaben amyloid PET scan. Amyloid PET was interpreted by visual assessment based on brain amyloid plaque load score (BAPL). The plasma p‐tau181 level were tested using Simoa assays. Another longitudinal cohort of 37 amnestic MCI patients were tested plasma p‐tau181 level at baseline were followed up at for at least one year. ANOVA and logistic regression were used to evaluate p‐tau181 level between amyloid and cognitive status. Cox regression was used to examine p‐tau181 level and MCI conversion to AD.ResultBrain amyloid deposition was found in 51% (21/43) of the demented participants, and 11% (6/55) in the nondemented. The plasma p‐tau181 level was significantly higher in the amyloid positive individuals (p&lt;0.001). P‐tau181 alone discriminates amyloid status with an AUC of (0.889, 95% CI 0.826–0.951). In the longitudinal amnestic MCI cohort, 49% (18/37) converted to AD during follow‐up. A P‐tau181 cutoff at 2.545 alone was able to predict conversion where higher Ptau181 has shorter conversion free survival (median survival time in month, 35.0 vs 14.0, p=0.029).ConclusionHigher plasma p‐tau181 was associated with brain amyloid deposition and MCI conversion to AD. Plasma p‐tau181 could be a surrogate blood‐based biomarker for amyloid positivity and predicts prognosis in MCI.

Personality and Biomarkers of Neurodegeneration and Alzheimer’s Disease in Swedish Older Adults

Abstract Background Personality is associated with dementia risk. Neuroticism and conscientiousness may be involved in resistance and resilience to Alzheimer’s Disease (AD) pathology (ADP). These traits have also been associated with unspecific biomarkers of neurodegeneration; glial fibrillary acidic protein (GFAP) and neurofilament light (NfL). This study explores the role of personality in cognitive ageing. Methods We used data from the Swedish population-based studies H70 (individuals age 70 years only), and SNAC-K (individuals ages 60-104). Personality was assessed with the NEO-five-factor inventory. In H70, biomarkers of ADP were measured in cerebrospinal fluid (CSF, N = 305), except NfL which was also available in plasma (N = 1082). In SNAC-K (N = 1754), all biomarkers were measured in serum. We used multivariable regression models to evaluate the association between personality traits and ADP biomarkers, GFAP and NfL among individuals without dementia. We further examined if associations differed by age (SNAC-K only) and sex. Results In H70, higher neuroticism and was associated with lower Aβ42/Aβ40 ratio (B=-0.01, p = 0.02). In SNAC-K, higher openness was associated with lower NfL (B=-0.04, p = 0.03). For age 60-66, higher openness was associated with lower NfL (B=-0.09, p = 0.01), higher neuroticism was associated with higher GFAP (B = 0.09, p = 0.01), and NfL (B = 0.10, p = 0.003). For age &amp;gt;80, higher openness was associated with higher ptau-181, (B = 0.14, p = 0.01), and ptau-181/Aβ42 ratio (B = 0.15, p = 0.003). Conclusions Higher neuroticism and lower openness are associated with neurodegeneration. Higher openness may also be associated with resilience to AD-pathology. Key messages • Neuroticism may contribute to neurodegeneration in people &amp;lt;70. • Openness may contribute to cognitive resilience to ADP in people &amp;gt;80.

Biomarker Assessment in Parkinson's Disease Dementia and Dementia with Lewy Bodies by the Immunomagnetic Reduction Assay and Clinical Measures.

Plasma biomarker assays provide an opportunity to reassess whether Alzheimer's disease, Parkinson's disease dementia (PDD), and dementia with Lewy bodies (DLB) plasma biomarkers are diagnostically useful. We hypothesized that immunomagnetic reduction (IMR) of plasma biomarkers could differentiate between patients with PDD and DLB and healthy patients when combined with established clinical testing measures. Plasma samples from 61 participants (12 PDD, 12 DLB, 37 controls) were analyzed using IMR to quantify amyloid-β 42 (Aβ42), total tau (t-tau), phosphorylated tau at threonine 181 (p-tau181), and α-synuclein (α-syn). Receiver operating characteristic curve (ROC) analysis was used to obtain sensitivity, specificity, and area under the ROC curve. Biomarker results were combined with clinical measures from the Unified Parkinson's Disease Rating Scale (UPDRS), Montreal Cognitive Assessment, and Hoehn-Yahr stage to optimize diagnostic test performance. Participants with PDD had higher α-syn than those with DLB and healthy participants and were distinguishable by their biomarker products Aβ42×p-tau181 and Aβ42×α-syn. Patients with DLB had higher p-tau181 than those with PDD and healthy participants and were distinguishable by their concentrations of α-syn×p-tau181. Plasma α-syn plus UPDRS versus either test alone increased sensitivity, specificity, and AUC when healthy patients were compared with those with PDD and DLB. Combined clinical examination scores and plasma biomarker products demonstrated utility in differentiating PDD from DLB when p-tau181 was combined with UPDRS, α-syn was combined with UPDRS, and α-syn×p-tau181 was combined with UPDRS. In this pilot study, IMR plasma p-tau181 and α-syn may discriminate between PDD and DLB when used in conjunction with clinical testing.

Plasma NfL, GFAP, amyloid, and p-tau species as Prognostic biomarkers in Parkinson’s disease

IntroductionThe prognostic role of plasma neurofilament light chain (NfL), phospho-tau, beta-amyloid, and GFAP is still debated in Parkinson’s disease (PD).MethodsPlasma p-tau181, p-tau231, Aβ1-40, Aβ1-42, GFAP, and NfL were measured by SIMOA in 136 PD with 2.9 + 1.7 years of follow-up and 76 controls. Differences in plasma levels between controls and PD and their correlation with clinical severity and progression rates were evaluated using linear regression analyses.ResultsPatients exhibited similar distribution of plasma biomarkers but higher P-tau181, P-tau231 and lower Aβ1-42 compared with controls. NfL and GFAP correlated with baseline motor and non-motor severity measures. At follow-up, NfL emerged as the best predictor of progression with marginal effect of GFAP and p-tau181 adjusting for age, sex, disease duration, and baseline motor severity.ConclusionThe present findings confirmed plasma NfL as best predictor of progression in PD, with a marginal role of p-tau181 and GFAP.

Cognition Mediates the Association Between Cerebrospinal Fluid Biomarkers of Amyloid and P-Tau and Neuropsychiatric Symptoms.

Neuropsychiatric symptoms (NPS) can be an early manifestation of Alzheimer's disease (AD). However, the associations among NPS, cognition, and AD biomarkers across the disease spectrum are unclear. We analyzed cross-sectional mediation pathways between cerebrospinal fluid (CSF) biomarkers of AD (Aβ1-42, p-tau181), cognitive function, and NPS. Primary models included 781 participants from the National Alzheimer's Coordinating Center (NACC) data set who had CSF analyzed for AD biomarkers using Lumipulse. NPS were assessed with the Neuropsychiatric Inventory Questionnaire (NPI-Q). We assessed cognition with the harmonized MMSE/MoCA, as well as neuropsychological tests sensitive to AD pathology: story recall, naming, animal fluency, and Trails B. The Clinical Dementia Rating (CDR®) scale assessed dementia severity. Mediation models were estimated with Kemeny metric covariance in a structural equation model framework, controlling for age, education, sex, and APOEɛ4. The sample was older adults (M = 73.85, SD = 6.68; 49.9% male, 390; 27.9% dementia, 218) who were predominantly white (n = 688, 88.1%). Higher p-tau181/Aβ1-42 ratio predicted higher NPI-Q, which was partially mediated by the MMSE/MoCA and, in a second model, story recall. No other pathway was statistically significant. Both the MMSE/MoCA and NPI-Q independently mediated the association between p-tau181/Aβ1-42 ratio and CDR global impairment. With dementia excluded, p-tau181/Aβ1-42 ratio was no longer associated with the NPI-Q. NPS may be secondary to cognitive impairment and AD pathology through direct and indirect pathways. NPS independently predict dementia severity in AD. However, AD pathology likely plays less of a role in NPS in samples without dementia.

Sex differences in Alzheimer's disease blood biomarkers in a Caribbean population of African ancestry: The Tobago Health Study.

Alzheimer's disease (AD) is increasing in the Caribbean, especially for persons of African ancestry (PAA) and women. However, studies have mostly utilized surveys without AD biomarkers. In the Tobago Health Study (n = 309; 109 women, mean age 70.3±6.6), we assessed sex differences and risk factors for serum levels of phosphorylated tau-181 (p-tau181), amyloid-beta (Aβ)42/40 ratio, glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). Blood samples were from 2010 to 2013 for men and from 2019 to 2023 for women. Women were more obese, hypertensive, and sedentary but reported less smoking and alcohol use than men (age-adjusted p<0.04). Compared to men, women had worse levels of AD biomarkers, with higher p-tau181 and lower Aβ42/40, independent of covariates (p<0.001). In sex-stratified analyses, higher p-tau181 was associated with older age in women and with hypertension in men. GFAP and NfL did not differ by sex. Women had worse AD biomarkers than men, unexplained by age, cardiometabolic diseases, or lifestyle. Studying risk factors for AD in PAA is warranted, especially for women earlier in life.

Alzheimer's Disease and Cognitive Decline in Patients with Cardiovascular Diseases Along the Heart-Brain Axis.

We hypothesize that Alzheimer's disease (AD)-related pathology may accelerate cognitive decline in patients with cardiovascular diseases. To investigate the association between blood-based biomarkers of AD, astrocyte activation, and neurodegeneration and cognitive decline. From the multi-center Heart-Brain study, we included 412 patients with heart failure, carotid occlusive disease or vascular cognitive impairment (age:68.6±9.0) and 128 reference participants (65.7±7.5). Baseline amyloid-β42/40 (Aβ42/40), phosphorylated-tau181 (pTau181), glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) were determined using SiMoA (Quanterix). Memory, attention, language, and executive functioning were evaluated (follow-up:2.1±0.3 years). We applied linear mixed models with terms for biomarker, time and biomarker*time interactions, adjusted for age, sex, education, and site, to assess associations between biomarkers and cognitive decline. Among patients, Aβ42/40 was not associated with cognitive performance at baseline. However, lower Aβ42/40 was associated with steeper decline in global cognition (β±SE:0.04±0.02). Higher pTau181 was associated with worse baseline performance on global cognition (-0.14±0.04) and memory (-0.31±0.09) and with steeper decline in global cognition (-0.07±0.02), memory (-0.09±0.04), attention (-0.05±0.02), and language (-0.10±0.03). Higher GFAP was associated with worse baseline performance on global cognition (-0.22±0.05), memory (-0.43±0.10), attention (-0.14±0.06), language (-0.15±0.05), and executive functioning (-0.15±0.05) and steeper decline in global cognition (-0.05±0.01). Higher NfL was associated with worse baseline performance on global cognition (-0.16±0.04), memory (-0.28±0.09), attention (-0.20±0.06), and executive functioning (-0.10±0.04), but was not associated with performance over time. In reference participants, no associations were found. Our findings suggest that blood-based biomarkers of AD-related pathology predict cognitive decline in patients with cardiovascular diseases.

Lifetime Stressful Events Associated with Alzheimer's Pathologies, Neuroinflammation and Brain Structure in a Risk Enriched Cohort.

Along with the known effects of stress on brain structure and inflammatory processes, increasing evidence suggest a role of chronic stress in the pathogenesis of Alzheimer's disease (AD). We investigated the association of accumulated stressful life events (SLEs) with AD pathologies, neuroinflammation, and gray matter (GM) volume among cognitively unimpaired (CU) individuals at heightened risk of AD. This cross-sectional cohort study included 1,290 CU participants (aged 48-77) from the ALFA cohort with SLE, lumbar puncture (n = 393), and/or structural magnetic resonance imaging (n = 1,234) assessments. Using multiple regression analyses, we examined the associations of total SLEs with cerebrospinal fluid (1) phosphorylated (p)-tau181 and Aβ1-42/1-40 ratio, (2) interleukin 6 (IL-6), and (3) GM volumes voxel-wise. Further, we performed stratified and interaction analyses with sex, history of psychiatric disease, and evaluated SLEs during specific life periods. Within the whole sample, only childhood and midlife SLEs, but not total SLEs, were associated with AD pathophysiology and neuroinflammation. Among those with a history of psychiatric disease SLEs were associated with higher p-tau181 and IL-6. Participants with history of psychiatric disease and men, showed lower Aβ1-42/1-40 with higher SLEs. Participants with history of psychiatric disease and women showed reduced GM volumes in somatic regions and prefrontal and limbic regions, respectively. We did not find evidence supporting the association of total SLEs with AD, neuroinflammation, and atrophy pathways. Instead, the associations appear to be contingent on events occurring during early and midlife, sex and history of psychiatric disease. ANN NEUROL 2024;95:1058-1068.

Plasma Markers of Alzheimer's Disease Pathology, Neuronal Injury, and Astrocytic Activation and MRI Load of Vascular Pathology and Neurodegeneration: TheSMART-MR Study.

Two of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aβ (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration. Cross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010). Plasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Association of Vascular Risk Factors and CSF and Imaging Biomarkers With White Matter Hyperintensities in Former American Football Players.

Recent data link exposure to repetitive head impacts (RHIs) from American football with increased white matter hyperintensity (WMH) burden. WMH might have unique characteristics in the context of RHI beyond vascular risk and normal aging processes. We evaluated biological correlates of WMH in former American football players, including markers of amyloid, tau, inflammation, axonal injury, neurodegeneration, and vascular health. Participants underwent clinical interviews, MRI, and lumbar puncture as part of the Diagnostics, Imaging, and Genetics Network for the Objective Study and Evaluation of Chronic Traumatic Encephalopathy Research Project. Structural equation modeling tested direct and indirect effects between log-transformed total fluid-attenuated inversion recovery (FLAIR) lesion volumes (TLV) and the revised Framingham stroke risk profile (rFSRP), MRI-derived global metrics of cortical thickness and fractional anisotropy (FA), and CSF levels of amyloid β1-42, p-tau181, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), and neurofilament light. Covariates included age, race, education, body mass index, APOE ε4 carrier status, and evaluation site. Models were performed separately for former football players and a control group of asymptomatic men unexposed to RHI. In 180 former football players (mean age = 57.2, 36% Black), higher log(TLV) had direct associations with the following: higher rFSRP score (B = 0.26, 95% CI 0.07-0.40), higher p-tau181 (B = 0.17, 95% CI 0.01-0.43), lower FA (B = -0.28, 95% CI -0.42 to -0.13), and reduced cortical thickness (B = -0.25, 95% CI -0.45 to -0.08). In 60 asymptomatic unexposed men (mean age = 59.3, 40% Black), there were no direct effects on log(TLV) (rFSRP: B = -0.03, 95% CI -0.48 to 0.57; p-tau181: B = -0.30, 95% CI -1.14 to 0.37; FA: B = -0.07, 95% CI -0.48 to 0.42; or cortical thickness: B = -0.28, 95% CI -0.64 to 0.10). The former football players showed stronger associations between log(TLV) and rFSRP (1,069% difference in estimates), p-tau181 (158%), and FA (287%) than the unexposed men. Risk factors and biological correlates of WMH differed between former American football players and asymptomatic unexposed men. In addition to vascular health, p-tau181 and diffusion tensor imaging indices of white matter integrity showed stronger associations with WMH in the former football players. FLAIR WMH may have specific risk factors and pathologic underpinnings in RHI-exposed individuals.

Cortical microstructural associations with CSF amyloid and pTau

Diffusion MRI (dMRI) can be used to probe microstructural properties of brain tissue and holds great promise as a means to non-invasively map Alzheimer’s disease (AD) pathology. Few studies have evaluated multi-shell dMRI models such as neurite orientation dispersion and density imaging (NODDI) and mean apparent propagator (MAP)-MRI in cortical gray matter where many of the earliest histopathological changes occur in AD. Here, we investigated the relationship between CSF pTau181 and Aβ1–42 burden and regional cortical NODDI and MAP-MRI indices in 46 cognitively unimpaired individuals, 18 with mild cognitive impairment, and two with dementia (mean age: 71.8 ± 6.2 years) from the Alzheimer’s Disease Neuroimaging Initiative. We compared findings to more conventional cortical thickness measures. Lower CSF Aβ1–42 and higher pTau181 were associated with cortical dMRI measures reflecting less hindered or restricted diffusion and greater diffusivity. Cortical dMRI measures, but not cortical thickness measures, were more widely associated with Aβ1–42 than pTau181 and better distinguished Aβ+ from Aβ- participants than pTau+ from pTau- participants. dMRI associations mediated the relationship between CSF markers and delayed logical memory performance, commonly impaired in early AD. dMRI metrics sensitive to early AD pathogenesis and microstructural damage may be better measures of subtle neurodegeneration in comparison to standard cortical thickness and help to elucidate mechanisms underlying cognitive decline.

The relationship between Structural, PET, and Plasma Alzheimer’s Disease Biomarkers and neuropsychological composites among Latino bilinguals and monolinguals

AbstractBackgroundEstimates from the Alzheimer’s Association indicate that approximately one in ten older adults in the US have Alzheimer’s disease (AD) dementia while 15 to 20% have mild cognitive impairment (MCI), projecting that about a third of those will develop dementia within five years. The Cognitive Reserve/ Resilience (CR/R) theory postulates that complex mental activity throughout the lifetime builds resilience to cognitive decline despite the biological risk (a neurodegenerative disease). Emerging evidence shows that bilingualism may be one of these neuroprotective factors in the aging brain, but results in bilingualism and CR/R remain inconsistent.MethodsWe studied 238 Latino older adults (age 71.8 ± 8.0 years old, 65% female) from the 1Florida Alzheimer’s Disease Research Center who were diagnosed as clinically normal, MCI, or dementia. Of these, 158 were Spanish‐English bilinguals and 80 were Spanish monolinguals. Bilingualism was assessed by a proficiency questionnaire. Six cognitive composites were developed (Figure 1). We investigated cognitive test correlates of plasma P‐tau181 (Quanterix simoa), hippocampal volume, and amyloid PET (Centiloid) biomarkers in both language groups, using 2×3 ANCOVAs (controlling for age and level of education). We analyzed correlations between biomarkers and cognition and performed multiple regression analyses within each language group.ResultsThe main effect of the diagnostic group was significant for all biomarkers (ps &lt; .001). There was no main effect of the language group and no significant interactions. The correlations between biomarkers were equally significant for both language groups but differences in the association of biomarkers with cognitive tests emerged between language groups. Bilinguals showed a stronger negative association between hippocampal volume and cognitive test scores than monolinguals. In bilinguals, higher PTau181 was associated with lower visuomotor composite scores, while amyloid PET positivity and lower hippocampal volume were associated with cognitive stress and working memory. In monolinguals, higher PTau181 was associated with worse inhibitory control, and amyloid PET positivity and lower hippocampal volume were associated with worse memory.ConclusionResults demonstrated discrepancies between bilingual and monolingual Latinos in the associations between cognitive composites and AD biomarkers. Further exploring the relationship between bilingualism, cognitive test scores, and biomarker patterns is warranted, especially longitudinally.

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aß42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.

Altered BOLD Signal Fluctuations in precuneus relate to inflammatory markers and vascular risk in the AD spectrum

AbstractBackgroundInflammation, vascular disease and Alzheimer’s Disease (AD) appear to be closely linked. We recently showed that increased vascular risk relates to certain inflammatory profiles in CSF in the DELCODE cohort (Hayek et al, AAIC 2022). Moreover, we found cerebrovascular alterations in posterior‐midline regions including precuneus in subjects at risk for AD and with cognitive impairment relative to controls (Behrenbruch et al). Here, we examined the contributions of vascular risk and related inflammatory markers to alterations in resting‐state fMRI BOLD fluctuations that are sensitive to cerebrovascular reactivity (CVR)—a proposed marker of cerebrovascular dysfunction.MethodLeveraging resting‐state fMRI BOLD signal, we mapped voxel‐wise relative CVR (rCVR), using mean global signal as regressor, and the relative coefficient of variation (rCV). See Figure 1 for methodological details. We derived average rCV/rCVR from the precuneus as region of interest. Inflammation‐related CSF markers and AD markers (ptau181 and Aβ42/40) from CSF were available in 205 subjects with rCVR/rCV maps. A Principal component (PC) analysis on 16 inflammation‐related CSF markers previously revealed 4 PCs. PC2 and PC3 were related to higher vascular risk scores (covering hypertension, diabetes and abnormal fat metabolism based on medical reports). We used linear regression models to assess how inflammation PC scores and AD biomarkers related to precuneus rCVR or rCV (controlling for age, sex, site, education and mean framewise displacement). We also tested if rCVR/rCV was related to vascular risk or memory.ResultLower precuneus rCVR was predicted by higher values of the inflammatory component PC2 (mainly driven by markers CRP, C1q and FactorB), with no additional effect of other PCs or AD markers. Lower precuneus rCV was predicted by higher values of the inflammatory component PC3 (mainly driven by IP10, MCP1, MIF, CRP, C4) and by higher ptau. Lower precuneus rCVR was also related to higher vascular risk. Lower rCVR and rCV related to worse memory. Figure 2 shows supplementary correlations of individual inflammation markers.ConclusionLower rCVR and rCV in the precuneus that are thought to reflect vascular dysfunction, relate to higher vascular‐risk related inflammatory markers beyond AD pathology. Their concurrent dynamics requires further investigation to understand their unique contributions to microvascular pathology.