Higher P-tau Research Articles

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 >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 <70. • Openness may contribute to cognitive resilience to ADP in people >80.

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

Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: 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.

The prognostic role of plasma neurofilament light chain (NfL), phospho-tau, beta-amyloid, and GFAP is still debated in Parkinson's disease (PD). Plasma p-tau181, p-tau231, Aβ1-40, Aβ1-42, GFAP, and NfL were measured by SIMOA in 136 PD with 2.9 + 1.7years 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. Patients 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. The 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.

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.

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.

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.

Proteomic Indicators of Health Predict Alzheimer's Disease Biomarker Levels and Dementia Risk.

Few studies have comprehensively examined how health and disease risk influence Alzheimer's disease (AD) biomarkers. The present study examined the association of 14 protein-based health indicators with plasma and neuroimaging biomarkers of AD and neurodegeneration. In 706 cognitively normal adults, we examined whether 14 protein-based health indices (ie, SomaSignal® tests) were associated with concurrently measured plasma-based biomarkers of AD pathology (amyloid-β [Aβ]42/40 , tau phosphorylated at threonine-181 [pTau-181]), neuronal injury (neurofilament light chain [NfL]), and reactive astrogliosis (glial fibrillary acidic protein [GFAP]), brain volume, and cortical Aβ and tau. In a separate cohort (n = 11,285), we examined whether protein-based health indicators associated with neurodegeneration also predict 25-year dementia risk. Greater protein-based risk for cardiovascular disease, heart failure mortality, and kidney disease was associated with lower Aβ42/40 and higher pTau-181, NfL, and GFAP levels, even in individuals without cardiovascular or kidney disease. Proteomic indicators of body fat percentage, lean body mass, and visceral fat were associated with pTau-181, NfL, and GFAP, whereas resting energy rate was negatively associated with NfL and GFAP. Together, these health indicators predicted 12, 31, 50, and 33% of plasma Aβ42/40 , pTau-181, NfL, and GFAP levels, respectively. Only protein-based measures of cardiovascular risk were associated with reduced regional brain volumes; these measures predicted 25-year dementia risk, even among those without clinically defined cardiovascular disease. Subclinical peripheral health may influence AD and neurodegenerative disease processes and relevant biomarker levels, particularly NfL. Cardiovascular health, even in the absence of clinically defined disease, plays a central role in brain aging and dementia. ANN NEUROL 2024;95:260-273.

57 CSF Markers of AD-Related Pathology Relate to aMCI among People with HIV

Objective:Older people with HIV (PWH) are at-risk for Alzheimer’s disease (AD) and its precursor, amnestic mild cognitive impairment (aMCI). Identifying aMCI among PWH is challenging because memory impairment is also common in HIV-associated neurocognitive disorders (HAND). The neuropathological hallmarks of aMCI/AD are amyloid-ß42 (Aß42) plaque and phosphorylated tau (p-tau) accumulation. Neurofilament light chain protein (NfL) is a marker of neuronal injury in AD and other neurodegenerative diseases. In this study, we assessed the prognostic value of the CSF AD pathology markers of lower Aß42, and higher p-tau, p-tau/Aß42 ratio, and NfL levels to identify an aMCI-like profile among older PWH and differentiating it from HAND. We assessed the relationship between aMCI and HAND diagnosis and AD biomarker levelsParticipants and Methods:Participants included 74 PWH (Mean age=48 [SD=8.5]; 87.4% male, 56.5% White) from the National NeuroAIDS Tissue Consortium (NNTC). CSF Aß42, Aß40, p-tau and NfL were measured by commercial immunoassay. Participants completed a neurocognitive evaluation assessing the domains of learning, recall, executive function, speed of information processing, working memory, verbal fluency, and motor. Memory domains were assessed with the Hopkins Verbal Learning Test-Revised and the Brief Visuospatial Memory Test-Revised, and aMCI was defined as impairment (&lt;1.0 SD below normative mean) on two or more memory outcomes among HVLT-R and BVMT-R learning, delayed recall and recognition with at-least one recognition impairment required. HAND was defined as impairment (&lt;1.0 SD below normative mean) in 2 or more cognitive domains. A series of separate linear regression models were used to examine how the levels of CSF p-tau, Aß42, p-tau/Aß42 ratio, and NfL relate to aMCI and HAND status while controlling for demographic variables (age, gender, race and education). Covariates were excluded from the model if they did not reach statistical significance.Results:58% percent of participants were diagnosed with HAND, 50.5% were diagnosed with aMCI. PWH with aMCI had higher levels of CSF p-tau/Aß42 ratio compared to PWH without aMCI (ß=.222, SE=.001, p=.043) while controlling for age (ß=.363, p=.001). No other AD biomarker significantly differed by aMCI or HAND status.Conclusions:Our results indicate that the CSF p-tau/Aß42 ratio relates specifically to an aMCI-like profile among PWH with high rates of cognitive impairment across multiple domains in this advanced HIV disease cohort. Thus, the p-tau/Aß42 ratio may have utility in disentangling aMCI from HAND and informing the need for further diagnostic procedures and intervention. Further research is needed to fully identify, among a broader group of PWH, who is at greatest risk for aMCI/AD and whether there is increased risk for aMCI/AD among PWH as compared to those without HIV.

Association of APOE gene with longitudinal changes of CSF amyloid beta and tau levels in Alzheimer's disease: racial differences.

The Apolipoprotein E (APOE) ε4 allele is a risk factor for late-onset Alzheimer's disease (AD). However, no investigation has focused on racial differences in the longitudinal effect of APOE genotypes on CSF amyloid beta (Aβ42) and tau levels in AD. This study used data from the Alzheimer's Disease Neuroimaging Initiative (ADNI): 222 participants with AD, 264 with cognitive normal (CN), and 692 with mild cognitive impairment (MCI) at baseline and two years follow-up. We used a linear mixed model to investigate the effect of APOE-ε4-genotypes on longitudinal changes in the amyloid beta and tau levels. Individuals with 1 or 2 APOE ε4 alleles revealed significantly higher t-Tau and p-Tau, but lower amyloid beta Aβ42 compared with individuals without APOE ε4 alleles. Significantly higher levels of log-t-Tau, log-p-Tau, and low levels of log-Aβ42 were observed in the subjects with older age, being female, and the two diagnostic groups (AD and MCI). The higher p-Tau and Aβ42 values are associated with poor Mini-Mental State Examination (MMSE) performance. Non-Hispanic Africa American (AA) and Hispanic participants were associated with decreased log-t-Tau levels (β = - 0.154, p = 0.0112; β = - 0.207, and p = 0.0016, respectively) as compared to those observed in Whites. Furthermore, Hispanic participants were associated with a decreased log-p-Tau level (β = - 0.224, p = 0.0023) compared to those observed in Whites. There were no differences in Aβ42 level for non-Hispanic AA and Hispanic participants compared with White participants. Our study, for the first time, showed that the APOE ε4 allele was associated with these biomarkers, however with differing degrees among racial groups.

Optimizing detection of Alzheimer’s disease in mild cognitive impairment: a 4-year biomarker study of mild behavioral impairment in ADNI and MEMENTO

BackgroundDisease-modifying drug use necessitates better Alzheimer disease (AD) detection. Mild cognitive impairment (MCI) leverages cognitive decline to identify the risk group; similarly, mild behavioral impairment (MBI) leverages behavioral change. Adding MBI to MCI improves dementia prognostication over conventional approaches of incorporating neuropsychiatric symptoms (NPS). Here, to determine if adding MBI would better identify AD, we interrogated associations between MBI in MCI, and cerebrospinal fluid biomarkers [β-amyloid (Aβ), phosphorylated-tau (p-tau), and total-tau (tau)-ATN], cross-sectionally and longitudinally.MethodsData were from two independent referral-based cohorts, ADNI (mean[SD] follow-up 3.14[1.07] years) and MEMENTO (4.25[1.40] years), collected 2003–2021. Exposure was based on three-group stratification: 1) NPS meeting MBI criteria; 2) conventionally measured NPS (NPSnotMBI); and 3) noNPS. Cohorts were analyzed separately for: 1) cross-sectional associations between NPS status and ATN biomarkers (linear regressions); 2) 4-year longitudinal repeated-measures associations of MBI and NPSnotMBI with ATN biomarkers (hierarchical linear mixed-effects models-LMEs); and 3) rates of incident dementia (Cox proportional hazards regressions).ResultsOf 510 MCI participants, 352 were from ADNI (43.5% females; mean [SD] age, 71.68 [7.40] years), and 158 from MEMENTO (46.2% females; 68.98 [8.18] years). In ADNI, MBI was associated with lower Aβ42 (standardized β [95%CI], -5.52% [-10.48-(-0.29)%]; p = 0.039), and Aβ42/40 (p = 0.01); higher p-tau (9.67% [3.96–15.70%]; p = 0.001), t-tau (7.71% [2.70–12.97%]; p = 0.002), p-tau/Aβ42 (p < 0.001), and t-tau/Aβ42 (p = 0.001). NPSnotMBI was associated only with lower Aβ42/40 (p = 0.045). LMEs revealed a similar 4-year AD-specific biomarker profile for MBI, with NPSnotMBI associated only with higher t-tau. MBI had a greater rate of incident dementia (HR [95%CI], 3.50 [1.99–6.17; p < 0.001). NPSnotMBI did not differ from noNPS (HR 0.96 [0.49–1.89]; p = 0.916). In MEMENTO, MBI demonstrated a similar magnitude and direction of effect for all biomarkers, but with a greater reduction in Aβ40. HR for incident dementia was 3.93 (p = 0.004) in MBI, and 1.83 (p = 0.266) in NPSnotMBI. Of MBI progressors to dementia, 81% developed AD dementia.ConclusionsThese findings support a biological basis for NPS that meet MBI criteria, the continued inclusion of MBI in NIA-AA ATN clinical staging, and the utility of MBI criteria to improve identification of patients for enrollment in disease-modifying drug trials or for clinical care.

Association of Alzheimer’s Plasma Biomarker Concentrations with Body Mass Index in Older Adults (P10-6.005)

<h3>Objective:</h3> To evaluate the relationship of chronic medical conditions and other characteristics, including body mass index (BMI), vascular risk factors, depression, head injury and education, with cognitive impairment and blood-based biomarkers of Alzheimer’s pathology, phosphorylated tau (P-tau 181, P-tau 217), in a multi-ethnic cohort. <h3>Background:</h3> Studies suggest that comorbidities may influence the levels of blood-based biomarkers for Alzheimer’s disease and their interpretation; however, these relationships must be further explored in ethnically diverse cohorts. In our recent multi-ethnic cohort study, 47% of cognitively impaired participants had low P-tau concentrations, and 31% of unimpaired participants had high P-tau concentrations. We sought to determine whether differences in risk factor profiles may help to explain the discordant groups in the same cohort. <h3>Design/Methods:</h3> Three hundred participants aged 65 and older were selected from a prospective community-based cohort for equal representation among three racial/ethnic groups: non-Hispanic White, Hispanic/Latino and African American/Black. Participants were classified into four diagnostic groups based on absence (Asym)/presence (Sym) of cognitive symptoms and low(−)/high(+) P-tau, determined in the same cohort: (Asym/P-tau−, Asym/P-tau+, Sym/P-tau−, Sym/P-tau). We examined differences in participant characteristics across the four groups. For significant factors, we also examined two-group differences according to cognitive symptoms (Asym/Sym) and P-tau (P-tau+/P-tau−). <h3>Results:</h3> BMI was lower in individuals with high P-tau 217 and 181 concentrations (25.7 vs. 27.9 kg/m²; 25.3 vs. 27.9 kg/m², respectively) but did not differ across dementia groups. Education was lower in individuals with dementia compared to those without (9.1 vs. 12.5 years), and it did not vary according to P-tau level. Frequencies of hypertension, diabetes, heart disease, smoking, head injury and depression did not differ between the four groups. <h3>Conclusions:</h3> Lower BMI is associated with higher P-tau concentrations but not with the presence or absence of dementia. This finding suggests that Alzheimer’s pathology may be accompanied by metabolic changes regardless of cognitive status. <b>Disclosure:</b> Ms. Hoost has nothing to disclose. Adam Brickman, PhD has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Cognition Therapeutics. Annie Lee has nothing to disclose. The institution of Dr. Gu has received research support from NIH. Ms. Sanchez has nothing to disclose. Mrs. Reyes-Dumeyer has nothing to disclose. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Honig has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Prevail. Dr. Honig has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cortexyme. Dr. Honig has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Legal Firms . The institution of Dr. Honig has received research support from Roche. The institution of Dr. Honig has received research support from Eisau. Dr. Honig has received research support from Alector. The institution of Dr. Honig has received research support from Transposon. The institution of Dr. Manly has received research support from NIH. Dr. Manly has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant with University of Mississippi. Rafael Lantigua has nothing to disclose. Dr. Kang has nothing to disclose. Dr. Dage has received personal compensation for serving as an employee of Eli Lilly and Company. Dr. Dage has stock in Eli Lilly and Company. Dr. Dage has stock in General Electric. Dr. Dage has received research support from Indiana University School Of Medicine. Dr. Dage has received intellectual property interests from a discovery or technology relating to health care. Dr. Mayeux has nothing to disclose.

Functional gradients of the medial parietal cortex in a healthy cohort with family history of sporadic Alzheimer’s disease

BackgroundThe medial parietal cortex is an early site of pathological protein deposition in Alzheimer’s disease (AD). Previous studies have identified different subregions within this area; however, these subregions are often heterogeneous and disregard individual differences or subtle pathological alterations in the underlying functional architecture. To address this limitation, here we measured the continuous connectivity gradients of the medial parietal cortex and assessed their relationship with cerebrospinal fluid (CSF) biomarkers, ApoE ε4 carriership and memory in asymptomatic individuals at risk to develop AD.MethodsTwo hundred sixty-three cognitively normal participants with a family history of sporadic AD who underwent resting-state and task-based functional MRI using encoding and retrieval tasks were included from the PREVENT-AD cohort. A novel method for characterizing spatially continuous patterns of functional connectivity was applied to estimate functional gradients in the medial parietal cortex during the resting-state and task-based conditions. This resulted in a set of nine parameters that described the appearance of the gradient across different spatial directions. We performed correlation analyses to assess whether these parameters were associated with CSF biomarkers of phosphorylated tau181 (p-tau), total tau (t-tau), and amyloid-ß1-42 (Aß). Then, we compared the spatial parameters between ApoE ε4 carriers and noncarriers, and evaluated the relationship between these parameters and memory.ResultsAlterations involving the superior part of the medial parietal cortex, which was connected to regions of the default mode network, were associated with higher p-tau, t-tau levels as well as lower Aß/p-tau levels during the resting-state condition (p < 0.01). Similar alterations were found in ApoE ε4 carriers compared to non-carriers (p < 0.003). In contrast, lower immediate memory scores were associated with changes in the middle part of the medial parietal cortex, which was connected to inferior temporal and posterior parietal regions, during the encoding task (p = 0.001). No results were found when using conventional connectivity measures.ConclusionsFunctional alterations in the medial parietal gradients are associated with CSF AD biomarkers, ApoE ε4 carriership, and lower memory in an asymptomatic cohort with a family history of sporadic AD, suggesting that functional gradients are sensitive to subtle changes associated with early AD stages.

MRI and fluid biomarkers reveal determinants of myelin and axonal loss with aging.

White matter damage is a feature of Alzheimer's disease, yet little is known about how facets of the Alzheimer's disease process relate to key features of white matter structure. We examined the association of Alzheimer's disease (Aß42/40 ratio; pTau181), neuronal injury (NfL), and reactive astrogliosis (GFAP) biomarkers with MRI measures of myelin content and axonal density. Among cognitively normal participants in the BLSA and GESTALT studies who received MRI measures of myelin content (defined by myelin water fraction [MWF]) and axonal density (defined by neurite density index [NDI]), we quantified plasma levels of Aβ42 , Aβ40 , pTau181, NfL, and GFAP. Linear regression models adjusted for demographic variables were used to relate these plasma biomarker levels to the MRI measures. In total, 119 participants received MWF imaging (age: 56 [SD 21]), of which 43 received NDI imaging (age: 50 [SD 18]). We found no relationship between plasma biomarkers and total brain myelin content. However, secondary analysis found higher GFAP was associated with lower MWF in the temporal lobes (ß=-0.13; P =0.049). Further, higher levels of NfL (ß=-0.22; P =0.009) and GFAP (ß=-0.29; P =0.002) were associated with lower total brain axonal density. Secondary analyses found lower Aβ42/40 ratio and higher pTau181 were also associated with lower axonal density, but only in select brain regions. These results remained similar after additionally adjusting for cardiovascular risk factors. Plasma biomarkers of neuronal injury and astrogliosis are associated with reduced axonal density and region-specific myelin content. Axonal loss and demyelination may co-occur with neurodegeneration and astrogliosis ahead of clinically meaningful cognitive decline.