Black individuals are disproportionately exposed to adverse childhood experiences (ACEs) in comparison to White individuals, including greater violence exposure, neighborhood disadvantage, and poverty. Neural circuitry that includes the amygdala, hippocampus, prefrontal cortex (ventromedial, dorsomedial, and dorsolateral), and inferior parietal lobule support stress-related emotional processes. ACEs may modify emotion-related activity within these brain regions, which, in turn, may modulate emotional behavior. However, the extent to which ACEs underlie race-related differences in emotional function remains to be determined. Therefore, this study investigated whether stress-elicited brain activity varies with race-related differences in ACEs. Functional magnetic resonance imaging (fMRI) data from 301 Black and White participants were acquired during the Montreal Imaging Stress Task. Violence exposure, neighborhood disadvantage, and family income were measured during adolescence to assess ACEs, whereas stress-elicited brain function was assessed in emerging adulthood. Behavioral (stress ratings) and psychophysiological data (skin conductance and heart rate) were collected alongside fMRI. Race-related differences were observed in behavioral (stress ratings), psychophysiological (heart rate), and neural (fMRI) responses to stress. Further, a significant relationship was observed between stress reactivity and ACEs. Importantly, adjusting for ACEs reduced race-related differences in stress reactivity (stress ratings and brain function), suggesting that the neurobehavioral response to stress may be shaped, in part, by ACEs. These findings provide new insight into the socioenvironmental factors that influence emotional function.

Background and Objectives:Brain age is a global measure that compares structural brain MRI with large reference datasets. Predicted age deviation (PAD) is the deviation between predicted brain age and chronological age, with positive values indicating advanced aging. Identifying blood-based biomarkers that approximate brain PAD could provide an accessible and cost-effective measure of brain health as an alternative to MRI, but no blood-based biomarkers have yet been identified. This study aimed to investigate novel blood-based biomarkers associated with accelerated PAD using an unbiased proteomics approach to discover new biomarkers. Methods:This study is a secondary analysis with a cross-sectional case-control design using the LIMBIC-CENC dataset as a discovery approach to understand novel biomarker patterns. Brain age was estimated using brainageR in 137 participants aged ≤40 years with no substantial cognitive deficits or neurological disorders. Cases (n = 76) included individuals with brain age ≥5 years older than chronological age, whereas controls (n = 61) had brain age equal to or younger than chronological age (PAD range: -1.3 to 0; mean = -0.9) and were otherwise matched on demographics and clinical features. Unbiased proteomic profiling of ∼5,400 proteins was performed using the Olink Explore platform. Differential protein expression between groups was assessed using Wilcoxon tests with Benjamini-Hochberg correction. Receiver operating characteristic (ROC) analysis was performed on probabilities derived from generalized linear models (GLMs) to identify optimal protein combinations, prioritizing maximizing both sensitivity and negative predictive value. Results:Olink analyses identified 418 proteins that were significantly different between groups after multiple-comparison correction. Upregulated proteins in participants with PAD≥5 years included: component inhibitor-nuclear factor kappa-b kinase (CHUK), methenyltetrahydrofolate synthetase domain containing (MTHFSD), and epidermal growth factor (EGF), with log2 fold changes of 1.70-1.80. Insulin-like peptide 3 (INSL3) was the most downregulated protein (log2 fold change -2.27). Enriched pathways involved nuclear factor kappa-b (NF-κB), heat-shock protein, and Wingless/Integrated (Wnt) signaling. Models including 6-7 dysregulated proteins (e.g., CHUK and INSL3) achieved AUCs>0.9, with sensitivities >0.90 and specificities >0.70. Discussion:These discovery-based findings warrant validation in larger cohorts and suggest potential for blood-based protein panel detection of early, clinically silent, pre-pathological accelerated brain aging changes when interventions may be most effective.

Growth/differentiation factor-15 (GDF15) is a secreted cytokine strongly associated with dementia risk. However, the extent to which GDF15 represents a biomarker and driver of dementia risk remains unclear. Across multiple cohorts, we demonstrated that plasma GDF15 is associated with greater dementia risk over 15- to 25-year follow-up periods when measured in midlife, with stronger associations observed for vascular, compared to Alzheimer's disease (AD), dementia. Two-sample Mendelian randomization supported plasma GDF15's mechanistic role in AD and related dementias, while cohort studies linked it to cerebral small vessel disease, neurodegeneration, phosphorylated tau, and a cerebrospinal fluid proteomic signature indicative of neuroimmune activation. Exposure of cultured myeloid cells to recombinant GDF15 altered biological pathways that we subsequently demonstrated are predictive of dementia risk, including interferon/antiviral responses. These findings support circulating GDF15's role as an early biomarker-particularly for vascular dementia and neuroinflammation-and identify the mechanisms by which it may drive dementia risk.

Biofluid proteomics can enhance our understanding of the neurodegenerative mechanisms underlying Alzheimer’s disease and related dementias (ADRDs). Oligodendrocyte myelin glycoprotein (OMG) is a brain-specific protein implicated in myelination, but its potential mechanistic, biomarker, and therapeutic roles in ADRDs requires further elucidation. After detecting an inverse association between its abundance in peripheral circulation and cortical amyloid deposition in two community-based cohorts, the current study characterized OMG’s role in ADRDs with high-throughput proteomics from sixteen independent cohorts. Data included a variety of cross-sectional and longitudinal community-based and clinical cohorts from North America, Europe, and Asia, and incorporated complementary biofluids, biospecimens, and proteomic platforms. Statistical analyses were conducted separately in each cohort. We detected lower plasma OMG in individuals with cortical amyloid deposition, compromised brain structure, dementia, and multiple sclerosis, as well as in individuals who developed dementia over 7- to 20-year follow-up periods. OMG’s CSF and brain proteomic signatures reflected broader neuroprotective mechanisms, especially axonal structural integrity, and two-sample Mendelian randomization causally implicated OMG as protective against multiple neurodegenerative diseases. Our findings implicate OMG as a mechanistic determinant of neurodegenerative resiliency among older adults, which is reliably captured by its abundance in peripheral circulation

INTRODUCTION:There is an unmet need for tools to quantify dementia risk during its multi-decade preclinical/prodromal phase, given that current biomarkers predict risk over shorter follow-up periods and are specific to Alzheimer's disease. METHODS:Using high-throughput proteomic assays and machine learning techniques in the Atherosclerosis Risk in Communities study (n = 11,277), we developed the Dementia SomaSignal Test (dSST). RESULTS:In addition to outperforming existing plasma biomarkers, the dSST predicted mid-life dementia risk over a 20-year follow-up across two independent cohorts with different ethnic backgrounds (areas under the curve [AUCs]: dSST 0.68-0.70, dSST+age 0.75-0.81). In a separate cohort, the dSST was associated with longitudinal declines across multiple cognitive domains, accelerated brain atrophy, and elevated measures of neuropathology (as evidenced by positron emission tomography and plasma biomarkers). DISCUSSION:The dSST is a cost-effective, scalable, and minimally invasive protein-based prognostic aid that can quantify risk up to two decades before dementia onset. HIGHLIGHTS:The Dementia SomaSignal Test (dSST) predicts 20-year dementia risk across two independent cohorts. dSST outperforms existing plasma biomarkers in predicting multi-decade dementia risk. dSST predicts cognitive decline and accelerated brain atrophy in a third cohort. dSST is a prognostic aid that can predict dementia risk over two decades.

Background: Adolescent substance use is associated with disrupted communication among brain regions underlying reward-driven behaviors (e.g., nucleus accumbens (NAcc)) and cognitive/emotional control (e.g., prefrontal cortex (PFC); medial temporal lobe), which may be linked to poor future outcomes (e.g., substance use disorder). However, the relationship functional brain connectivity has with trajectories of adolescent alcohol, tobacco, and cannabis use has received limited attention. Aims: Investigate relationships between adolescent substance use trajectories and young adult whole-brain NAcc resting-state functional connectivity (rsFC). Methods: Substance use was assessed at ages 11, 13, 16, and 19. Subsequently (age 20), a subset of participants ( N = 299) completed a single neuroimaging session. Latent growth curve models estimated substance use trajectories that included the intercept (age 14 use), linear slope (progression), and quadratic slope (acceleration), which served as predictors in neuroimaging analyses. Hypotheses: Substance use trajectories representing greater age 14 usage, faster progression of use, and acceleration of use across adolescence would show stronger NAcc rsFC with regions implicated in cognitive/emotional control. Results: Age 14 use (alcohol, tobacco, and cannabis) was associated with NAcc rsFC with dorsolateral PFC, dorsomedial PFC, parahippocampal gyrus (PHG), hippocampus, and amygdala. Progression of use was associated with NAcc rsFC with dorsolateral PFC, dorsomedial PFC, ventrolateral PFC, PHG, and amygdala. Finally, acceleration of use was linked with NAcc rsFC with dorsolateral PFC, ventromedial PFC, PHG, and hippocampus. Conclusions: NAcc rsFC with several brain regions (e.g., PFC subregions) varied with adolescent substance use, which may represent common neural mechanisms linking adolescent substance use with common psychological outcomes.

Violence exposure has deleterious effects on emotional well-being, including higher rates of future mental illness. Adolescence is an important period of neural development within brain regions (e.g., prefrontal cortex) that support emotional processes. The relationship between brain activity and emotion may vary with violence exposure. Thus, this study investigated the relationship between violence exposure, stress-elicited brain activity, and emotion in young people. Violence exposure was measured four times from 11 to 19 years of age. Participants (n = 301) returned 1 year later (age = 20) to complete mental health (i.e., anxiety, depression, and posttraumatic stress) questionnaires and the Montreal Imaging Stress Task during behavioral (e.g., skin conductance response and cortisol) and neuroimaging data collection. Data were collected from 2004 to 2018. Violence exposure was positively associated with mental health symptoms. Further, violence exposure moderated the relationship between stress-elicited dorsolateral prefrontal cortex activity and depression, cortisol, and skin conductance response. These findings suggest that violence exposure moderates the relationship between stress-elicited brain function and emotion-related behavior in young people. These findings provide novel insight into neural processes that may underlie the relationship between prior violence exposure and emotional function, which may have important implications for mental health. (PsycInfo Database Record (c) 2026 APA, all rights reserved).

BACKGROUND AND OBJECTIVES:Alzheimer disease (AD) is defined by cortical β-amyloid (Aβ), tau, and neurodegeneration, which contribute to cognitive decline, in part, by altering large-scale functional brain networks. While cortical Aβ and tau have been associated with changes in functional brain connectivity, it is unknown whether plasma biomarkers relate to such changes. In a healthy community sample of cognitively unimpaired adults free from major CNS disease from the Baltimore Longitudinal Study of Aging, we examined whether plasma biomarkers of AD pathology (Aβ42/40, phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal changes in functional connectivity and whether changes in functional connectivity were related to longitudinal cognition. METHODS:Plasma biomarkers were measured using the Quanterix SIMOA assays. Intranetwork connectivity (3T resting-state fMRI) from 7 functional networks was derived using a predefined cortical parcellation mask for each participant visit. Cognitive performance was assessed concurrently with fMRI scan. Covariate-adjusted linear mixed-effect models were used to determine (1) whether plasma biomarkers were associated with longitudinal changes in connectivity, (2) whether the magnitude of the biomarker-connectivity relationships differed by amyloid status, and (3) whether changes in connectivity co-occurred with longitudinal changes in cognition. RESULTS:Our primary findings (n = 486; age = 65.5 ± 16.2 years; 54% female; mean follow-up time = 4.3 ± 1.7 years) showed that higher baseline GFAP was associated with faster declines in somatomotor (β = -0.04, p = 0.01, 95% CI -0.06 to -0.01), limbic (β = -0.03, p = 0.02, 95% CI -0.06 to -0.005), and frontoparietal (β = -0.04, p = 0.02, 95% CI -0.07 to -0.01) network connectivity. Amyloid status moderated several biomarker-connectivity associations. For instance, higher baseline NfL was related to faster declines in visual and limbic network connectivity, but only among amyloid-positive participants. Among 421 participants with ≥2 fMRI visits (age = 71.7 ± 11.4 years; 55% female; follow-up time = 3.9 ± 1.6 years), longitudinal changes in connectivity were associated with concurrent declines in cognition; however, these results did not survive multiple comparison correction. DISCUSSION:Among cognitively unimpaired participants, plasma biomarkers of amyloidosis, astrogliosis, and neuronal injury are associated with declines in network connectivity, particularly among amyloid-positive participants. Major limitations include the lack of inclusion of the sensitive pTau-217 and pTau-231 isoforms and comparative PET biomarkers.

AD is defined by cortical amyloid-β (Aβ), tau neurofibrillary tangles, and neurodegeneration, pathological processes which may contribute to cognitive decline by altering large scale functional brain networks. To test this hypothesis, we examined whether plasma biomarkers of AD pathology (Aβ 42/40 , phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) related to longitudinal changes in resting-state functional connectivity (rsFC) in cognitively unimpaired participants from the Baltimore Longitudinal Study of Aging. Baseline plasma biomarkers were measured with Quanterix SIMOA assays. Functional connectivity (3T resting-state fMRI) was derived using a predefined cortical parcellation mask from which intra-network connectivity from seven functional networks was extracted for each participant. Amyloid status (positive/negative) was defined using plasma Aβ 42/40 (Figure 1). Linear mixed effects models adjusted for age, sex, race, education, gray matter volume, and time-covariate interactions were used to determine whether 1) baseline plasma biomarkers predicted longitudinal changes in rsFC, 2) the magnitude of the biomarker-related rsFC changes differed by amyloid status, and 3) rsFC predicted longitudinal changes in cognition. Longitudinal connectivity analyses (mean age±SD=65.49±16.17) included 490 participants (1190 visits; mean follow-up time=4.31±1.68 years). Higher Aβ 42/40 , GFAP, and NfL were associated with faster declines in rsFC within several networks (P-range=0.01-0.04; Figure 2). Overall, plasma biomarker-rsFC associations differed by amyloid status (P-range=0.01-0.045). Among amyloid-positive participants, lower levels of Aβ 42/40 , and higher levels of GFAP, and NfL (Figure 2) were associated with faster declines in rsFC in the visual, dorsal and ventral attention, limbic, and frontoparietal networks (P range=<0.002-0.04). There were no statistically significant associations between plasma biomarkers and rsFC change among amyloid-negative participants. Among 760 participants with at least one rsFC scan (mean age±SD=67.21±14.93; 1550 visits, follow-up time=3.94±1.60 years), we found that baseline rsFC in several networks predicted changes in cognition, e.g., working memory, verbal fluency, and visuospatial abilities (P range=0.02-0.049; Figure 3). Among cognitively normal individuals, plasma biomarkers of Aβ 42/40 , astrogliosis, and neuronal injury are associated with future intra-network functional brain changes, particularly in the context of elevated amyloid. Hypo- and hyper- intra-network connectivity may drive changes in cognitive performance.

Abstract Background Although blood-based biomarkers have been identified as cost-effective and scalable alternatives to PET and CSF markers of neurodegenerative disease, little is known about how these biomarkers predict future brain atrophy and cognitive decline in cognitively unimpaired individuals. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of Alzheimer’s disease (AD) pathology (amyloid-β [Aβ42/40], phosphorylated tau [pTau-181]), astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Additionally, we determined whether sex, APOEε4 status, and plasma amyloid-β status modified these associations. Methods Plasma biomarkers were measured using Quanterix SIMOA assays. Regional brain volumes were measured by 3T MRI, and a battery of neuropsychological tests assessed five cognitive domains. Linear mixed effects models adjusted for demographic factors, kidney function, and intracranial volume (MRI analyses) were completed to relate baseline plasma biomarkers to baseline and longitudinal brain volume and cognitive performance. Results Brain volume analyses included 622 participants (mean age ± SD: 70.9 ± 10.2) with an average of 3.3 MRI scans over 4.7 years. Cognitive performance analyses included 674 participants (mean age ± SD: 71.2 ± 10.0) with an average of 3.9 cognitive assessments over 5.7 years. Higher baseline pTau-181 was associated with steeper declines in total gray matter volume and steeper regional declines in several medial temporal regions, whereas higher baseline GFAP was associated with greater longitudinal increases in ventricular volume. Baseline Aβ42/40 and NfL levels were not associated with changes in brain volume. Lower baseline Aβ42/40 (higher Aβ burden) was associated with a faster decline in verbal memory and visuospatial performance, whereas higher baseline GFAP was associated with a faster decline in verbal fluency. Results were generally consistent across sex and APOEε4 status. However, the associations of higher pTau-181 with increasing ventricular volume and memory declines were significantly stronger among individuals with higher Aβ burden, as was the association of higher GFAP with memory decline. Conclusions Among cognitively unimpaired older adults, plasma biomarkers of AD pathology (pTau-181) and astrogliosis (GFAP), but not neuronal injury (NfL), serve as markers of future brain atrophy and cognitive decline.

Recent technological advances have improved the sensitivity and specificity of blood-based biomarkers for Alzheimer's disease and related dementias. Accurate quantification of amyloid-ss peptide, phosphorylated tau (pTau) isoforms, as well as markers of neurodegeneration (neurofilament light chain [NfL]) and neuro-immune activation (glial fibrillary acidic protein [GFAP] and chitinase-3-like protein 1 [YKL-40]) in blood has allowed researchers to characterize neurobiological processes at scale in a cost-effective and minimally invasive manner. Although currently used primarily for research purposes, these blood-based biomarkers have the potential to be highly impactful in the clinical setting - aiding in diagnosis, predicting disease risk, and monitoring disease progression. Whereas plasma NfL has shown promise as a non-specific marker of neuronal injury, plasma pTau181, pTau217, pTau231, and GFAP have demonstrated desirable levels of sensitivity and specificity for identification of individuals with Alzheimer's disease pathology and Alzheimer's dementia. In this forward looking review, we (i) provide an overview of the most commonly used blood-based biomarkers for Alzheimer's disease and related dementias, (ii) discuss how comorbid medical conditions, demographic, and genetic factors can inform the interpretation of these biomarkers, (iii) describe ongoing efforts to move blood-based biomarkers into the clinic, and (iv) highlight the central role that clinical neuropsychologists may play in contextualizing and communicating blood-based biomarker results for patients.

INTRODUCTION:Plasma proteomic analyses of unique brain atrophy patterns may illuminate peripheral drivers of neurodegeneration and identify novel biomarkers for predicting clinically relevant outcomes. METHODS:We identified proteomic signatures associated with machine learning-derived aging- and Alzheimer's disease (AD) -related brain atrophy patterns in the Baltimore Longitudinal Study of Aging (n = 815). Using data from five cohorts, we examined whether candidate proteins were associated with AD endophenotypes and long-term dementia risk. RESULTS:Plasma proteins associated with distinct patterns of age- and AD-related atrophy were also associated with plasma/cerebrospinal fluid (CSF) AD biomarkers, cognition, AD risk, as well as mid-life (20-year) and late-life (8-year) dementia risk. EFEMP1 and CXCL12 showed the most consistent associations across cohorts and were mechanistically implicated as determinants of brain structure using genetic methods, including Mendelian randomization. DISCUSSION:Our findings reveal plasma proteomic signatures of unique aging- and AD-related brain atrophy patterns and implicate EFEMP1 and CXCL12 as important molecular drivers of neurodegeneration. HIGHLIGHTS:Plasma proteomic signatures are associated with unique patterns of brain atrophy. Brain atrophy-related proteins predict clinically relevant outcomes across cohorts. Genetic variation underlying plasma EFEMP1 and CXCL12 influences brain structure. EFEMP1 and CXCL12 may be important molecular drivers of neurodegeneration.

Exposure to violence during childhood can lead to functional changes in brain regions that are important for emotion expression and regulation, which may increase susceptibility to internalizing disorders in adulthood. Specifically, childhood violence exposure can disrupt the functional connectivity among brain regions that include the prefrontal cortex (PFC), hippocampus, and amygdala. Together, these regions are important for modulating autonomic responses to stress. However, it is unclear to what extent changes in brain connectivity relate to autonomic stress reactivity and how the relationship between brain connectivity and autonomic responses to stress varies with childhood violence exposure. Thus, the present study examined whether stress-induced changes in autonomic responses (e.g., heart rate, skin conductance level (SCL)) varied with amygdala-, hippocampus-, and ventromedial prefrontal cortex (vmPFC)-whole brain resting-state functional connectivity (rsFC) as a function of violence exposure. Two hundred and ninety-seven participants completed two resting-state functional magnetic resonance imaging scans prior to (pre-stress) and after (post-stress) a psychosocial stress task. Heart rate and SCL were recorded during each scan. Post-stress heart rate varied negatively with post-stress amygdala-inferior parietal lobule rsFC and positively with post-stress hippocampus-anterior cingulate cortex rsFC among those exposed to high, but not low, levels of violence. Results from the present study suggest that post-stress fronto-limbic and parieto-limbic rsFC modulates heart rate and may underlie differences in the stress response among those exposed to high levels of violence.

Although plasma Alzheimer’s disease (AD) and neurodegenerative disease biomarkers have been associated with reduced cognition and lower brain volume, few studies have examined whether plasma biomarkers measured in predominately cognitively unimpaired adults are associated with longitudinal brain volume loss and cognitive decline. Using data from the Baltimore Longitudinal Study of Aging (BLSA), we examined whether plasma biomarkers of AD pathology (Aβ 42/40 , phosphorylated tau [pTau-181]), reactive astrogliosis (glial fibrillary acidic protein [GFAP]), and neuronal injury (neurofilament light chain [NfL]) were associated with longitudinal brain volume loss and cognitive decline. Plasma biomarkers (Aβ 42/40 , pTau-181, GFAP, NfL) were measured using Quanterix SIMOA assays. Baseline visits were considered the earliest visits that had concurrent 3T MRI scans and plasma biomarker measurements, and the earliest visits that had concurrent cognitive assessments and plasma biomarker measurements. Composite Z scores were computed to reflect 5 cognitive domains ( Figure 1 ). Linear mixed effects models adjusted for baseline age, sex, race, education, estimated glomerular filtration rate, and total intracranial volume (brain volume analyses), were used to examine the association of plasma biomarkers with baseline and longitudinal brain volume and cognition. False Discovery Rate correction was used to adjust for multiple comparisons. Brain volume analyses included 628 participants (mean age±SD: 71.0±10.2; Table 1 ) with an average of 3.3 MRI scans over 4.7 years. Cognition analyses included 686 participants (mean age±SD: 71.4±10.1) with an average of 3.9 cognitive assessments over 5.7 years. Although Aβ 42/40 was unrelated to brain volume changes, higher pTau-181 was associated with longitudinal declines in total gray matter volume and regional declines in medial temporal regions. Higher GFAP was associated with longitudinal increases in ventricular volume, whereas NfL was not associated with brain volume change ( Table 2 ). Both lower Aβ 42/40 and higher pTau-181 were associated with a decline in verbal memory. Additionally, lower Aβ 42/40 was associated with a decline in visuospatial performance. Further, higher GFAP was associated with a decline in verbal fluency ( Figure 1 ). Plasma biomarkers of AD pathology and astrogliosis may serve as markers of future brain atrophy and cognitive decline.

Objective: Determine whether proteomic indicators of peripheral (non-neurologic) health are associated with change in cognition and brain volume. Background: Numerous peripheral diseases have been associated with brain health. Changes in the plasma proteome related to physical health and disease status likely contribute to cognitive and structural brain changes. Plasma proteomic changes may therefore be leveraged to study the link between peripheral health and brain health. Design/Methods: We used plasma samples from participants of the Baltimore Longitudinal Study of Aging (BLSA) to assess 7000+ proteins using SomaScan assay. Brain health was assessed using in BLSA participants with concurrent 3T brain MR imaging to assess total brain volume (TBV). Using SomaLogic's SomaSignal Test (SST) algorithm, we generated protein-based measures of cardiovascular risk, kidney disease, resting energy rate, body composition, and other health indicators. Linear mixed effects models were used to examine the relationship between SST protein-based health indicators and longitudinal change in TBV and memory. Results: The analysis included 1220 participants (mean age: 68.1 [14.3 SD]; 99% cognitively normal). We evaluated 14 unique protein-based health indices (SSTs). None were associated with longitudinal brain volume loss. At baseline, the protein-based indicator of liver fat was associated with better memory. Protein-based indicators of lower V02 max and kidney disease risk were associated with longitudinal declines in memory. Conclusions: Protein-based health indicators can be used to understand how facets of peripheral health and disease risk influence brain health in cognitively healthy older adults. Our findings implicate cardiovascular, pulmonary, and kidney health in brain structure or function. Disclosure: Ms. Daya has nothing to disclose. Dr. Dark has nothing to disclose. Dr. Duggan has nothing to disclose. Dr. Peng has nothing to disclose. An immediate family member of Dr. Moore has received personal compensation for serving as an employee of Gilead. Dr. Tanaka has nothing to disclose. Dr. Candia has nothing to disclose. The institution of Keenan Walker has received research support from NIH.

OBJECTIVE: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. METHODS: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. RESULTS: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. INTERPRETATION: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.

INTRODUCTION:Non-Hispanic Black, compared to non-Hispanic White, older adults are at increased risk for dementia. This may be due partly to greater exposure to psychosocial stressors, such as discrimination; however, few studies have examined this association.METHODS:We examined the association of perceived discrimination (e.g., everyday, lifetime, and discrimination burden) with dementia risk in 1583 Black adults co-enrolled in the Atherosclerosis Risk in Communities (ARIC) Study and the Jackson Heart Study (JHS). Perceived discrimination (defined continuously and using tertiles) was assessed at JHS Exam 1 (2000-2004; mean age ± SD:66.2 ± 5.5) and related to dementia risk through ARIC visit 6 (2017) using covariate-adjusted Cox proportional hazards models.RESULTS:Associations of perceived everyday, lifetime, and burden of discrimination with dementia risk were not supported in age-adjusted models or demographic- and cardiovascular health-adjusted models. Results were similar across sex, income, and education.DISCUSSION:In this sample, associations between perceived discrimination and dementia risk were not supported.HIGHLIGHTS:In Black older adults perceived discrimination not associated with dementia risk. Younger age and greater education linked to greater perceived discrimination. Older age and less education among factors associated with dementia risk. Factors increasing exposure to discrimination (education) are also neuroprotective.

OBJECTIVE: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. METHODS: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. RESULTS: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. INTERPRETATION: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.

BACKGROUND: Proteins expressed by brain endothelial cells (BECs), the primary cell type of the blood-brain barrier, may serve as sensitive plasma biomarkers for neurological and neurovascular conditions, including cerebral small vessel disease. METHODS: Using data from the BLSA (Baltimore Longitudinal Study of Aging; n=886; 2009–2020), BEC-enriched proteins were identified among 7268 plasma proteins (measured with SomaScanv4.1) using an automated annotation algorithm that filtered endothelial cell transcripts followed by cross-referencing with BEC-specific transcripts reported in single-cell RNA-sequencing studies. To identify BEC-enriched proteins in plasma most relevant to the maintenance of neurological and neurovascular health, we selected proteins significantly associated with 3T magnetic resonance imaging–defined white matter lesion volumes. We then examined how these candidate BEC biomarkers related to white matter lesion volumes, cerebral microhemorrhages, and lacunar infarcts in the ARIC study (Atherosclerosis Risk in Communities; US multisite; 1990–2017). Finally, we determined whether these candidate BEC biomarkers, when measured during midlife, were related to dementia risk over a 25-year follow-up period. RESULTS: Of the 28 proteins identified as BEC-enriched, 4 were significantly associated with white matter lesion volumes (CDH5 [cadherin 5], CD93 [cluster of differentiation 93], ICAM2 [intracellular adhesion molecule 2], GP1BB [glycoprotein 1b platelet subunit beta]), while another approached significance (RSPO3 [R-Spondin 3]). A composite score based on 3 of these BEC proteins accounted for 11% of variation in white matter lesion volumes in BLSA participants. We replicated the associations between the BEC composite score, CDH5, and RSPO3 with white matter lesion volumes in ARIC, and further demonstrated that the BEC composite score and RSPO3 were associated with the presence of ≥1 cerebral microhemorrhages. We also showed that the BEC composite score, CDH5, and RSPO3 were associated with 25-year dementia risk. CONCLUSIONS: In addition to identifying BEC proteins in plasma that relate to cerebral small vessel disease and dementia risk, we developed a composite score of plasma BEC proteins that may be used to estimate blood-brain barrier integrity and risk for adverse neurovascular outcomes.

Exposure to environmental toxicants have serious implications for the general health and well-being of children, particularly during pivotal neurodevelopmental stages. The Environmental Protection Agency's (EPA) Superfund program has identified several areas (Superfund sites) across the United States with high levels of environmental toxicants, which affect the health of many residents in nearby communities. Exposure to these environmental toxicants has been linked to changes in the structure and function of the brain. However, limited research has investigated the relationship between the proximity of childhood homes to a Superfund site and the development of subcortical structures like the hippocampus and amygdala. The present study investigated the hippocampal and amygdala volumes of young adults in relation to the proximity of their childhood homes to Birmingham, Alabama's 35th Avenue Superfund site. Forty participants who either lived within or adjacent to the Superfund site (Proximal group; n = 20) or who lived elsewhere in the greater Birmingham metropolitan area (Distal group; n = 20) were included in this study. Both groups were matched on age, sex, race, and years of education. Magnetic resonance imaging (MRI) was used to compare the gray matter volume of the hippocampus and amygdala between groups. Differences in bilateral hippocampal and left amygdala volumes were observed. Specifically, hippocampal and amygdala volumes were greater in the Proximal than Distal group. These findings suggest that the proximity of children's homes to environmental toxicants may impact the development of the hippocampus and amygdala. (PsycInfo Database Record (c) 2023 APA, all rights reserved).