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

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-ß [Aß]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 Aß 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 Aß42/40 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 Aß42/40 , 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.

Psychosocial Health and the Association Between Cerebral Small Vessel Disease Markers With Dementia: The ARIC Study.

BACKGROUND: Associations between magnetic resonance imaging markers of cerebral small vessel disease (CSVD) and dementia risk in older adults have been established, but it remains unclear how lifestyle factors, including psychosocial health, may modify this association. METHODS: Social support and social isolation were assessed among participants of the community-based ARIC (Atherosclerosis Risk in Communities) Study, via self-reported questionnaires (1990-1992). Following categorization of both factors, participants were classified as having strong or poor mid-life social relationships. At visit 5 (2011-2013), participants underwent 3T brain magnetic resonance imaging quantifying CSVD measures: white matter hyperintensity volume, microbleeds (subcortical), infarcts (lacunar), and white matter integrity (diffusion tensor imaging). Incident dementia cases were identified from the time of imaging through December 31, 2020 with ongoing surveillance. Associations between CSVD magnetic resonance imaging markers and incident dementia were evaluated using Cox proportional-hazard regressions adjusted for demographic and additional risk factors (from visit 2). Effect modification by mid-life social relationships was evaluated. RESULTS: Of the 1977 participants with magnetic resonance imaging, 1617 participants (60.7% women; 26.5% Black participants; mean age at visit 2, 55.4 years) were examined. In this sample, mid-life social relationships significantly modified the association between white matter hyperintensity volume and dementia risk (P interaction=0.001). Greater white matter hyperintensity volume was significantly associated with risk of dementia in all participants, yet, more substantially in those with poor (hazard ratio, 1.84 [95% CI, 1.49-2.27]) versus strong (hazard ratio, 1.26 [95% CI, 1.08-1.47]) mid-life social relationships. Although not statistically significant, subcortical microbleeds in participants with poor mid-life social relationships were associated with a greater risk of dementia, relative to those with strong social relationships, in whom subcortical microbleeds were no longer associated with elevated dementia risk. CONCLUSIONS: The elevated risk of dementia associated with CSVD may be reduced in participants with strong mid-life social relationships. Future studies evaluating psychosocial health through the life course and the mechanisms by which they modify the relationship between CSVD and dementia are needed.

Development, characterization, and replication of proteomic aging clocks: Analysis of 2 population-based cohorts.

BACKGROUND: Biological age may be estimated by proteomic aging clocks (PACs). Previous published PACs were constructed either in smaller studies or mainly in white individuals, and they used proteomic measures from only one-time point. In this study, we created de novo PACs and compared their performance to published PACs at 2 different time points in the Atherosclerosis Risk in Communities (ARIC) study of white and black participants (around 75% white and 25% black). MEDTHODS AND FINDINGS: A total of 4,712 plasma proteins were measured using SomaScan in blood samples collected in 1990 to 1992 from 11,761 midlife participants (aged 46 to 70 years) and in 2011 to 2013 from 5,183 late-life participants (aged 66 to 90 years). The de novo ARIC PACs were constructed by training them against chronological age using elastic net regression in two-thirds of healthy participants in midlife and late life and validated in the remaining one-third of healthy participants at the corresponding time point. We also computed 3 published PACs. We estimated age acceleration for each PAC as residuals after regressing each PAC on chronological age. We also calculated the change in age acceleration from midlife to late life. We examined the associations of age acceleration and change in age acceleration with mortality through 2019 from all-cause, cardiovascular disease (CVD), cancer, and lower respiratory disease (LRD) using Cox proportional hazards regression in participants (irrespective of health) after excluding the training set. The model was adjusted for chronological age, smoking, body mass index (BMI), and other confounders. We externally validated the midlife PAC using the Multi-Ethnic Study of Atherosclerosis (MESA) Exam 1 data. The ARIC PACs had a slightly stronger correlation with chronological age than published PACs in healthy participants at each time point. Associations with mortality were similar for the ARIC PACs and published PACs. For late-life and midlife age acceleration for the ARIC PACs, respectively, hazard ratios (HRs) per 1 standard deviation were 1.65 and 1.38 (both p < 0.001) for all-cause mortality, 1.37 and 1.20 (both p < 0.001) for CVD mortality, 1.21 (p = 0.028) and 1.04 (p = 0.280) for cancer mortality, and 1.46 and 1.68 (both p < 0.001) for LRD mortality. For the change in age acceleration, HRs for all-cause, CVD, and LRD mortality were comparable to the HRs for late-life age acceleration. The association between the change in age acceleration and cancer mortality was not significant. The external validation of the midlife PAC in MESA showed significant associations with mortality, as observed for midlife participants in ARIC. The main limitation is that our PACs were constructed in midlife and late-life participants. It is unknown whether these PACs could be applied to young individuals. CONCLUSIONS: In this longitudinal study, we found that the ARIC PACs and published PACs were similarly associated with an increased risk of mortality. These findings suggested that PACs show promise as biomarkers of biological age. PACs may be serve as tools to predict mortality and evaluate the effect of anti-aging lifestyle and therapeutic interventions.

Proteome-wide analysis identifies plasma immune regulators of amyloid-beta progression.

While immune function is known to play a mechanistic role in Alzheimer's disease (AD), whether immune proteins in peripheral circulation influence the rate of amyloid-ß (Aß) progression - a central feature of AD - remains unknown. In the Baltimore Longitudinal Study of Aging, we quantified 942 immunological proteins in plasma and identified 32 (including CAT [catalase], CD36 [CD36 antigen], and KRT19 [keratin 19]) associated with rates of cortical Aß accumulation measured with positron emission tomography (PET). Longitudinal changes in a subset of candidate proteins also predicted Aß progression, and the mid- to late-life (20-year) trajectory of one protein, CAT, was associated with late-life Aß-positive status in the Atherosclerosis Risk in Communities (ARIC) study. Genetic variation that influenced plasma levels of CAT, CD36 and KRT19 predicted rates of Aß accumulation, including causal relationships with Aß PET levels identified with two-sample Mendelian randomization. In addition to associations with tau PET and plasma AD biomarker changes, as well as expression patterns in human microglia subtypes and neurovascular cells in AD brain tissue, we showed that 31 % of candidate proteins were related to mid-life (20-year) or late-life (8-year) dementia risk in ARIC. Our findings reveal plasma proteins associated with longitudinal Aß accumulation, and identify specific peripheral immune mediators that may contribute to the progression of AD pathophysiology.

Plasma proteins related to inflammatory diet predict future cognitive impairment.

Dysregulation of the immune system and dietary patterns that increase inflammation can increase the risk for cognitive decline, but the mechanisms by which inflammatory nutritional habits may affect the development of cognitive impairment in aging are not well understood. To determine whether plasma proteins linked to inflammatory diet predict future cognitive impairment, we applied high-throughput proteomic assays to plasma samples from a subset (n = 1528) of Women's Health Initiative Memory Study (WHIMS) participants (mean [SD] baseline age, 71.3 [SD 3.8] years). Results provide insights into how inflammatory nutritional patterns are associated with an immune-related proteome and identify a group of proteins (CXCL10, CCL3, HGF, OPG, CDCP1, NFATC3, ITGA11) related to future cognitive impairment over a 14-year follow-up period. Several of these inflammatory diet proteins were also associated with dementia risk across two external cohorts (ARIC, ESTHER), correlated with plasma biomarkers of Alzheimer's disease (AD) pathology (Aß42/40) and/or neurodegeneration (NfL), and related to an MRI-defined index of neurodegenerative brain atrophy in a separate cohort (BLSA). In addition to evaluating their biological relevance, assessing their potential role in AD, and characterizing their immune-tissue/cell-specific expression, we leveraged published RNA-seq results to examine how the in vitro regulation of genes encoding these candidate proteins might be altered in response to an immune challenge. Our findings indicate how dietary patterns with higher inflammatory potential relate to plasma levels of immunologically relevant proteins and highlight the molecular mediators which predict subsequent risk for age-related cognitive impairment.

Plasma metabolomic markers underlying skeletal muscle mitochondrial function relationships with cognition and motor function.

BACKGROUND: Lower skeletal muscle mitochondrial function is associated with future cognitive impairment and mobility decline, but the biological underpinnings for these associations are unclear. We examined metabolomic markers underlying skeletal muscle mitochondrial function, cognition and motor function. METHODS: We analysed data from 560 participants from the Baltimore Longitudinal Study of Aging (mean age: 68.4 years, 56% women, 28% Black) who had data on skeletal muscle oxidative capacity (post-exercise recovery rate of phosphocreatine, kPCr) via 31P magnetic resonance spectroscopy and targeted plasma metabolomics using LASSO model. We then examined which kPCr-related markers were also associated with cognition and motor function in a larger sample (n = 918, mean age: 69.4, 55% women, 27% Black). RESULTS: The LASSO model revealed 24 metabolites significantly predicting kPCr, with the top 5 being asymmetric dimethylarginine, lactic acid, lysophosphatidylcholine a C18:1, indoleacetic acid and triacylglyceride (17:1_34:3), also significant in multivariable linear regression. The kPCr metabolite score was associated with cognitive or motor function, with 2.5-minute usual gait speed showing the strongest association (r = 0.182). Five lipids (lysophosphatidylcholine a C18:1, phosphatidylcholine ae C42:3, cholesteryl ester 18:1, sphingomyelin C26:0, octadecenoic acid) and 2 amino acids (leucine, cystine) were associated with both cognitive and motor function measures. CONCLUSION: Our findings add evidence to the hypothesis that mitochondrial function is implicated in the pathogenesis of cognitive and physical decline with aging and suggest that targeting specific metabolites may prevent cognitive and mobility decline through their effects on mitochondria. Future omics studies are warranted to confirm these findings and explore mechanisms underlying mitochondrial dysfunction in aging phenotypes.

Associations of Prior Head Injury With Mild Behavioral Impairment Domains.

OBJECTIVE: This study investigated associations of prior head injury and number of prior head injuries with mild behavioral impairment (MBI) domains. SETTING: The Atherosclerosis Risk in Communities (ARIC) Study. PARTICIPANTS: A total of 2534 community-dwelling older adults who took part in the ARIC Neurocognitive Study stage 2 examination were included. DESIGN: This was a prospective cohort study. Head injury was defined using self-reported and International Classification of Diseases, Ninth Revision ( ICD -9) code data. MBI domains were defined using the Neuropsychiatric Inventory Questionnaire (NPI-Q) via an established algorithm mapping noncognitive neuropsychiatric symptoms to the 6 domains of decreased motivation, affective dysregulation, impulse dyscontrol, social inappropriateness, and abnormal perception/thought content. MAIN MEASURES: The primary outcome was the presence of impairment in MBI domains. RESULTS: Participants were a mean age of 76 years, with a median time from first head injury to NPI-Q administration of 32 years. The age-adjusted prevalence of symptoms in any 1+ MBI domains was significantly higher among individuals with versus without prior head injury (31.3% vs 26.0%, P = .027). In adjusted models, a history of 2+ head injuries, but not 1 prior head injury, was associated with increased odds of impairment in affective dysregulation and impulse dyscontrol domains, compared with no history of head injury (odds ratio [OR] = 1.83, 95% CI = 1.13-2.98, and OR = 1.74, 95% CI = 1.08-2.78, respectively). Prior head injury was not associated with symptoms in MBI domains of decreased motivation, social inappropriateness, and abnormal perception/thought content (all P > .05). CONCLUSION: Prior head injury in older adults was associated with greater MBI domain symptoms, specifically affective dysregulation and impulse dyscontrol. Our results suggest that the construct of MBI can be used to systematically examine the noncognitive neuropsychiatric sequelae of head injury; further studies are needed to examine whether the systematic identification and rapid treatment of neuropsychiatric symptoms after head injury is associated with improved outcomes.

Alterations in the Circulating Proteome Associated with Albuminuria.

SIGNIFICANCE STATEMENT: We describe circulating proteins associated with albuminuria in a population of African American Study of Kidney Disease and Hypertension with CKD (AASK) using the largest proteomic platform to date: nearly 7000 circulating proteins, representing approximately 2000 new targets. Findings were replicated in a subset of a general population cohort with kidney disease (ARIC) and a population with CKD Chronic Renal Insufficiency Cohort (CRIC). In cross-sectional analysis, 104 proteins were significantly associated with albuminuria in the Black group, of which 67 of 77 available proteins were replicated in ARIC and 68 of 71 available proteins in CRIC. LMAN2, TNFSFR1B, and members of the ephrin superfamily had the strongest associations. Pathway analysis also demonstrated enrichment of ephrin family proteins. BACKGROUND: Proteomic techniques have facilitated understanding of pathways that mediate decline in GFR. Albuminuria is a key component of CKD diagnosis, staging, and prognosis but has been less studied than GFR. We sought to investigate circulating proteins associated with higher albuminuria. METHODS: We evaluated the cross-sectional associations of the blood proteome with albuminuria and longitudinally with doubling of albuminuria in the African American Study of Kidney Disease and Hypertension (AASK; 38% female; mean GFR 46; median urine protein-to-creatinine ratio 81 mg/g; n =703) and replicated in two external cohorts: a subset of the Atherosclerosis Risk in Communities (ARIC) study with CKD and the Chronic Renal Insufficiency Cohort (CRIC). RESULTS: In cross-sectional analysis, 104 proteins were significantly associated with albuminuria in AASK, of which 67 of 77 available proteins were replicated in ARIC and 68 of 71 available proteins in CRIC. Proteins with the strongest associations included LMAN2, TNFSFR1B, and members of the ephrin superfamily. Pathway analysis also demonstrated enrichment of ephrin family proteins. Five proteins were significantly associated with worsening albuminuria in AASK, including LMAN2 and EFNA4, which were replicated in ARIC and CRIC. CONCLUSIONS: Among individuals with CKD, large-scale proteomic analysis identified known and novel proteins associated with albuminuria and suggested a role for ephrin signaling in albuminuria progression.

Changes in Alzheimer Disease Blood Biomarkers and Associations With Incident All-Cause Dementia.

Importance: Plasma biomarkers show promise for identifying Alzheimer disease (AD) neuropathology and neurodegeneration, but additional examination among diverse populations and throughout the life course is needed. Objective: To assess temporal plasma biomarker changes and their association with all-cause dementia, overall and among subgroups of community-dwelling adults. Design, Setting, and Participants: In 1525 participants from the US-based Atherosclerosis Risk in Communities (ARIC) study, plasma biomarkers were measured using stored specimens collected in midlife (1993-1995, mean age 58.3 years) and late life (2011-2013, mean age 76.0 years; followed up to 2016-2019, mean age 80.7 years). Midlife risk factors (hypertension, diabetes, lipids, coronary heart disease, cigarette use, and physical activity) were assessed for their associations with change in plasma biomarkers over time. The associations of biomarkers with incident all-cause dementia were evaluated in a subpopulation (n = 1339) who were dementia-free in 2011-2013 and had biomarker measurements in 1993-1995 and 2011-2013. Exposure: Plasma biomarkers of amyloid-ß 42 to amyloid-ß 40 (Aß42:Aß40) ratio, phosphorylated tau at threonine 181 (p-tau181), neurofilament light (NfL), and glial fibrillary acidic protein (GFAP) were measured using the Quanterix Simoa platform. Main Outcomes and Measures: Incident all-cause dementia was ascertained from January 1, 2012, through December 31, 2019, from neuropsychological assessments, semiannual participant or informant contact, and medical record surveillance. Results: Among 1525 participants (mean age, 58.3 [SD, 5.1] years), 914 participants (59.9%) were women, and 394 participants (25.8%) were Black. A total of 252 participants (16.5%) developed dementia. Decreasing Aß42:Aß40 ratio and increasing p-tau181, NfL, and GFAP were observed from midlife to late life, with more rapid biomarker changes among participants carrying the apolipoprotein E epsilon 4 (APOEε4) allele. Midlife hypertension was associated with a 0.15-SD faster NfL increase and a 0.08-SD faster GFAP increase per decade; estimates for midlife diabetes were a 0.11-SD faster for NfL and 0.15-SD faster for GFAP. Only AD-specific biomarkers in midlife demonstrated long-term associations with late-life dementia (hazard ratio per SD lower Aß42:Aß40 ratio, 1.11; 95% CI, 1.02-1.21; per SD higher p-tau181, 1.15; 95% CI, 1.06-1.25). All plasma biomarkers in late life had statistically significant associations with late-life dementia, with NfL demonstrating the largest association (1.92; 95% CI, 1.72-2.14). Conclusions and Relevance: Plasma biomarkers of AD neuropathology, neuronal injury, and astrogliosis increase with age and are associated with known dementia risk factors. AD-specific biomarkers' association with dementia starts in midlife whereas late-life measures of AD, neuronal injury, and astrogliosis biomarkers are all associated with dementia.

Proteomic analyses reveal plasma EFEMP1 and CXCL12 as biomarkers and determinants of neurodegeneration.

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.

Liver integrity and the risk of Alzheimer's disease and related dementias.

INTRODUCTION: We examined midlife (1990-1992, mean age 57) and late-life (2011-2013, mean age 75) nonalcoholic fatty liver disease (NAFLD) and aminotransferase with incident dementia risk through 2019 in the Atherosclerosis Risk in Communities (ARIC) Study. METHODS: We characterized NAFLD using the fatty liver index and fibrosis-4, and we categorized aminotransferase using the optimal equal-hazard ratio (HR) approach. We estimated HRs for incident dementia ascertained from multiple data sources. RESULTS: Adjusted for demographics, alcohol consumption, and kidney function, individuals with low, intermediate, and high liver fibrosis in midlife (HRs: 1.45, 1.40, and 2.25, respectively), but not at older age, had higher dementia risks than individuals without fatty liver. A U-shaped association was observed for alanine aminotransferase with dementia risk, which was more pronounced in late-life assessment. DISCUSSION: Our findings highlight dementia burden in high-prevalent NAFLD and the important feature of late-life aminotransaminase as a surrogate biomarker linking liver hypometabolism to dementia. Highlights Although evidence of liver involvement in dementia development has been documented in animal studies, the evidence in humans is limited. Midlife NAFLD raised dementia risk proportionate to severity. Late-life NAFLD was not associated with a high risk of dementia. Low alanine aminotransferase was associated with an elevated dementia risk, especially when measured in late life.

Patterns of cognitive domain abnormalities enhance discrimination of dementia risk prediction: The ARIC study.

INTRODUCTION: The contribution of neuropsychological assessments to risk assessment for incident dementia is underappreciated. METHODS: We analyzed neuropsychological testing results in dementia-free participants in the Atherosclerosis Risk in Communities (ARIC) study. We examined associations of index domain-specific neuropsychological test performance with incident dementia using cumulative incidence curves and Cox proportional hazards models. RESULTS: Among 5296 initially dementia-free participants (mean [standard deviation] age of 75.8 [5.1] years; 60.1% women, 22.2% Black) over a median follow-up of 7.9 years, the covariate-adjusted hazard ratio varied substantially depending on the pattern of domain-specific performance and age, in an orderly manner from single domain language abnormalities (lowest risk) to single domain executive or memory abnormalities, to multidomain abnormalities including memory (highest risk). DISCUSSION: By identifying normatively defined cognitive abnormalities by domains based on neuropsychological test performance, there is a conceptually orderly and age-sensitive spectrum of risk for incident dementia that provides valuable information about the likelihood of progression. HIGHLIGHTS: Domain-specific cognitive profiles carry enhanced prognostic value compared to mild cognitive impairment. Single-domain non-amnestic cognitive abnormalities have the most favorable prognosis. Multidomain amnestic abnormalities have the greatest risk for incident dementia. Patterns of domain-specific risks are similar by sex and race.

Cerebral Microbleed Patterns and Cortical Amyloid-ß: The ARIC-PET Study.

BACKGROUND: Cerebral microbleeds (CMBs) are associated with cognitive decline, but their importance outside of cerebral amyloid angiopathy and the mechanisms of their impact on cognition are poorly understood. We evaluated the cross-sectional association between CMB patterns and cerebral Aß (amyloid-ß) deposition, by florbetapir positron emission tomography. METHODS: The longitudinal ARIC study (Atherosclerosis Risk in Communities) recruited individuals from 4 US communities from 1987 to 1989. From 2012 to 2014, the ARIC-PET (Atherosclerosis Risk in Communities - Positron Emission Tomography) ancillary recruited 322 nondemented ARIC participants who completed 3T brain magnetic resonance imaging with T2*GRE as part of ARIC visit 5 to undergo florbetapir positron emission tomography imaging. Magnetic resonance imaging images were read for CMBs and superficial siderosis; on positron emission tomography, global cortical standardized uptake value ratio >1.2 was considered a positive Aß scan. Multivariable logistic regression models evaluated CMB characteristics in association with Aß positivity. Effect modification by sex, race, APOE status, and cognition was evaluated. RESULTS: CMBs were present in 24% of ARIC-PET participants. No significant associations were found between CMBs and Aß positivity, but a pattern of isolated lobar CMBs or superficial siderosis was associated with over 4-fold higher odds of elevated Aß when compared with those with no CMBs (odds ratio, 4.72 [95% CI, 1.16-19.16]). A similar elevated risk was not observed in those with isolated subcortical or mixed subcortical and either lobar CMBs or superficial siderosis. Although no significant interactions were found, effect estimates for elevated Aß were nonsignificantly lower (P>0.10, odds ratio, 0.4-0.6) for a mixed CMB pattern, and odds ratios were nonsignificantly higher for lobar-only CMBs for 4 subgroups: women (versus men); Black participants (versus White participants), APOE ε4 noncarriers (versus carriers), and cognitively normal (versus mild cognitive impairment). CONCLUSIONS: In this community-based cohort of nondemented adults, lobar-only pattern of CMBs or superficial siderosis is most strongly associated with brain Aß, with no elevated risk for a mixed CMB pattern. Further studies are needed to understand differences in CMB patterns and their meaning across subgroups.

Identification of Clinically Relevant Brain Endothelial Cell Biomarkers in Plasma.

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.

Associations of Vascular Risk and Amyloid Burden with Subsequent Dementia.

OBJECTIVE: Midlife vascular risk factors (MVRFs) are associated with incident dementia, as are amyloid ß (Aß) deposition and neurodegeneration. Whether vascular and Alzheimer disease-associated factors contribute to dementia independently or interact synergistically to reduce cognition is poorly understood. METHODS: Participants in the Atherosclerosis Risk in Communities-Positron Emission Tomography study were followed from 1987-1989 (45-64 years old) through 2016-2017 (74-94 years old), with repeat cognitive assessment and dementia adjudication. In 2011-2013, dementia-free participants underwent brain magnetic resonance imaging (with white matter hyperintensity [WMH] and brain volume measurement) and florbetapir (Aß) positron emission tomography. The relative contributions of vascular risk and injury (MVRFs, WMH volume), elevated Aß standardized uptake value ratio (SUVR), and neurodegeneration (smaller temporoparietal brain regions) to incident dementia were evaluated with adjusted Cox models. RESULTS: In 298 individuals, 36 developed dementia (median follow-up = 4.9 years). Midlife hypertension and Aß each independently predicted dementia risk (hypertension: hazard ratio [HR] = 2.57, 95% confidence interval [CI] = 1.16-5.67; Aß SUVR [per standard deviation (SD)]: HR = 2.57, 95% CI = 1.72-3.84), but did not interact significantly, whereas late life diabetes (HR = 2.50, 95% CI = 1.18-5.28) and Aß independently predicted dementia risk. WMHs (per SD: HR = 1.51, 95% CI = 1.03-2.20) and Aß SUVR (HR = 2.52, 95% CI = 1.83-3.47) independently contributed to incident dementia, but WMHs lost significance when MVRFs were included. Smaller temporoparietal brain regions were associated with incident dementia, independent of Aß and MVRFs (HR = 2.18, 95% CI = 1.18-4.01). INTERPRETATION: Midlife hypertension and late life Aß are independently associated with dementia risk, without evidence for synergy on a multiplicative scale. Given the independent contributions of vascular and amyloid mechanisms, multiple pathways should be considered when evaluating interventions to reduce the burden of dementia. ANN NEUROL 2022;92:607-619.

Energizing Mitochondria to Prevent Mobility Loss in Aging: Rationale and Hypotheses.

Based on recent studies from our group and others, we hypothesize that mitochondrial dysfunction during aging may be the root cause of mobility decline through deficits in the musculoskeletal and central nervous systems. Mitochondrial dysfunction could be a therapeutic target to prevent mobility decline in aging.

Skeletal muscle mitochondrial function predicts cognitive impairment and is associated with biomarkers of Alzheimer's disease and neurodegeneration.

INTRODUCTION: Mitochondrial dysfunction is implicated in the pathophysiology of many chronic diseases. Whether it is related to cognitive impairment and pathological markers is unknown. METHODS: We examined the associations of in vivo skeletal muscle mitochondrial function (post-exercise recovery rate of phosphocreatine [kPCr] via magnetic resonance [MR] spectroscopy with future mild cognitive impairment (MCI) or dementia, and with positron emission tomography (PET) and blood biomarkers of Alzheimer's disease [AD] and neurodegeneration (i.e., Pittsburgh Compound-B [PiB] distribution volume ratio [DVR] for amyloid beta [Aß], flortaucipir (FTP) standardized uptake value ratio [SUVR] for tau, Aß42 /40 ratio, phosphorylated tau 181 [p-tau181], neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]). RESULTS: After covariate adjustment, each standard deviation (SD) higher kPCr level was associated with 52% lower hazards of developing MCI/dementia, and with 59% lower odds of being PiB positive with specific associations in DVR of frontal, parietal, and temporal regions, and cingulate cortex and pallidum. Higher kPCr level was also associated with lower plasma GFAP. DISCUSSION: In aging, mitochondrial dysfunction may play a vital role in AD pathological changes and neuroinflammation. Highlights Higher in vivo mitochondrial function is related to lower risk of mild cognitive impairment (MCI)/dementia. Higher in vivo mitochondrial function is related to lower amyloid tracer uptake. Higher in vivo mitochondrial function is related to lower plasma neuroinflammation. Mitochondrial dysfunction may play a key role in Alzheimer's disease (AD) and neurodegeneration.

Longitudinal changes in Alzheimer's-related plasma biomarkers and brain amyloid.

INTRODUCTION: Understanding longitudinal plasma biomarker trajectories relative to brain amyloid changes can help devise Alzheimer's progression assessment strategies. METHODS: We examined the temporal order of changes in plasma amyloid-ß ratio ( A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ ), glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), and phosphorylated tau ratios ( p-tau181 / A ß 42 $\text{p-tau181}/\mathrm{A}{\beta}_{42}$ , p-tau231 / A ß 42 $\text{p-tau231}/\mathrm{A}{\beta}_{42}$ ) relative to 11 C-Pittsburgh compound B (PiB) positron emission tomography (PET) cortical amyloid burden (PiB-/+). Participants (n = 199) were cognitively normal at index visit with a median 6.1-year follow-up. RESULTS: PiB groups exhibited different rates of longitudinal change in A ß 42 / A ß 40 ( ß = 5.41 × 10 - 4 , SE = 1.95 × 10 - 4 , p = 0.0073 ) ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}\ ( {\beta \ = \ 5.41 \times {{10}}^{ - 4},{\rm{\ SE\ }} = \ 1.95 \times {{10}}^{ - 4},\ p\ = \ 0.0073} )$ . Change in brain amyloid correlated with change in GFAP (r = 0.5, 95% CI = [0.26, 0.68]). The greatest relative decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ (-1%/year) preceded brain amyloid positivity by 41 years (95% CI = [32, 53]). DISCUSSION: Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may begin declining decades prior to brain amyloid accumulation, whereas p-tau ratios, GFAP, and NfL increase closer in time. HIGHLIGHTS Plasma A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ declines over time among PiB- but does not change among PiB+. Phosphorylated-tau to Aß42 ratios increase over time among PiB+ but do not change among PiB-. Rate of change in brain amyloid is correlated with change in GFAP and neurofilament light chain. The greatest decline in A ß 42 / A ß 40 ${{\rm A}\beta }_{42}/{{\rm A}\beta }_{40}$ may precede brain amyloid positivity by decades.

Association of change in cardiovascular risk factors with incident dementia.

INTRODUCTION: We evaluated whether better cardiovascular health at midlife and improvement of cardiovascular health within midlife were associated with dementia risk. METHODS: Two longitudinal population-based studies were used: Atherosclerosis Risk in Communities (ARIC) (n = 11,460/visits at ages 54 and 60), and Age, Gene/Environment Susceptibility (AGES)-Reykjavik (n = 3907/visit at age 51). A cardiovascular health score (range 0-12/0-14, depending on diet availability) including six/seven items was calculated at each visit, with weight assigned to each item as poor (0), intermediate (1), or ideal (2). Cardiovascular health was defined as low (score 0-4/0-5), intermediate (5-7/6-9), or high (8-12/10-14). Incident dementia was ascertained through linkage to health records and with neuropsychological examinations. RESULTS: Midlife high compared to low cardiovascular health (hazard ratios [HRs]: for ARIC: 0.60 [95% confidence interval: 0.52, 0.69]); for AGES-Reykjavik: 0.83 [0.66, 0.99] and improvement of cardiovascular health score within midlife (HR per one-point increase: ARIC: 0.94 [0.92, 0.96]) were associated with lower dementia risk. DISCUSSION: Better cardiovascular health at midlife and improvement of cardiovascular health within midlife are associated with lower dementia risk. HIGHLIGHTS: Cardiovascular health and dementia were studied in two large cohort studies. Better cardiovascular health at midlife relates to lower dementia risk. Improvement of cardiovascular health within midlife relates to lower dementia risk. Promotion of cardiovascular health at midlife can help to reduce dementia risk.

The association of perceived discrimination with dementia risk in Black older adults.

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.