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Abstract Background Apolipoprotein E (APOE) ε4 allele is the strongest genetic risk factor for late onset Alzheimer’s disease (AD). This case-cohort study used targeted plasma biomarkers and large-scale proteomics to examine the biological mechanisms that allow some APOEε4 carriers to maintain normal cognitive functioning in older adulthood. Methods APOEε4 carriers and APOEε3 homozygotes enrolled in the Women’s Health Initiative Memory Study (WHIMS) from 1996 to 1999 were classified as resilient if they remained cognitively unimpaired beyond age 80, and as non-resilient if they developed cognitive impairment before or at age 80. AD pathology (Aß42/40) and neurodegeneration (NfL, tau) biomarkers, as well as 1007 proteins (Olink) were quantified in blood collected at study enrollment (on average 14 years prior) when participants were cognitively normal. We identified plasma proteins that distinguished between resilient and non-resilient APOEε4 carriers, examined whether these associations generalized to APOEε3 homozygotes, and replicated these findings in the UK Biobank. Results A total of 1610 participants were included (baseline age: 71.3 [3.8 SD] years; all White; 42% APOEε4 carriers). Compared to resilient APOEε4 carriers, non-resilient APOEε4 carriers had lower Aß42/40/tau ratio and greater NfL at baseline. Proteomic analyses identified four proteins differentially expressed between resilient and non-resilient APOEε4 carriers at an FDR-corrected P

Adult-onset diabetes increases one’s risk of neurodegenerative disease including Alzheimer’s disease (AD); however, the risk associated with youth-onset diabetes (Y-DM) remains underexplored. We quantified plasma biomarkers of neurodegeneration and AD in participants with Y-DM from the SEARCH cohort at adolescence and young adulthood (Type 1, n = 25; Type 2, n = 25; 59% female; adolescence, age = 15 y/o [2.6]; adulthood, age = 27.4 y/o [2.2]), comparing them with controls (adolescence, n = 25, age = 14.8 y/o [2.7]; adulthood, n = 21, age = 24.9 y/o [2.8]). Plasma biomarkers, including glial fibrillary acidic protein (GFAP), neurofilament light chain protein (NfL), phosphorylated tau-181 (pTau181), and amyloid beta (Aβ40, Aβ42), were measured via Simoa. A subset of participants (n = 7; age = 27.5 y/o [5.7]) and six controls (age = 25.1 y/o [4.5]) underwent PET scans to quantify brain amyloid and tau densities in AD sensitive brain regions. Y-DM adolescents exhibited lower plasma levels of Aβ40, Aβ42, and GFAP, and higher pTau181 compared to controls (p < 0.05), a pattern persisting into adulthood (p < 0.001). All biomarkers showed significant increases from adolescence to adulthood in Y-DM (p < 0.01), though no significant differences in brain amyloid or tau were noted between Y-DM and controls in adulthood. Preliminary evidence suggests that preclinical AD neuropathology is present in young people with Y-DM, indicating a potential increased risk of neurodegenerative diseases.

Abstract Background Retinal microvascular signs are accessible measures of early alterations in microvascular dysregulation and have been associated with dementia; it is unclear if they are associated with AD (Alzheimer’s disease) pathogenesis as a potential mechanistic link. This study aimed to test the association of retinal microvascular abnormalities in mid and late life and late life cerebral amyloid. Methods Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study with a valid retinal measure (N = 285) were included. The associations of mid- and late-life retinal signs with late-life amyloid-β (Aβ) by florbetapir PET were tested. Two different measures of Aβ burden were included: (1) elevated amyloid (SUVR > 1.2) and (2) continuous amyloid SUVR. The retinal measures’ association with Aβ burden was assessed using logistic and robust linear regression models. A newly created retinal score, incorporating multiple markers of retinal abnormalities, was also evaluated in association with greater Aβ burden. Results Retinopathy in midlife (OR (95% CI) = 0.36 (0.08, 1.40)) was not significantly associated with elevated amyloid burden. In late life, retinopathy was associated with increased continuous amyloid standardized value uptake ratio (SUVR) (β (95%CI) = 0.16 (0.02, 0.32)) but not elevated amyloid burden (OR (95%CI) = 2.37 (0.66, 9.88)) when accounting for demographic, genetic and clinical risk factors. A high retinal score in late life, indicating a higher burden of retinal abnormalities, was also significantly associated with increased continuous amyloid SUVR (β (95% CI) = 0.16 (0.04, 0.32)) independent of vascular risk factors. Conclusions Retinopathy in late life may be an easily obtainable marker to help evaluate the mechanistic vascular pathway between retinal measures and dementia, perhaps acting via AD pathogenesis. Well-powered future studies with a greater number of retinal features and other microvascular signs are needed to test these findings.

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.

Summary: Given expanding studies in epidemiology and disease-oriented human studies offering hundreds of associations between the human “ome” and disease, prioritizing molecules relevant to disease mechanisms among this growing breadth is important. Here, we link the circulating proteome to human heart failure (HF) propensity (via echocardiographic phenotyping and clinical outcomes) across the lifespan, demonstrating key pathways of fibrosis, inflammation, metabolism, and hypertrophy. We observe a broad array of genes encoding proteins linked to HF phenotypes and outcomes in clinical populations dynamically expressed at a transcriptional level in human myocardium during HF and cardiac recovery (several in a cell-specific fashion). Many identified targets do not have wide precedent in large-scale genomic discovery or human studies, highlighting the complementary roles for proteomic and tissue transcriptomic discovery to focus epidemiological targets to those relevant in human myocardium for further interrogation.

Abstract Background Specific peripheral proteins have been implicated to play an important role in the development of Alzheimer’s disease (AD). However, the roles of additional novel protein biomarkers in AD etiology remains elusive. The availability of large-scale AD GWAS and plasma proteomic data provide the resources needed for the identification of causally relevant circulating proteins that may serve as risk factors for AD and potential therapeutic targets. Methods We established and validated genetic prediction models for protein levels in plasma as instruments to investigate the associations between genetically predicted protein levels and AD risk. We studied 71,880 (proxy) cases and 383,378 (proxy) controls of European descent. Results We identified 69 proteins with genetically predicted concentrations showing associations with AD risk. The drugs almitrine and ciclopirox targeting ATP1A1 were suggested to have a potential for being repositioned for AD treatment. Conclusions Our study provides additional insights into the underlying mechanisms of AD and potential therapeutic strategies.

Abstract INTRODUCTION This study aimed to assess whether social relationships in mid‐life reduce the risk of dementia related to amyloid burden. METHODS Participants in the Atherosclerosis Risk in Communities (ARIC) study were assessed for social support and isolation (visit 2; 1990–1992). A composite measure, “social relationships,” was generated. Brain amyloid was evaluated with florbetapir positron emission tomography (PET); (visit 5; 2012–2014). Incident dementia cases were identified following visit 5 through 2019 using ongoing surveillance. Relative contributions of mid‐life social relationships and elevated brain amyloid to incident dementia were evaluated with Cox regression models. RESULTS Among 310 participants without dementia, strong mid‐life social relationships were associated independently with lower dementia risk. Elevated late‐life brain amyloid was associated with greater dementia risk. DISCUSSION Although mid‐life social relationships did not moderate the relationship between amyloid burden and dementia, these findings affirm the importance of strong social relationships as a potentially protective factor against dementia.

Abstract Identifying circulating proteins associated with cognitive function may point to biomarkers and molecular process of cognitive impairment. Few studies have investigated the association between circulating proteins and cognitive function. We identify 246 protein measures quantified by the SomaScan assay as associated with cognitive function (p

Abstract Peripheral inflammation, defined as inflammation that occurs outside the central nervous system, is an age-related phenomenon that has been identified as a risk factor for Alzheimer’s disease. While the role of chronic peripheral inflammation has been well characterized in the context of dementia and other age-related conditions, less is known about the neurologic contribution of acute inflammatory insults that take place outside the central nervous system. Herein, we define acute inflammatory insults as an immune challenge in the form of pathogen exposure (e.g., viral infection) or tissue damage (e.g., surgery) that causes a large, yet time-limited, inflammatory response. We provide an overview of the clinical and translational research that has examined the connection between acute inflammatory insults and Alzheimer’s disease, focusing on three categories of peripheral inflammatory insults that have received considerable attention in recent years: acute infection, critical illness, and surgery. Additionally, we review immune and neurobiological mechanisms which facilitate the neural response to acute inflammation and discuss the potential role of the blood–brain barrier and other components of the neuro-immune axis in Alzheimer’s disease. After highlighting the knowledge gaps in this area of research, we propose a roadmap to address methodological challenges, suboptimal study design, and paucity of transdisciplinary research efforts that have thus far limited our understanding of how pathogen- and damage-mediated inflammatory insults may contribute to Alzheimer’s disease. Finally, we discuss how therapeutic approaches designed to promote the resolution of inflammation may be used following acute inflammatory insults to preserve brain health and limit progression of neurodegenerative pathology.

Dementia poses a substantial global health challenge, warranting an exploration of its intricate pathophysiological mechanisms and potential intervention targets. Leveraging multi-omic technology, this study utilizes data from 2251 participants to construct classification models using lipidomic, gut metabolomic, and cerebrospinal fluid (CSF) proteomic markers to distinguish between the states of cognitive decline, namely, the cognitively unimpaired state, mild cognitive impairment, and dementia. The analysis identifies three CSF proteins (apolipoprotein E, neuronal pentraxin-2, and fatty-acid-binding protein), four lipids (DEDE.18.2, DEDE.20.4, LPC.O.20.1, and LPC.P.18.1), and five serum gut metabolites (Hyodeoxycholic acid, Glycohyodeoxycholic acid, Hippuric acid, Glyceric acid, and Glycodeoxycholic acid) capable of predicting dementia prevalence from cognitively unimpaired participants, achieving Area Under the Curve (AUC) values of 0.879 (95% CI: 0.802–0.956), 0.766 (95% CI: 0.700–0.835), and 0.717 (95% CI: 0.657–0.777), respectively. Furthermore, exclusively three CSF proteins exhibit the potential to predict mild cognitive impairment prevalence from cognitively unimpaired subjects, with an AUC of 0.760 (95% CI: 0.691–0.828). In conclusion, we present novel combinations of lipids, gut metabolites, and CSF proteins that showed discriminative abilities between the states of cognitive decline and underscore the potential of these molecules in elucidating the mechanisms of cognitive decline.

Abstract 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.

Abstract SomaScan is a high-throughput, aptamer-based proteomics assay designed for the simultaneous measurement of thousands of proteins with a broad range of endogenous concentrations. In its most current version, the 7k SomaScan assay v4.1 is capable of measuring 7288 human proteins. In this work, we present an extensive technical assessment of this platform based on a study of 2050 samples across 22 plates. Included in the study design were inter-plate technical duplicates from 102 human subjects, which allowed us to characterize different normalization procedures, evaluate assay variability by multiple analytical approaches, present signal-over-background metrics, and discuss potential specificity issues. By providing detailed performance assessments on this wide range of technical aspects, we aim for this work to serve as a valuable resource for the growing community of SomaScan users.

Aging is characterized by the accumulation of damage to macromolecules and cell architecture that triggers a proinflammatory state in blood and solid tissues, termed inflammaging. Inflammaging has been implicated in the pathogenesis of many age-associated chronic diseases as well as loss of physical and cognitive function. The search for mechanisms that underlie inflammaging focused initially on the hallmarks of aging, but it is rapidly expanding in multiple directions. Here, we discuss the threads connecting cellular senescence and mitochondrial dysfunction to impaired mitophagy and DNA damage, which may act as a hub for inflammaging. We explore the emerging multi-omics efforts that aspire to define the complexity of inflammaging — and identify molecular signatures and novel targets for interventions aimed at counteracting excessive inflammation and its deleterious consequences while preserving the physiological immune response. Finally, we review the emerging evidence that inflammation is involved in brain aging and neurodegenerative diseases. Our goal is to broaden the research agenda for inflammaging with an eye on new therapeutic opportunities.

OBJECTIVES/GOALS: Motoric cognitive risk (MCR) is a pre-dementia syndrome characterized by slow gait and subjective cognitive complaints. In the Atherosclerosis Risk in Communities (ARIC) study, we aim to (1) identify plasma proteins and protein modules associated with MCR and (2) compare the proteomic signature of MCR to that of mild cognitive impairment (MCI). METHODS/STUDY POPULATION: Nondemented ARIC participants were classified by MCR status (yes/no) according to a memory questionnaire and 4-meter walk. MCI status (yes/no) was classified by expert diagnosis using standardized criteria. We measured 4,877 proteins in plasma collected at ARIC Visit 5 (late-life) and Visit 2 (midlife) utilizing the SomaScan4 proteomic assay. Multivariable logistic regression”adjusted for demographic variables, kidney function, cardiovascular risk factors, and APOE4 status”related each protein to MCR at late-life. An FDR corrected P RESULTS/ANTICIPATED RESULTS: Proteome-wide association study among 4076 ARIC participants (mean age=75; 58% women, 17% Black, 4% MCR+, 21% MCI+; MCR+ and MCI+ groups overlapped) at late-life identified 26 MCR-associated proteins involved in metabolism, vascular/visceral smooth muscle, and extracellular matrix organization. At an uncorrected P DISCUSSION/SIGNIFICANCE: This proteomic characterization of MCR identifies novel plasma proteins and networks, both distinct from and overlapping with those of MCI, thus highlighting the partially divergent mechanisms underlying these pre-dementia syndromes. These findings may be leveraged toward dementia prognostication and targeted therapeutic approaches.

Abstract Objective Although small strokes typically result in “good” functional outcomes, significant cognitive impairment can occur. This longitudinal study examined a cohort of patients with minor stroke to determine the pattern of deficits, evolution over time, and factors associated with outcome. Methods Patients admitted to the hospital with their first clinical minor stroke (NIH Stroke Scale [NIHSS] ≤ 10, absence of severe hemiparesis, aphasia, or neglect) were assessed at 1 month post‐infarct, and a subset were followed over time (with 6‐ and 12‐month evaluations). Composite scores at each time point were generated for global cognition, verbal memory, spatial memory, motor speed, processing speed, and executive function. Paired t‐tests evaluated change in scores over time. Regression models identified factors associated with initial performance and better recovery. Results Eighty patients were enrolled, evaluated at 1 month, and prospectively followed. The average age of the participants was 62.3 years, and mean education was 13.5 years. The average stroke volume was 6.6 cc; mean NIHSS score was 2.8. At 1 month, cognitive scores were below the normative range and > 1 standard deviation below the patient's peak (“recovery”) score for every cognitive domain, strongly suggesting that they were well below patients’ prestroke baselines. Forty‐eight patients followed up at 6 months, and 39 at 12 months. Nearly all (98%) patients significantly improved in global cognition (averaged across domains) between 1 and 6 months. Between 6 and 12 months, recovery was variable. Higher education, occupational class, and Caucasian race were associated with higher recovery scores for most domains. Conclusions Cognitive impairment across multiple domains is common following minor stroke regardless of infarct location, suggesting a global process such as network dysfunction that improves over 6 months. Degree of recovery can be predicted using baseline factors.

Background White matter abnormalities are a common feature of aging and Alzheimer disease, and tend to be more severe among Black individuals. However, the extent to which white matter abnormalities relate to amyloid deposition, a marker of Alzheimer pathology, remains unclear. This cross‐sectional study examined the association of white matter abnormalities with cortical amyloid in a community sample of older adults without dementia and examined the moderating effect of race. Methods and Results Participants from the ARIC‐PET (Atherosclerosis Risk in Communities‐Positron Emission Tomography) study underwent brain magnetic resonance imaging, which quantified white matter hyperintensity volume and microstructural integrity using diffusion tensor imaging. Participants received florbetapir positron emission tomography imaging to measure brain amyloid. Associations between measures of white matter structure and elevated amyloid status were examined using multivariable logistic regression. Among 322 participants (43% Black), each SD increase in white matter hyperintensity volume was associated with a greater odds of elevated amyloid (odds ratio [OR], 1.37; 95% CI, 1.03–1.83) after adjusting for demographic and cardiovascular risk factors. In race‐stratified analyses, a greater white matter hyperintensity volume was more strongly associated with elevated amyloid among Black participants (OR, 2.00; 95% CI, 1.15–3.50), compared with White participants (OR, 1.29; 95% CI, 0.89–1.89). However, the race interaction was not statistically significant (P interaction=0.09). We found no association between white matter microstructure and elevated amyloid. Conclusions The results suggest a modest positive relationship between white matter hyperintensity and elevated amyloid in older adults without dementia. Although the results indicate that this association is nonsignificantly stronger among Black participants, these findings will need to be confirmed or refuted using larger multiracial cohorts.

Background The impact of the new 2017 American College of Cardiology/American Heart Association (ACC/AHA) hypertension guideline on dementia risk at the population level has not been evaluated. Methods and Results We studied dementia‐free participants in the ARIC (Atherosclerosis Risk in Communities) Study cohort in 1987 to 1989. Hypertension was defined by 2003 Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and 2017 ACC/AHA guidelines using blood pressure measured at baseline. Dementia was defined using adjudicated consensus diagnoses, informant telephone interviews, and discharge codes from hospitalizations and death certificates. Cox regression estimated hazard ratios (HRs) for dementia and 95% CIs by hypertension categories, adjusting for confounders. Population attributable fraction of dementia was calculated by hypertension categories. Among 13 971 participants followed up for a median of 23 years, 1381 dementia cases were identified. Prevalence of hypertension was 34% and 48%, according to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure and ACC/AHA criteria, respectively. HRs (95% CIs) compared with normal blood pressure, according to ACC/AHA categories, were 1.35 (1.12–1.61) for elevated blood pressure, 1.28 (1.07–1.52) for hypertension stage 1, and 1.36 (1.18–1.57) for hypertension stage 2. Population attributable fractions (95% CIs) of dementia from blood pressure categories were 3% (1%–5%), 3% (1%–5%), and 9% (4%–14%), respectively. Population attributable fractions (95% CIs) using the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure categories were 6% (3%–9%) for prehypertension, 0% (−2% to 2%) for hypertension stage 1, and 9% (5%–13%) for hypertension stage 2. Conclusions Risk of dementia increased across hypertension categories defined by ACC/AHA guidelines. The population impact on dementia incidence using ACC/AHA categories was similar to the impact of the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.

Background Changes in white matter microstructural integrity are detectable before appearance of white matter lesions on magnetic resonance imaging as a manifestation of cerebral small‐vessel disease. The information relating poor white matter microstructural integrity to aortic stiffness, a hallmark of aging, is limited. We aimed to examine the association between aortic stiffness and white matter microstructural integrity among older adults. Methods and Results We conducted a cross‐sectional study to examine the association between aortic stiffness and white matter microstructural integrity among 1484 men and women (mean age, 76 years) at the 2011 to 2013 examination of the ARIC‐NCS (Atherosclerosis Risk in Communities Neurocognitive Study). Aortic stiffness was measured as carotid‐femoral pulse wave velocity. Cerebral white matter microstructural integrity was measured as fractional anisotropy and mean diffusivity using diffusion tensor imaging. Multivariable linear regression was used to examine the associations of carotid‐femoral pulse wave velocity with fractional anisotropy and mean diffusivity of the overall cerebrum and at regions of interest. Each 1‐m/s higher carotid‐femoral pulse wave velocity was associated with lower overall fractional anisotropy (β=−0.03; 95% CI, −0.05 to −0.02) and higher overall mean diffusivity (β=0.03; 95% CI, 0.02–0.04). High carotid‐femoral pulse wave velocity (upper 25th percentile) was associated with lower fractional anisotropy (β=−0.40; 95% CI, −0.61 to −0.20) and higher overall mean diffusivity (β=0.27; 95% CI, 0.10–0.43). Similar associations were observed at individual regions of interest. Conclusions High aortic stiffness is associated with low cerebral white matter microstructural integrity among older adults. Aortic stiffness may serve as a target for the prevention of poor cerebral white matter microstructural integrity.

ObjectiveTo examine the prospective association between blood biomarkers of immune functioning (i.e., innate immune activation, adaptive immunity, and inflammation) and subsequent cognitive decline and clinical progression to mild cognitive impairment (MCI) in cognitively normal individuals.MethodsThe BIOCARD study is an observational cohort study of N = 191 initially cognitively healthy participants (mean age 65.2 years). Blood plasma samples were assayed for markers of chronic inflammation (TNFR1, IL-6), adaptive immunity (CD25), and innate immune activation (CD14 and CD163). Participants were followed annually for ongoing clinical assessment and cognitive testing for up to 7.3 years. Primary study outcomes were progression to MCI and cognitive change over time, as measured by a global factor score encompassing multiple cognitive domains.ResultsHigher levels of plasma TNFR1 were associated with greater risk of progression from normal cognition to MCI (HR: 3.27; 95% confidence interval, CI: 1.27, 8.40). Elevated levels of TNFR1 were also associated with steeper rate of cognitive decline on follow-up but not with baseline cognitive performance. Baseline IL-6 levels and markers of innate and adaptive immune activation showed no relationship with MCI risk or cognitive decline.ConclusionInflammation, mediated by TNF signaling, may play a selective role in the early phase of AD. Accordingly, plasma TNFR1 may facilitate improved prediction of disease progression for individuals in the preclinical stage of AD.

Intrinsic functional connectivity of large-scale brain networks has been shown to change with aging and Alzheimer’s disease (AD). These alterations are thought to reflect changes in synaptic function, but the underlying biological mechanisms are poorly understood. This study examined whether Neuronal Pentraxin 2 (NPTX2), a synaptic protein that mediates homeostatic strengthening of inhibitory circuits to control cortical excitability, is associated with functional connectivity as measured by resting-state functional magnetic resonance imaging (rsfMRI) in five large-scale cognitive brain networks. In this cross-sectional study, rsfMRI scans were obtained from 130 older individuals (mean age = 69 years) with normal cognition (N = 113) and Mild Cognitive Impairment (N = 17); NPTX2 was measured in the same individuals in cerebrospinal fluid (CSF). Higher levels of NPTX2 in CSF were associated with greater functional connectivity in the salience/ventral attention network, based on linear regression analysis. Moreover, this association was stronger among individuals with lower levels of cognitive reserve, as measured by a composite score (comprised of years of education, reading, and vocabulary measures). Additionally, higher connectivity in the salience/ventral attention network was related to better performance on a composite measure of executive function. Levels of NPTX2 were not associated with connectivity in other networks (executive control, limbic, dorsal attention, and default-mode). Findings also confirmed prior reports that individuals with MCI have lower levels of NPTX2 compared to those with normal cognition. Taken together, the results suggest that NPTX2 mechanisms may play a central role among older individuals in connectivity within the salience/ventral attention network and for cognitive tasks that require modulation of attention and response selection.