Gut microbiota disturbances in hospitalized older adults with malnutrition and clinical outcomes.

OBJECTIVE: Malnutrition is one of the most threatening conditions in geriatric populations. The gut microbiota has an important role in the host's metabolic and muscular health: however, its interplay with disease-related malnutrition is not well understood. We aimed to identify the association of malnutrition with the gut microbiota and predict clinical outcomes in hospitalized acutely ill older adults. METHODS: We performed a secondary longitudinal analysis in 108 geriatric patients from a prospective cohort evaluated at admission and 72 h of hospitalization. We collected clinical, demographic, nutritional, and 16S rRNA gene-sequenced gut microbiota data. Microbiota diversity, overall composition, and differential abundance were calculated and compared between patients with and without malnutrition. Microbiota features associated with malnutrition were used to predict clinical outcomes. RESULTS: Patients with malnutrition (51%) had a different microbiota composition compared to those who were well-nourished during hospitalization (ANOSIM R = 0.079, P = 0.003). Patients with severe malnutrition showed poorer α-diversity at admission (Shannon P = 0.012, Simpson P = 0.018) and follow-up (Shannon P = 0.023, Chao1 P = 0.008). Differential abundance of Lachnospiraceae NK4A136 group, Subdoligranulum, and Faecalibacterium prausnitzii were significantly lower and inversely associated with malnutrition, while Corynebacterium, Ruminococcaceae Incertae Sedis, and Fusobacterium were significantly increased and positively associated with malnutrition. Corynebacterium, Ruminococcaceae Incertae Sedis, and the overall composition were important predictors of critical care in patients with malnutrition during hospitalization. CONCLUSION: Older adults with malnutrition, especially in a severe stage, may be subject to substantial gut microbial disturbances during hospitalization. The gut microbiota profile of patients with malnutrition might help us to predict worse clinical outcomes.

Low circulating adropin concentrations predict increased risk of cognitive decline in community-dwelling older adults.

The secreted peptide adropin is highly expressed in human brain tissues and correlates with RNA and proteomic risk indicators for dementia. Here we report that plasma adropin concentrations predict risk for cognitive decline in the Multidomain Alzheimer Preventive Trial (ClinicalTrials.gov Identifier, NCT00672685; mean age 75.8y, SD = 4.5 years, 60.2% female, n = 452). Cognitive ability was evaluated using a composite cognitive score (CCS) that assessed four domains: memory, language, executive function, and orientation. Relationships between plasma adropin concentrations and changes in CCS (∆CCS) were examined using Cox Proportional Hazards Regression, or by grouping into tertiles ranked low to high by adropin values and controlling for age, time between baseline and final visits, baseline CCS, and other risk factors (e.g., education, medication, APOE4 status). Risk of cognitive decline (defined as a ∆CCS of - 0.3 or more) decreased with increasing plasma adropin concentrations (hazard ratio = 0.873, 95% CI 0.780-0.977, P = 0.018). Between adropin tertiles, ∆CCS was significantly different (P = 0.01; estimated marginal mean ± SE for the 1st to 3rd tertile, - 0.317 ± 0.064; - 0.275 ± 0.063; - 0.042 ± 0.071; n = 133,146, and 130, respectively; P < 0.05 for 1st vs. 2nd and 3rd adropin tertiles). Normalized plasma Aß42/40 ratio and plasma neurofilament light chain, indicators of neurodegeneration, were significantly different between adropin tertile. These differences were consistent with reduced risk of cognitive decline with higher plasma adropin levels. Overall, these results suggest cognitive decline is reduced in community-dwelling older adults with higher circulating adropin levels. Further studies are needed to determine the underlying causes of the relationship and whether increasing adropin levels can delay cognitive decline.

Low circulating adropin levels in late-middle aged African Americans with poor cognitive performance.

We recently reported accelerated cognitive decline in Europeans aged > 70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR = 0.775, P < 0.05; age range 45-65 y, n = 352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Adropin expression in all cell-types declines with advance age, but is not affected by dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin and transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Declining adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline.

Antisense oligonucleotides targeting the miR-29b binding site in the GRN mRNA increase progranulin translation.

Heterozygous GRN (progranulin) mutations cause frontotemporal dementia (FTD) due to haploinsufficiency, and increasing progranulin levels is a major therapeutic goal. Several microRNAs, including miR-29b, negatively regulate progranulin protein levels. Antisense oligonucleotides (ASOs) are emerging as a promising therapeutic modality for neurological diseases, but strategies for increasing target protein levels are limited. Here, we tested the efficacy of ASOs as enhancers of progranulin expression by sterically blocking the miR-29b binding site in the 3' UTR of the human GRN mRNA. We found 16 ASOs that increase progranulin protein in a dose-dependent manner in neuroglioma cells. A subset of these ASOs also increased progranulin protein in iPSC-derived neurons and in a humanized GRN mouse model. In FRET-based assays, the ASOs effectively competed for miR-29b from binding to the GRN 3' UTR RNA. The ASOs increased levels of newly synthesized progranulin protein by increasing its translation, as revealed by polysome profiling. Together, our results demonstrate that ASOs can be used to effectively increase target protein levels by partially blocking miR binding sites. This ASO strategy may be therapeutically feasible for progranulin-deficient FTD as well as other conditions of haploinsufficiency.

Anorexia of aging: An international assessment of healthcare providers' knowledge and practice gaps.

BACKGROUND: Anorexia of aging is a common geriatric syndrome that includes loss of appetite and/or reduced food intake, with associated undernutrition, unintended weight loss, sarcopenia, functional decline, loss of independence and other adverse health outcomes. Anorexia of aging can have multiple and severe consequences and is often overlooked by healthcare professionals (HCPs). Even more concerningly, clinicians commonly accept anorexia of aging as an inevitable part of 'normal' aging. The aim of this assessment was to identify current gaps in professional knowledge and practice in identifying and managing older persons with anorexia. Results may guide educational programmes to fill the gaps identified and therefore improve patient outcomes. METHODS: This international assessment was conducted using a mixed-methods approach, including focus group interviews with subject matter experts and an electronic survey of practicing HCPs. The assessment was led by the Society on Sarcopenia, Cachexia and Wasting Disorders (SCWD) and was supported by in-country collaborating organizations. RESULTS: A quantitative survey of 26 multiple-choice questions was completed by physicians, dietitians and other HCPs (n = 1545). Most HCPs (56.8%) recognize a consistent definition of anorexia of aging as a loss of appetite and/or low food intake. Cognitive changes/dementia (91%) and dysphagia (87%) are seen as the biggest risk factors. Most respondents were confident to give nutritional (62%) and physical activity (59.4%) recommendations and engaged caregivers such as family members in supporting older adults with anorexia (80.6%). Most clinicians assessed appetite at each visit (66.7%), although weight is not measured at every visit (41.5%). Apart from the Mini-Nutritional Assessment Short Form (39%), other tools to screen for appetite loss are not frequently used or no tools are used at all (29.4%). A high number of respondents (38.7%) believe that anorexia is a normal part of aging. Results show that treatment is focused on swallowing disorders (78%), dentition issues (76%) and increasing oral intake (fortified foods [75%] and oral nutritional supplements [74%]). Nevertheless, the lack of high-quality evidence is perceived as a barrier to optimal treatment (49.2%). CONCLUSIONS: Findings from this international assessment highlight the challenges in the care of older adults with or at risk for anorexia of aging. Identifying professional practice gaps between individual HCPs and team-based gaps can provide a basis for healthcare education that is addressed at root causes, targeted to specific audiences and developed to improve individual and team practices that contribute to improving patient outcomes.

Lower risk for COVID-19 hospitalization among patients in the United States with past vaccinations for herpes zoster and tetanus, diphtheria and pertussis.

Influenza, tetanus, diphtheria, and herpes zoster (HZ) vaccination received within 10 years of the COVID-19 pandemic have been associated with less severe COVID-19 infection. We expanded on this evidence to determine if a receiving two different vaccinations (i.e., HZ and tetanus, diphtheria, and pertussis (Tdap)) was associated with a lower risk for COVID-19 hospitalization. De-identified medical record data from a large mid-western health care system was used to determine if, compared to those with neither HZ or Tdap vaccination, patients with either HZ or Tdap and patients with both HZ and Tdap vaccination had lower risk for COVID-19 hospitalization between 4/1/2020 and 12/31/2020. Confounding was controlled using entropy balancing. Patients (n = 363,293) were 71.5 (±8.4) years of age, 57.8% female and 89.2% White race. Prior to controlling for confounding, as compared to patients without either vaccination, those that had either HZ or Tdap were significantly less likely to have a COVID-19 hospitalization (RR = 0.85; 95 %CI: 0.75-0.95). The risk for hospitalization decreased further among those with both HZ and Tdap vaccination (RR = 0.45; 95 %CI:0.28-0.71). After controlling for confounding, including healthy patient bias, receiving both vs. neither vaccinations remained significantly associated with a lower risk of COVID-19 hospitalization (RR = 0.48; 95 %CI: 0.26-0.90). Receiving both Tdap and HZ vaccination is associated with lower risk for COVID-19 hospitalization. Whether there is any benefit of past vaccination exposure in COVID-19 vaccinated patients should be investigated.

Anxiety disorders, benzodiazepine prescription, and incident dementia.

BACKGROUND: Prescribing benzodiazepines to older patients is controversial. Anxiety disorders and benzodiazepines have been associated with dementia, but literature is inconsistent. It is unknown if anxiety treated with a benzodiazepine, compared to anxiety disorder alone is associated with dementia risk. METHODS: A retrospective cohort study (n = 72,496) was conducted using electronic health data from 2014 to 2021. Entropy balancing controlled for bias by indication and other confounding factors. PARTICIPANTS: Eligible patients were ≥65 years old, had clinic encounters before and after index date and were free of dementia for 2 years prior to index date. Of the 72,496 eligible patients, 85.6% were White and 59.9% were female. Mean age was 74.1 (SD ± 7.1) years. EXPOSURE: Anxiety disorder was a composite of generalized anxiety disorder, anxiety not otherwise specified, panic disorder, and social phobia. Sustained benzodiazepine use was defined as at least two separate prescription orders in any 6-month period. MAIN OUTCOME AND MEASURES: ICD-9 or ICD-10 dementia diagnoses. RESULTS: Six percent of eligible patients had an anxiety diagnosis and 3.6% received sustained benzodiazepine prescriptions. There were 6640 (9.2%) incident dementia events. After controlling for confounders, both sustained benzodiazepine use (HR 1.28, 95% CI: 1.11-1.47) and a diagnosis of anxiety (HR 1.19, 95% CI: 1.06-1.33) were associated with incident dementia in patients aged 65-75. Anxiety disorder with sustained benzodiazepine, compared to anxiety disorder alone, was not associated with incident dementia (HR 1.18, 95% CI: 0.92-1.51) after controlling for confounding. Results were not significant when limiting the sample to those ≥75 years of age. CONCLUSIONS: Benzodiazepines and anxiety disorders are associated with increased risk for dementia. In patients with anxiety disorders, benzodiazepines were not associated with additional dementia risk. Further research is warranted to determine if benzodiazepines are associated with a reduced or increased risk for dementia compared to other anxiolytic medications in patients with anxiety disorders.

Aging, Plasminogen Activator Inhibitor 1, Brain Cell Senescence, and Alzheimer's Disease.

The etiology for late-onset Alzheimer's disease (LOAD), which accounts for >95% of Alzheimer's disease (AD) cases, is unknown. Emerging evidence suggests that cellular senescence contributes importantly to AD pathophysiology, although the mechanisms underlying brain cell senescence and by which senescent cells promote neuro-pathophysiology remain unclear. In this study we show for the first time that the expression of plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor, is increased, in correlation with the increased expression of cell cycle repressors p53 and p21, in the hippocampus/cortex of senescence accelerated mouse prone 8 (SAMP8) mice and LOAD patients. Double immunostaining results show that astrocytes in the brain of LOAD patients and SAMP8 mice express higher levels of senescent markers and PAI-1, compared to astrocytes in the corresponding controls. In vitro studies further show that overexpression of PAI-1 alone, intracellularly or extracellularly, induced senescence, whereas inhibition or silencing PAI-1 attenuated H2O2-induced senescence, in primary mouse and human astrocytes. Treatment with the conditional medium (CM) from senescent astrocytes induced neuron apoptosis. Importantly, the PAI-1 deficient CM from senescent astrocytes that overexpress a secretion deficient PAI-1 (sdPAI-1) has significantly reduced effect on neurons, compared to the PAI-1 containing CM from senescent astrocytes overexpressing wild type PAI-1 (wtPAI-1), although sdPAI-1 and wtPAI-1 induce similar degree of astrocyte senescence. Together, our results suggest that increased PAI-1, intracellularly or extracellularly, may contribute to brain cell senescence in LOAD and that senescent astrocytes can induce neuron apoptosis through secreting pathologically active molecules, including PAI-1.

Blood-brain barrier penetration of non-replicating SARS-CoV-2 and S1 variants of concern induce neuroinflammation which is accentuated in a mouse model of Alzheimer's disease.

COVID-19 and especially Long COVID are associated with severe CNS symptoms and may place persons at risk to develop long-term cognitive impairments. Here, we show that two non-infective models of SARS-CoV-2 can cross the blood-brain barrier (BBB) and induce neuroinflammation, a major mechanism underpinning CNS and cognitive impairments, even in the absence of productive infection. The viral models cross the BBB by the mechanism of adsorptive transcytosis with the sugar N-acetylglucosamine being key. The delta and omicron variants cross the BB B faster than the other variants of concern, with peripheral tissue uptake rates also differing for the variants. Neuroinflammation induced by icv injection of S1 protein was greatly enhanced in young and especially in aged SAMP8 mice, a model of Alzheimer's disease, whereas sex and obesity had little effect.

Using minimal clinically important differences to measure long-term transitions of osteosarcopenia: The New Mexico Aging Process Study.

BACKGROUND/OBJECTIVE: By having a better understanding of transitions in osteosarcopenia, interventions to reduce morbidity and mortality can be better targeted. The aim of this study was to show the rationale and method of using minimal clinically important differences (MCID's) to classify transitions, and the effects of demographic variables on transitions in a 9-year follow-up data from the New Mexico Aging Process Study (NMAPS). METHODS: Transitions were identified in four aspects of osteosarcopenia: bone mineral density (BMD), appendicular skeletal muscle mass/body mass index ratio (ASM/BMI), grip strength and gait speed. Transitions were identified using a MCID score. As there is currently no available MCID for BMD and ASM/BMI, those were determined using a distribution-based and an anchor-based method. Total transitions were calculated for all four measures of osteosarcopenia in all transition categories (maintaining a health status, beneficial transition, harmful transitions). Poisson regression was used to test for effects of demographic variables, including age, sex, physical activity, medication, and health status, on transitions. RESULTS: Over the 9-year follow-up, a total of 2163 MCID-derived BMD transitions were reported, 1689 ASM/BMI transitions, 2339 grip strength transitions, and 2151 gait speed transitions. Additionally, some MCID-derived transition categories were associated with sex, age, and health status. CONCLUSION: Use of MCID-derived transitions reflected the fluctuation and the dynamic nature of health in older adults. Future research should focus on transitions of modifiable markers in osteosarcopenia to design intervention trials.

TNFR-1 and GDF-15 Are Associated With Plasma Neurofilament Light Chain and Progranulin Among Community-Dwelling Older Adults: A Secondary Analysis of the MAPT Study.

There is growing evidence that cognitive decline can be affected by both nutritional aspects and inflammation. Plasma neurodegenerative biomarkers stand out as minimally invasive useful measures to monitor the potential risk of cognitive decline. This study aimed to investigate the associations between biomarkers of neurodegeneration, nutrition, and inflammation among community-dwelling older adults, and to verify if associations differed according to apolipoprotein E (APOE) ε4 status. This cross-sectional analysis included 475 participants ≥70 years old from the Multidomain Alzheimer Preventive Trial (MAPT), mean age 76.8 years (SD = 4.5), 59.4% women. Biomarkers of neurodegeneration (plasma amyloid-ß 42/40-Aß 42/40, neurofilament light chain-NfL, progranulin), nutrition (erythrocyte docosahexaenoic acid, eicosapentaenoic acid, omega-3 index; plasma homocysteine-Hcy, 25 hydroxyvitamin D), inflammation (plasma tumor necrosis factor receptor 1-TNFR-1, monocyte chemoattractant protein 1-MCP-1, interleukin 6-IL-6), and cellular stress (plasma growth differentiation factor 15-GDF-15) were assessed. Linear regression analyses were performed to investigate the associations between nutritional and inflammatory biomarkers (independent variables) and neurodegenerative biomarkers (dependent variables), with adjustments for age, sex, education, body mass index, physical activity, allocation to MAPT groups, and APOE ε4 status. After adjusting for confounders, Aß 42/40 was not associated with nutritional or inflammatory markers. NfL was positively associated with GDF-15, TNFR-1, IL-6, and Hcy. Progranulin was positively associated with GDF-15, TNFR-1, and MCP-1. Analyses restricted to APOE ε4 carriers (n = 116; 26.9%) or noncarriers were mostly similar. Our cross-sectional study with community-dwelling older adults corroborates previous evidence that inflammatory pathways are associated to plasma markers of neurodegeneration. Clinical Trials Registration Number: NCT00672685.

Comparisons of Cognitive Stimulation Therapy Between Community Versus Hospital-Based Settings: A Multi-Site Study.

BACKGROUND: Non-pharmacological interventions such as Cognitive Stimulation Therapy (CST) have been shown to help persons living with dementia in improving cognitive function and recall. While previous CST interventions have been conducted largely with community populations, none have explored the outcomes of CST in larger healthcare settings. Our study explored differences of cognitive function, mood, and quality-of-life from CST groups both community and residential-based groups. METHOD: Participants (N = 258) from academic and rural, hospital-based settings in Missouri engaged in 14-session psychosocial groups to aid reminiscence for enhanced cognitive function and recall. RESULTS: Post-intervention cognitive function improvements occurred for community (t = -7.48, p < .001) and residential samples (t = -2.46, p < .05). Community groups showed significant improvement in overall mood related to their dementia (t = 6.37, p < .001). CONCLUSION: Healthcare providers should consider CST as a supplemental intervention for older patients receiving usual care for dementia-related symptoms.

Falls across Health Care Settings: Findings from a Geriatric Screening Program.

Falls are a major public health problem for older adults, resulting in injuries and mortality. Screening is recommended to identify the multifactorial fall risks that can be addressed with interventions to prevent future falls. This study examined the utility of using the Rapid Geriatric Assessment (RGA) tool to identify fall risks across multiple settings. RGA data was collected at primary care sites, hospitals, long-term care settings, and community events (n = 8686, 65% female, mean age 77.6). Multinomial logistic regression was used to determine predictors of falls using the RGA. The FRAIL, SARC-F, Rapid Cognitive Screen and SNAQ measures all significantly predicted history of falls. The RGA provides a brief screening that can be used in any setting by multiple providers to identify fall risk.

Patterns of participation restriction among older adults at risk of falls and relationship with intrinsic capacity: A latent cluster analysis.

Introduction: The concept of participation restriction was first described by the World Health Organization in 2001 as a component of The International Classification of Functioning, Disability and Health Framework. Both falls and fear of falling (FOF) are associated with social isolation, depression, anxiety, poor quality of life and cognitive impairment resulting in participation restriction. Life-space mobility (LSM) is an important indicator for participation restriction which depends on multiple inter-related factors. We aimed to determine participation patterns using latent cluster analysis (LCA) in older adults at risk of falls, its relationship with intrinsic capacity (IC) and its risk prediction. Methods: Cross-sectional study of 154 community dwelling older adults ≥ 60 years with falls or risk of falls was conducted. Questionnaires were administered on demographics, hearing, LSM, frailty (FRAIL scale), anorexia of aging (SNAQ), cognition (Montreal Cognitive Assessment, MoCA), FOF (Falls Efficacy Scale-International), physical function, and assessment for handgrip strength (HGS), gait speed, 5-times sit to stand (STS), vision and times-up-and-go (TUG) were performed. Six IC domains (vision and hearing, cognition, nutrition, mobility and depression) were measured. Results: Three pattern of participation cluster were identified, high (n = 63, 40.9%), moderate (n = 83, 53.9%) and low (n = 8, 33 5.2%). Individuals in the high participation cluster were significantly younger, had higher LSM scores and lower FES-I scores, more robust, fewer ADL and IADL limitations, lower prevalence of low HGS, higher gait speed and shorter TUG. In the fully adjusted model compared to the high participation cluster, moderate participation was significantly associated with low MoCA scores (OR 4.2, 95% CI 1.7-10.4, p = 0.02), poor STS (OR 7.1, 95% CI 3.0-17.0, p < 0.001) whereas low participation was associated with anorexia of aging (OR 9.9, 95% CI 1.6-60.9, p = 0.014), poor STS (OR 19.1, 95% CI 2.0-187.5, p = 0.011) and hearing impairment (OR 9.8, 95% CI 1.4-70.8, p = 0.024). Participants with 3 out of 6 IC decline had a probability of greater than 80% to belong to the low/moderate participation class. Discussion: Physical function, cognition, hearing and nutrition were significantly associated with low and/or moderate participation class. Future studies are needed to evaluate improvement in participation of those with falls or at risk for falls through restoration of IC.

Healthcare for older adults in North America: challenges, successes and opportunities.

Older adults in North America face similar challenges to successful ageing as other adults around the world, including an increased risk of geriatric syndromes and functional decline, limited access to healthcare professionals specialising in geriatrics and constraints on healthcare spending for Long-Term Services and Supports. Geriatrics as a specialty has long been established, along with the creation of a variety of screening tools for early identification of geriatric syndromes. Despite this, workforce shortages in all older adult care service areas have led to significant gaps in care, particularly in community settings. To address these gaps, innovative programs that expand the reach of geriatric specialists and services have been developed. Opportunities exist for further dissemination of these programs and services, as well as for expansion of an ageing capable workforce.

Changing Hospital Care For Older Adults: The Case for Geriatric Hospitals in the United States.

Hospital care of frail older adults is far from optimal. Although some geriatric models of care have been shown to improve outcomes, the effect size is small and models are difficult to fully implement, sustain and replicate. The two root causes for these shortcomings are competing interests (high revenue generating diseases, procedures and surgeries) and current hospital cultures (for example a culture of safety that emphasizes bed alarms and immobility rather than frequent ambulation). Geriatric hospitals would be hospitals completely dedicated to the care of frail older patients, a group which is most vulnerable to the negative consequences of a hospitalization. They would differ from a typical adult hospital because they could implement evidence based principles of successful geriatric models of care on a hospital wide basis, which would make them sustainable and allow for scaling up of proven outcomes. Innovative structural designs, unachievable in a typical adult hospital, would enhance mobility while maintaining safety. Financial viability and stability would be a challenge but should be feasible, likely through affiliation with larger health care systems with other hospitals because of cost savings associated with geriatric models of care (decreased length of stay, increased likelihood of discharge home, without increasing costs).

Serum neurofilament light levels are predictive of all-cause mortality in late middle-aged individuals.

BACKGROUND: Blood biomarkers can offer valuable and easily accessible indicators of normal biological processes, pathogenic conditions, and responses to therapeutic interventions. Recent studies found that levels of neurofilament light chain (NfL) in the blood are associated with mortality in three European cohorts of older adults (median ages 73, 93, and 100 years). Whether similar associations exist in younger adults and in other ethnic groups is currently not known. METHODS: We utilized a cohort study that included 294 African Americans (baseline ages 49-65). Serum NfL levels were measured using a Meso Scale Discovery-based assay. Vital status was determined by matching through the National Death Index. FINDINGS: Seventy-two participants (24.5%) died during the 14-15 years of follow up (2000-2014). Baseline serum NfL levels were significantly higher in the decedent group (86.1±65.7 pg/ml vs. 50.1±28.0 pg/ml, p < 0·001). In binomial logistic regression models adjusted for age, gender, education, baseline smoking status, BMI, and total comorbidities (0-11), serum NfL levels remained a strong predictor of all-cause mortality, and sensitivity analyses employing multiple additional covariates did not substantively change the relationship. Further, Kaplan-Meier curves based on serum NfL quartiles showed reduced survival in groups with higher serum NfL levels. INTERPRETATION: This study found a positive association between serum NfL levels and mortality in late middle-aged and older individuals. While our findings support that serum NfL levels may be a useful biomarker for all-cause mortality, further studies are needed to understand the biological mechanisms underlying this association. FUNDING: National Institute on Aging, Saint Louis University.

Investigating the combination of plasma amyloid-beta and geroscience biomarkers on the incidence of clinically meaningful cognitive decline in older adults.

We investigated combining a core AD neuropathology measure (plasma amyloid-beta [Aß] 42/40) with five plasma markers of inflammation, cellular stress, and neurodegeneration to predict cognitive decline. Among 401 participants free of dementia (median [IQR] age, 76 [73-80] years) from the Multidomain Alzheimer Preventive Trial (MAPT), 28 (7.0%) participants developed dementia, and 137 (34.2%) had worsening of clinical dementia rating (CDR) scale over 4 years. In the models utilizing plasma Aß alone, a tenfold increased risk of incident dementia (nonsignificant) and a fivefold increased risk of worsening CDR were observed as each nature log unit increased in plasma Aß levels. Models incorporating Aß plus multiple plasma biomarkers performed similarly to models included Aß alone in predicting dementia and CDR progression. However, improving Aß model performance for composite cognitive score (CCS) decline, a proxy of dementia, was observed after including plasma monocyte chemoattractant protein 1 (MCP1) and growth differentiation factor 15 (GDF15) as covariates. Participants with abnormal Aß, GDF15, and MCP1 presented higher CCS decline (worsening cognitive function) compared to their normal-biomarker counterparts (adjusted ß [95% CI], - 0.21 [- 0.35 to - 0.06], p = 0.005). In conclusion, our study found limited added values of multi-biomarkers beyond the basic Aß models for predicting clinically meaningful cognitive decline among non-demented older adults. However, a combined assessment of inflammatory and cellular stress status with Aß pathology through measuring plasma biomarkers may improve the evaluation of cognitive performance.