Blood proteins have provided essential insights into how humans responded to the recent pandemic. To expand our understanding beyond patients seeking medical care, we conducted a citizen-centric survey with 2,000 random residents (age: 18–69 years) from Sweden's two largest cities in 2021. With self-sampled dried blood spots (DBS) and health information from 437 (22%) volunteers, we performed multi-analyte COVID-19 serology, measured autoantibodies (AAbs) against 22 interferons, and quantified 502 circulating low-abundant immune-related blood proteins. Antibody assays confirmed self-reported infections (26%) and vaccinations (40%), showed timing-dependent discrepancies in the immune response, and revealed anti-type I interferon AAbs co-occurring frequently alongside natural infections. Proteomics data added plausible mechanistic insights into cell-mediated processes: data-driven analyses revealed 24% of participants presented deviating immune phenotypes linked to infections, immunity, respiratory effects, and age. Multi-molecular DBS analysis of random layperson samples captured the broader spectrum of immune system states, adding relevant insights for clinical and public health investigations.

Background and Objectives

Impaired kidney function has been linked to altered concentrations of blood biomarkers of Alzheimer disease (AD), but the underlying mechanisms and its potential role in dementia development remain poorly understood. We explored the associations between estimated glomerular filtration rate (eGFR), blood-based biomarkers of AD, and dementia development.

Methods

Data were extracted from the Swedish National Study on Aging and Care in Kungsholmen, an ongoing longitudinal population-based study. Kidney function was assessed using eGFR based on serum creatinine. AD biomarkers (amyloid beta [A beta 42/40], phosphorylated tau [p-tau181 and p-tau217] and total tau [t-tau] proteins, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) were measured from peripheral blood samples using the Simoa platform. Dementia was diagnosed according to DSM-IV criteria. Quantile regression models assessed the cross-sectional associations between eGFR and AD biomarkers; Cox regression models were used to examine the association of kidney function and biomarkers with incident dementia.

Results

At baseline, 2,279 dementia-free participants with available blood samples were included (median age 72 (interquartile range, 61-81) years; 62% female). Lower eGFR was associated with higher median z-score levels of all examined AD blood biomarkers, except A beta 42/40, following a nonlinear relationship. At eGFR = 30 mL/min/1.73 m(2), estimated differences were as follows: p-tau181: beta, 0.22 [95% CI 0.09-0.35]; p-tau217: beta, 0.20 [95% CI 0.10-0.31]; t-tau: beta, 0.24 [95% CI 0.05-0.42]; NfL: beta, 0.88 [95% CI 0.80-0.95]; GFAP: beta, 0.10 [95% CI 0.03-0.16]. During a mean follow-up period of 8.3 (SD, 4.3) years, 362 participants developed dementia. In multivariable-adjusted models, impaired kidney function (eGFR < 60 mL/min/1.73 m(2)) was not associated with an increased hazard of dementia compared with preserved kidney function (eGFR >= 60 mL/min/1.73 m(2)) (hazard ratio [HR], 0.93 [95% CI 0.72-1.21]). The relationship between increased (high vs low) NfL and dementia was stronger among individuals with impaired (vs preserved) kidney function (HR, 3.85 [95% CI 1.87-7.95] vs HR, 1.84 [95% CI 1.34-2.53], respectively).

Discussion.

Impaired kidney function was associated with elevated circulating level of most AD blood biomarkers. However, the presence of impaired kidney function did not independently increase the risk of dementia but rather seemed to accelerate the clinical expression of underlying neurodegenerative pathology.

Aging is accompanied by the progressive accumulation of biological deficits, which increases susceptibility to developing multiple chronic diseases (that is, multimorbidity). The biological underpinnings of multimorbidity remain poorly understood. Here we analyzed 54 blood biomarkers reflecting inflammatory, vascular, metabolic and neurodegenerative processes in 2,247 individuals aged 60 and over from the Swedish National Study on Aging and Care in Kungsholmen. Multimorbidity was assessed using three measures: baseline total disease count, baseline multimorbidity patterns identified through latent class analysis and 15-year rate of disease accumulation. Associations between baseline biomarkers and multimorbidity measures were examined using least absolute shrinkage and selection operator regression. Growth differentiation factor 15, hemoglobin A1c, cystatin C, leptin and insulin were consistently and positively associated with all multimorbidity measures. Additional biomarkers demonstrated specific associations with distinct multimorbidity patterns. Moreover, faster disease accumulation was directly associated with gamma-glutamyl transferase and inversely with albumin. Longitudinal results were externally validated in 522 participants from the Baltimore Longitudinal Study of Aging, with comparable predictive accuracy. Our findings suggest that multiple biological processes contribute to multimorbidity through shared and distinct mechanisms. Metabolic disturbances emerged as a key driver of multimorbidity. If confirmed, these processes could represent targets for interventions to mitigate disease accumulation.

Background Age-related muscle function decline is a major impediment to healthy ageing. We aimed to investigate the association between a panel of Alzheimer's disease-related biomarkers and longitudinal trajectories of muscle strength, while exploring the influence of cognitive function. Methods In this cohort study, we gathered data from the Swedish National study on Aging and Care in Kungsholmen (SNAC-K), an ongoing prospective study that includes adults aged 60 years and older, from central Stockholm, Sweden. We included data from baseline to the fourth follow-up (March 21, 2001, to Dec 31, 2016). Seven Alzheimer's disease-related blood biomarkers were measured in dementia-free, community dwelling participants: total tau, phosphorylated tau181 (p-tau181), phosphorylated tau217 (p-tau217), amyloid beta 40 and 42, neurofilament light chain, and glial fibrillary acidic protein (GFAP). Muscle strength was measured through the handgrip strength and chair-stand tests. Linear mixed models were used to explore the association between baseline Alzheimer's disease-related biomarkers and muscle strength trajectories. Findings The baseline SNAC-K cohort included 3363 individuals, of whom 1953 participants were included in our analyses (mean age 70.2 [SD 9.1] years; 780 [39.9%] male and 1173 [60.1%] female participants). In adjusted models, higher concentrations of p-tau181 (beta per year 0.93 [95% CI 0.71 to 1.16]; p<0.0001), p-tau217 (beta per year 1.31 [1.03 to 1.58]; p<0.0001), neurofilament light chain (beta per year 0.76 [0.56 to 0.96]; p<0.0001), and GFAP (beta per year 0.37 [0.21 to 0.53]; p<0.0001) were associated with an accelerated decline of chair-stand performance over time. The adjustment for Mini-Mental State Examination (MMSE) score led to the attenuation of these associations. Higher concentrations of p-tau181 (beta per year-0.12 [95% CI-0.17 to-0.07]; p<0.0001), p-tau217 (beta per year-0.13 [-0.20 to-0.07]; p<0.0001), and neurofilament light chain (beta per year-0.05 [-0.09 to-0.001]; p=0.047) were also associated with faster handgrip strength decline, with no attenuation after adjusting for MMSE score. Sex-specific differences were observed, with female participants showing a stronger association between biomarker concentrations and muscle strength decline than male participants, particularly in the chair-stand test. Interpretation Our findings suggest that blood Alzheimer's disease-related biomarkers might help estimate progressive muscle strength decline among older adults, elucidating the influence of brain pathology and cognitive ageing on this association. These Alzheimer's disease-related biomarkers could aid in identifying individuals for early intervention to prevent sarcopenia. Copyright

Blood biomarkers of Alzheimer’s disease (AD) are promising for dementia prediction, but their association with progression across intermediate stages of cognitive decline in the general population remains unclear. We followed 2148 dementia-free individuals from a Swedish population-based cohort for up to 16 years. Associations between baseline AD blood biomarkers and transitions between normal cognition, mild cognitive impairment (MCI), and dementia were examined. Lower amyloid-β42/40 ratio and higher phosphorylated-tau181 (p-tau181), p-tau217, total-tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were associated with faster progression from MCI to all-cause and AD dementia, with the strongest associations for NfL and p-tau217. Elevated NfL and GFAP were linked to reduced MCI reversion to normal cognition, whereas no biomarker was associated with MCI development from normal cognition. These findings show robust group-level associations and indicate that AD blood biomarkers may help stratify dementia risk at the MCI stage in the community.

Evidence regarding the clinical validity of blood biomarkers of Alzheimer's disease (AD) in the general population is limited. We estimated the hazard and predictive performance of six AD blood biomarkers for incident all-cause and AD dementia-the ratio of amyloid-beta 42 to amyloid-beta 40 and levels of tau phosphorylated at T217 (p-tau217), tau phosphorylated at T181 (p-tau181), total tau, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)-in a cohort of 2,148 dementia-free older adults from Sweden, who were followed for up to 16 years. In multi-adjusted Cox regression models, elevated baseline levels of p-tau181, p-tau217, NfL, and GFAP were associated with a significantly increased hazard for all-cause and AD dementia, displaying a non-linear dose-response relationship. Elevated concentrations of p-tau181, p-tau217, NfL, and GFAP demonstrated strong predictive performance (area under the curve ranging from 70.9% to 82.6%) for 10-year all-cause and AD dementia, with negative predictive values exceeding 90% but low positive predictive values (PPVs). Combining p-tau217 with NfL or GFAP further improved prediction, with PPVs reaching 43%. Our findings suggest that these biomarkers have the potential to rule out impending dementia in community settings, but they might need to be combined with other biological or clinical markers to be used as screening tools.

Olfactory impairment is common in older age and is a known early feature of several dementia diseases. Blood-based biomarkers of Alzheimer's disease (AD) now offer a scalable method for detecting pathophysiological mechanisms related to olfactory decline in the general population. However, few studies have examined how these biomarkers relate to long-term olfactory trajectories. Most existing work has been limited to cross-sectional settings. In this population-based study, we used biomarker data collected at baseline and followed participants for up to 15 years, enabling us to test whether early biological changes are temporally linked to subsequent olfactory decline. Data came from the ongoing Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), a longitudinal population-based study with baseline assessments from March 21, 2001, through August 30, 2004. We included participants without prevalent neurodegenerative diseases who completed olfactory assessment at baseline. The 15-year follow-up was finished in December 2019. Data were analysed from December 2023 to April 2024. Serum-derived biomarkers of tau phosphorylated at threonine 217 (p-tau217) and at theorine181 (p-tau181), total tau (t-tau), amyloid-beta ratio (A beta 42/A beta 40), neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) were obtained at baseline. Linear mixed models examined associations between biomarker quartiles and Sniffin' Sticks odor identification performance over 15 years, adjusting for demographics, health conditions, and semantic knowledge. We included 1868 participants (mean [SD] age 71.3 [9.9] years; 1122 females [60.1%]). In fully adjusted models, higher quartiles of p-tau217, p-tau181, NfL, and GFAP, and lower quartiles of A beta 42/A beta 40, were associated with steeper olfactory decline, with the steepest decline among participants in the highest quartiles (beta for Q4 vs Q1: -0.20 [95% CI: -0.26 to -0.15] for p-tau217; -0.19 [95% CI: -0.25 to -0.13] for p-tau181; -0.23 [95% CI: -0.29 to -0.17] for NfL; beta = -0.17 [95% CI: -0.23 to -0.11] for GFAP. Participants in the lowest A beta 42/A beta 40 quartile declined more steeply than those in the highest (beta = -0.09 [95% CI: -0.14 to -0.04]). Associations appeared stronger in the oldest participants, in APOE epsilon 4 carriers for p-tau181, in non-carriers for NfL and GFAP, and among former smokers for NfL. Blood-based biomarkers of AD were consistently associated with faster olfactory decline in older adults, particularly in the highest biomarker quartiles. These results provide large-scale longitudinal evidence, across up to 15 years of follow-up, that olfactory decline in the general population is linked to AD-related blood biomarkers, supporting the hypothesis that common olfactory losses in ageing partly reflect dementia-related processes.

Plasma proteomics technologies are advancing rapidly, offering new opportunities for biomarker discovery and precision medicine. Direct comparisons of available technologies are needed to understand how platform selection affects downstream findings. We compared the performance of a peptide fractionation-based mass spectrometry method (HiRIEF LC-MS/MS) and the Olink Explore 3072 proximity extension assays on 88 plasma samples, analyzing 1129 proteins with both methods. The platforms exhibited complementary proteome coverage, high precision, and concordance in estimating sex differences in protein levels. Quantitative agreement between platforms was moderate (median correlation 0.59, interquartile range 0.33-0.75), mainly influenced by technical factors. Finally, we present a publicly available tool for peptide-level analysis of platform agreement and demonstrate its utility in clarifying cross-platform discrepancies in protein and proteoform measurements. Our findings provide insights for platform selection and study design, and highlight the value of combining mass spectrometry and affinity-based approaches for more comprehensive and reliable plasma proteome profiling.

Background: Diet can impact cognitive aging, but comprehensive data from human studies is lacking and the underlying biological mechanisms are still not fully understood. Objectives: To investigate the associations between two dietary patterns consistently linked to inflammation and brain health [the Mediterranean diet (MDS) and inflammatory potential of diet (EDII)] and five blood-based biomarkers of Alzheimer's disease (AD) in a sample of dementia-free community-dwelling older adults. Design and setting: We used cross-sectional data from the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K). Participants: Participants who were institutionalized, had dementia or Parkinson's disease, or had missing data on diet and/or biomarkers were excluded. Our study sample consisted of 1907 adults >= 60 years old. Measurements: Adherence to the MDS and EDII was assessed using a validated food frequency questionnaire. Ttau, p-tau181, A beta 42/40, NfL, and GFAP were measured in serum. Associations were estimated through quantile regression models at the 25th, 50th, and 75th percentiles of the biomarkers' levels, and were adjusted for potential confounders and stratified by sex, age, and APOE-e4 genotype. Results: In the whole sample, higher adherence to the MDS was associated with lower levels of p-tau181 at the 50th and 75th percentiles [beta (95% CI) per 1-SD increment =-0.028 (-0.053,-0.002) and-0.036 (-0.072,-0.001), respectively], while higher adherence to the EDII was associated with higher levels of NfL at the 75th percentile [beta (95% CI) per 1-SD increment = 0.031 (0.008, 0.053)]. Associations with other biomarkers were only apparent at lower levels of their distribution. Subgroup analyses showed: 1) a stronger inverse association between the MDS and p-tau181 in APOE-e4 carriers than non-carriers, and 2) an inverse association of the MDS with GFAP only in participants >= 78 years. Conclusions: Diet seems to be associated with biomarkers of AD pathology in cognitively intact older adults. Some associations were more apparent in the presence of genetic predisposition for AD or advanced age.

INTRODUCTION: Alzheimer's disease (AD) blood biomarkers hold clinical potential but their concentration may vary with somatic conditions.

METHODS: We investigated the concentration of six AD blood biomarkers in relation to multimorbidity as disease count and four multimorbidity patterns in 2290 cognitively unimpaired older adults.

RESULTS: Levels of phosphorylated tau (p‐tau)181, p‐tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP) increased with increasing number of diseases. In multi‐adjusted regressions, compared to individuals without multimorbidity, the anemia/sensory impairment pattern was associated with altered levels of all biomarkers except amyloid beta (Aβ)42/40, GFAP, and total tau (p‐tau181: β = 0.18, 95% confidence interval [CI]: 0.08, 0.28; p‐tau217: β = 0.11, 95% CI: 0.03, 0.18; NfL: β = 0.14, 95% CI: 0.06, 0.21) and the cardiometabolic/inflammatory pattern was associated with altered levels of all biomarkers except Aβ42/40 and GFAP (p‐tau181: β = 0.24, 95% CI: 0.12, 0.36; p‐tau217: β = 0.23, 95% CI: 0.14, 0.32; NfL: β = 0.32, 95% CI: 0.23, 0.40; total tau: β = 0.23, 95% CI: 0.07, 0.39). Results remained unchanged after excluding those who developed dementia in 15 years.

DISCUSSION: More diseases and specific multimorbidity patterns altered the levels of several AD blood biomarkers, highlighting caution when using them in adults with complex health profiles.

Highlights: In cognitively unimpaired older adults blood biomarkers of Alzheimer's disease varied depending on the number of chronic diseases and specific patterns of multimorbidity. Phosphorylated tau (p‐tau)181, p‐tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein levels increased along with increasing numbers of chronic diseases. P‐tau181, p‐tau217, and NfL levels were significantly higher in individuals in the anemia/sensory impairment and cardiometabolic/inflammatory multimorbidity patterns compared to those without multimorbidity. Results remained unchanged after excluding participants who developed dementia during 15‐year follow‐up. In cognitively unimpaired older adults blood biomarkers of Alzheimer's disease varied depending on the number of chronic diseases and specific patterns of multimorbidity.Phosphorylated tau (p‐tau)181, p‐tau217, neurofilament light chain (NfL), and glial fibrillary acidic protein levels increased along with increasing numbers of chronic diseases.P‐tau181, p‐tau217, and NfL levels were significantly higher in individuals in the anemia/sensory impairment and cardiometabolic/inflammatory multimorbidity patterns compared to those without multimorbidity.Results remained unchanged after excluding participants who developed dementia during 15‐year follow‐up.