Jul 2026· The journal of prevention of Alzheimer's disease· Vol 13· 0 citations· 47 references
Medicine
TL;DR
A stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Abstract
Background Although blood-based biomarkers are now available for diagnosing Alzheimer’s disease (AD), the best biomarker for AD-specific neurodegeneration and cognitive decline remains unclear. This study aimed to determine the relative importance of four plasma biomarkers—phosphorylated tau (p-tau) 217, p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP)—in AD-specific neurodegeneration and cognition. Methods We analyzed cross-sectional data from two independent, ethnically distinct cohorts spanning the clinical spectrum from cognitively unimpaired to dementia: 150 participants from the SAMD cohort (100% Asian) and 284 participants from the ADNI cohort (94.0% White). Plasma biomarker levels were quantified using Single-Molecule Array (Simoa) assays. We employed dominance analysis to determine the hierarchical contributions of these biomarkers to AD signature regions of interest (ROI) thickness (entorhinal, inferior temporal, middle temporal, and fusiform regions), total cognition, and memory, stratified by amyloid-PET status. Three sensitivity analyses were further conducted to validate the findings across these cohorts, mitigating potential biases arising from differences in demographic characteristics and clinical severity. All analyses were adjusted for age, sex, education, and APOE ε4 status. Results The dominance hierarchy differed markedly according to the amyloid status. Plasma GFAP and p-tau217 emerged as the dominant predictors for AD signature ROI thickness and cognitive impairment in amyloid-positive participants. Specifically, GFAP demonstrated superior dominance in explaining cortical atrophy within the SAMD cohort, whereas p-tau217 was the dominant predictor in the ADNI cohort. P-tau217 generally outperformed the others in explaining total cognition and memory in the amyloid (+) group. In contrast, among amyloid (−) participants, plasma NfL showed greater explanatory power than GFAP for both neurodegeneration and cognitive decline across both cohorts. Conclusion The efficacy of plasma biomarkers in reflecting AD-related neurodegeneration varies significantly depending on the presence of amyloid pathology. While GFAP and p-tau217 are robust indicators of AD-associated changes linked to plaque pathology, NfL better reflects non-specific neurodegeneration involving axonal damage. Consequently, a stratified approach based on amyloid status is essential for the optimal application of blood-based biomarkers in monitoring disease progression and evaluating therapeutic efficacy in future clinical trials and precision medicine.
Alzheimer’s disease (AD) and related dementias are a growing health and economic burden in India. Blood levels of amyloid beta (Ab), tau, and other proteins marking neuronal injury are biomarkers of AD risk and are potentially important for AD prevention.
In 2,224 participants from the Harmonized Diagnostic Assessment of Dementia for the Longitudinal Aging Study in India (LASI-DAD), we performed gene-based analyses on (1) missense/loss-of-function (LoF) single-nucleotide variants (SNVs) and (2) brain-specific promoter/enhancer SNVs across 84 genes selected from AD GWAS and 25 gene-biomarker pairs selected from biomarker GWAS. We used variant-Set Test for Association using Annotation infoRmation (STAAR) across 7 neurodegenerative biomarkers measured in blood: Ab40, Ab42, Ab42/Ab40, total tau (tTau), tau phosphorylated at threonine 181 (pTau), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL). We adjusted for age, sex, and genetic ancestry, with random intercepts for genetic relatedness and biomarker plate. Analyses incorporated weighted annotation scores (e.g., deleteriousness). Significant results (FDR-
q
< 0.1) were followed up with single variant analysis. Genes were also assessed for sex- and age-interactions using iSKAT.
Missense/LoF variants in 6 AD-associated genes (
ECHDC3
,
CLU
,
APOE
,
EPHA1
,
ICA1L
,
CASS4
) and 1 biomarker-associated gene (
APOE
) were associated with Ab40, Ab42/Ab40, pTau, and/or GFAP (FDR
q
< 0.1), with the most significant SNVs tending to be rare/low-frequency (MAF ≤ 0.05) and potentially deleterious. Promoter/enhancer variants in 1 AD-associated gene (
CCDC6
) were associated with Ab42/Ab40, with the index SNV being a potentially deleterious common variant (MAF = 0.27). Several associated variants appeared to have higher frequency in India compared to other global populations. Missense/LoF SNVs in two AD genes (
EPHA1
,
MS4A6A
) had sex-specific effects on Ab42 and/or tTau, and promoter/enhancer SNVs in four AD genes (
DGKQ
,
MS4A6A
,
MS4A4A
,
JAZF1
) had sex-specific effects on tTau and/or pTau. Missense variants in 12 AD genes and promoter/enhancer variants in two AD genes showed interaction with age on at least one biomarker, primarily GFAP and NfL with genetic effects tending to be stronger at older ages.
Rare and common variants in AD- and neurodegenerative biomarker-associated genes with increased frequency in India compared to other populations may impact blood levels of neurodegenerative biomarkers in South Asians.
Hasan Abu-Amara, Wei Zhao, Zheng Li et al.· Frontiers in Aging Neuroscie...· 0 citations
In cognitively unimpaired older adults, elevated blood p-tau217 was linked to faster shrinkage in AD-specific brain regions, whereas NfL and GFAP were associated with more widespread atrophy, with NfL also associated with accelerated WMH accumulation.
Martina Valletta, D. L. Vetrano, E. Laukka et al.· Annals of Neurology· 0 citations
Abstract INTRODUCTION Upstream neuroinflammation plays an important role in Alzheimer's disease (AD) but remains poorly understood. We tested whether two distinct neuroinflammatory markers are associated with cerebrovascular burden and amyloid beta (Aβ), and downstream, with plasma phosphorylated tau (p‐tau217), medial temporal lobe (MTL) cortical and hippocampal atrophy, and memory deficits. METHODS Cognitively unimpaired older adults without dementia or mild cognitive impairment were recruited from a community sample (Biomarker Exploration in Aging, Cognition, and Neurodegeneration; [BEACoN]; N = 126). We used structural equation modeling to test whether plasma chitinase‐3‐like protein 1 (YKL‐40) and glial fibrillary acidic protein (GFAP) contribute to distinct pathways. RESULTS Higher plasma YKL‐40 was associated with greater white matter hyperintensity (WMH), whereas higher plasma GFAP was related to increased 18F‐florbetapir (FBP) standardized uptake value ratio (SUVR). Higher plasma GFAP, WMH, and FBP SUVR were independently associated with increased p‐tau217. Plasma p‐tau217 was associated with reduced MTL cortical thickness and hippocampal volume. Reduced hippocampal volume was related to worse memory. DISCUSSION Future work can further investigate these neuroinflammatory pathways as potential therapeutic targets for AD.
Batool Rizvi, Jenna N. Adams, Alison R. Bamford et al.· Alzheimer's & Dementia· 1 citation
Serum NfL was associated with anatomically specific WM microstructural changes, with differing patterns across clinical groups, and no significant associations were observed between serum or CSF GFAP concentrations and diffusion tensor imaging metrics.
T. Magalhães, R. Casseb, A. Moraes et al.· Journal of Alzheimer's Disea...· 0 citations
Phosphorylated-tau (p-tau217) is a promising blood-based biomarker for Alzheimer’s dementia (AD) in clinical settings. However, research from prospective cohort studies is sparse. We measured plasma p-tau217 levels in baseline blood samples of 779 participants in a population-based cohort of older adults followed over 17 years. Associations with AD were assessed and compared to those with previous measurements of p-tau181, neurofilament light chain (NfL), and glial fibrillary acidic protein (GFAP). Comparisons to the amyloid beta (Aβ) misfolding biomarker were performed in a subgroup analysis. P-tau217, NfL and GFAP showed strong associations with AD risk, especially within the first 9 years of follow-up, outperforming p-tau181. Over the later years of follow-up, the predictive accuracy of p-tau217 was significantly reduced. In contrast, the Aβ misfolding biomarker demonstrated superior performance especially as a preclinical indicator of the risk of AD many years before diagnosis. The combination of p-tau217 with NfL, GFAP, basic demographic and genetic information, as well as the misfolding biomarker yielded an AUC 0.86 for AD diagnoses over the entire 17-year follow-up period. P-tau217 is a promising blood-based biomarker for Alzheimer’s dementia (AD) in the clinical stage. In this prospective cohort study, it showed better performance in the prodromal than in the preclinical stage up to 17 years before diagnosis. In a subgroup analysis, the Aß misfolding biomarker showed higher discriminative ability in the preclinical stage compared to p-tau217. A prediction model including p-tau217, NfL, GFAP, Aß misfolding as well as basic demographic and genetic information reached an AUC of 0.86 for AD over the entire follow-up period. In a subgroup analysis, the Aß misfolding biomarker showed higher discriminative ability in the preclinical stage compared to p-tau217. A prediction model including p-tau217, NfL, GFAP, Aß misfolding as well as basic demographic and genetic information reached an AUC of 0.86 for AD over the entire follow-up period. P-tau217 is a promising blood-based biomarker for Alzheimer’s dementia (AD) in the clinical stage. In this prospective cohort study, it showed better performance in the prodromal than in the preclinical stage up to 17 years before diagnosis.
K. Trares, D. Duman, L. Beyer et al.· EMBO Molecular Medicine· 0 citations
Key Points Question What is the association of different blood-based biomarkers of Alzheimer disease (AD) with global and domain-specific cognitive decline in the general population? Findings In this cohort study of 2008 older adult participants in the Swedish National Study on Aging and Care–Kungsholmen, AD-related biomarkers, especially phosphorylated tau 217, phosphorylated tau 181, neurofilament light chain, and glial fibrillary acidic protein, were associated with faster rates of cognitive decline over up to 15 years of follow-up. Associations differed depending on the biomarker measured and participant sex and APOE genotype. Meaning Easily accessible blood-based biomarkers of AD may be linked to subsequent faster cognitive decline in the general older population, with patterns suggesting some heterogeneity across biomarkers and that individual characteristics may influence clinical interpretation.
E. Laukka, Ingrid Ekström, Martina Valletta et al.· JAMA Network Open· 0 citations