Association of plasma biomarkers, p‐tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long‐term clinical Alzheimer's disease risk: Results from a prospective cohort followed over 17 years

Stocker, Hannah; Beyer, Léon; Perna, Laura; Rujescu, Dan; Holleczek, Bernd; Beyreuther, Konrad; Stockmann, Julia; Schöttker, Ben; Gerwert, Klaus; Brenner, Hermann

doi:10.1002/alz.12614

Cited by 45 publications

(54 citation statements)

References 42 publications

(95 reference statements)

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“…These clinical observations fit well with pathology studies that show a gradual increase of GFAP levels in the brain in relation to AD severity 44,45 . Plasma GFAP levels have also been reported to associate with longitudinal cognitive decline and cerebral atrophy, which is confirmed in our study, [46][47][48][49] and higher incident dementia risk 35,42 . Thus, familial, clinical, and population-based studies suggest that increased plasma or serum GFAP levels not only associate with, but also predict, disease progression in AD.…”

Section: Discussionsupporting

confidence: 90%

“…This is the first study to evaluate plasma GFAP levels across the ADAD trajectory. Elevated plasma GFAP in mutation carriers compared with non-carriers was observed around 10 years prior to expected symptom onset and is consistent with studies reporting higher plasma GFAP in Aβ PET defined preclinical sporadic AD 18,20,[33][34][35] . Elevation in plasma GFAP relative to other biomarker and clinical events was observed after aberrant Aβ accumulation and before neurodegeneration and cognitive decline.…”

Section: Discussionsupporting

confidence: 88%

“…This is in line with studies in transgenic AD mouse models showing that astrocyte reactivity in the presence of Aβ pathology may drive disease progression in AD 8,11,36,37 . In addition, reports on the high discriminative performance of plasma GFAP for Aβ PET -/+ individuals with AUCs ranging between 76% to 81% within the sporadic AD continuum 18,20,[33][34][35] corroborate our observations in ADAD (AUCs 77%-84%), highlighting the commonalities between sporadic AD and ADAD, and the utility of ADAD as a model to explore biomarker trajectories in sporadic AD 38 .…”

Section: Discussionsupporting

confidence: 85%

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Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

Chatterjee

Vermunt

Gordon

et al. 2022

Preprint

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Glial fibrillary acidic protein (GFAP) is a promising candidate blood-based biomarker for Alzheimer’s disease (AD) diagnosis and prognostication. The timing of its disease-associated changes, its clinical correlates, and biofluid-type dependency will influence its clinical utility. We evaluated plasma, serum, and CSF GFAP in families with autosomal dominant AD (ADAD), leveraging the predictable age at symptom onset to determine changes by stage of disease. Plasma GFAP elevations appear a decade before expected symptom onset, after β-amyloid accumulation and prior to neurodegeneration and cognitive decline. Plasma GFAP distinguished β-amyloid-positive from β-amyloid-negative ADAD participants and showed a stronger relationship with β-amyloid load in asymptomatic than symptomatic ADAD. Higher plasma GFAP was associated with the degree and rate of neurodegeneration and cognitive impairment. Serum GFAP showed similar relationships, but these were less pronounced for CSF GFAP. Our findings support a role for plasma GFAP as a clinical biomarker for β-amyloid-associated cognitive deterioration in AD.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionsupporting

confidence: 88%

Section: Discussionsupporting

confidence: 85%

See 1 more Smart Citation

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

Chatterjee

Vermunt

Gordon

et al. 2022

Preprint

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“…The variation in diagnostic value is due to different study samples and assays and the presence or absence of brain Aβ in the clinical diagnosis. Higher p‐tau181 and NfL levels were associated with a risk of clinical AD incidence within 9 years of diagnosis in a community‐based cohort study 69 . Obj‐SCD is considered to be a particularly sensitive risk marker for future biomarker changes 27 .…”

Section: Discussionmentioning

confidence: 96%

“…Higher p‐tau181 and NfL levels were associated with a risk of clinical AD incidence within 9 years of diagnosis in a community‐based cohort study. 69 Obj‐SCD is considered to be a particularly sensitive risk marker for future biomarker changes. 27 When Obj‐SCD combining p‐tau181 and NfL can effectively identify AD‐related risks.…”

Section: Discussionmentioning

confidence: 99%

Associations of plasma phosphorylated tau181 and neurofilament light chain with brain amyloid burden and cognition in objectively defined subtle cognitive decline patients

Huang

Xie

et al. 2022

CNS Neurosci Ther

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Aims There is increasing evidence that plasma biomarkers are specific biomarkers for Alzheimer's disease (AD) pathology, but their potential utility in Obj‐SCD (objectively defined subtle cognitive decline) remains unclear. Methods A total of 234 subjects, including 65 with brain amyloid beta (Aβ) negative normal cognition (Aβ− NC), 58 with Aβ‐positive NC (Aβ+ NC), 63 with Aβ− Obj‐SCD, and 48 with Aβ+ Obj‐SCD were enrolled. Plasma Aβ42, Aβ40, Aβ42/Aβ40 ratio, phosphorylated tau181 (p‐tau181), neurofilament light chain (NfL), and total tau (T‐tau) were measured using Simoa assays. Logistic and linear regression analyses were used to examine the relationship between plasma biomarkers and brain amyloid, cognition, and imaging measures adjusting for age, sex, education, APOE ε4 status, and vascular risk scores. Receiver operating characteristics were used to evaluate the discriminative validity of biomarkers. Results After adjustment, only plasma p‐tau181 and NfL were significantly elevated in Aβ+ Obj‐SCD participants compared to Aβ− NC group. Elevated p‐tau181 was associated with brain amyloid accumulation, worse cognitive performance (visual episodic memory, executive function, and visuospatial function), and hippocampal atrophy. These associations mainly occurred in Aβ+ individuals. In contrast, higher NfL was correlated with brain amyloid burden and verbal memory decline. These associations predominantly occurred in Aβ− individuals. The adjusted diagnostic model combining p‐tau181 and NfL levels showed the best performance in identifying Aβ+ Obj‐SCD from Aβ− NC [area under the curve (AUC) = 0.814], which did not differ from the adjusted p‐tau181 model (AUC = 0.763). Conclusions Our findings highlight that plasma p‐tau181, alone or combined with NfL, contributes to identifying high‐risk AD populations.

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Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers

et al. 2023

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ImportancePrevious research has suggested an association of kidney function with risk of Alzheimer disease (AD) or other dementias and dementia-related blood biomarkers, but a distinct association remains unclear.ObjectiveTo evaluate the association of kidney function with risk of diagnosis of incident AD or dementia within 17 years and with the blood biomarkers neurofilament light (NfL), phosphorylated tau181 (p-tau181), and glial fibrillary acidic protein (GFAP).Design, Setting, and ParticipantsIn this prospective, population-based cohort study and nested case-control study, 9940 participants in Germany were enrolled between 2000 and 2002 by their general practitioners and followed up for up to 17 years. Participants were included if information on dementia status and creatinine/cystatin C measurements were available. A subsample of participants additionally had measurements of NfL, p-tau181, and GFAP obtained from blood samples. Statistical analysis was performed from January 3 to November 25, 2022.ExposuresImpaired kidney function, based on estimated glomerular filtration rate less than 60 mL/min/1.73 m2 according to the 2021 Chronic Kidney Disease Epidemiology Collaboration creatinine–cystatin C equation.Main Outcomes and MeasuresAll-cause dementia, AD, and vascular dementia diagnosis, as well as log-transformed levels of NfL, p-tau181, and GFAP in blood.ResultsOf 6256 participants (3402 women [54.4%]; mean [SD] age at baseline, 61.7 [6.6] years), 510 received an all-cause dementia diagnosis within 17 years of baseline. The dementia-related blood biomarker nested case-control sample included 766 participants. After adjusting for age and sex, impaired kidney function at baseline was not associated with a higher risk of all-cause dementia (hazard ratio [HR], 0.95; 95% CI, 0.69-1.29), AD (HR, 0.94; 95% CI, 0.55-1.63), or vascular dementia diagnosis (HR, 1.06; 95% CI, 0.65-1.70) within 17 years. In the cross-sectional analysis, after adjusting for age and sex, impaired kidney function was significantly associated with NfL and p-tau181 levels in blood (NfL: β = 0.47 and P &lt; .001; p-tau181: β = 0.21 and P = .003). After adjusting for age and sex, significant associations with GFAP levels were evident only among men (men: β = 0.31 and P = .006; women: β = −0.12 and P = .11).Conclusions and RelevanceIn this population-based study of community-dwelling adults, reduced kidney function was associated with increased levels of dementia-related blood biomarkers but not increased dementia risk. Kidney function might influence the accuracy of dementia-related blood biomarkers and should be considered in clinical translation.

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Association of plasma biomarkers, p‐tau181, glial fibrillary acidic protein, and neurofilament light, with intermediate and long‐term clinical Alzheimer's disease risk: Results from a prospective cohort followed over 17 years

Cited by 45 publications

References 42 publications

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

Plasma glial fibrillary acidic protein in autosomal dominant Alzheimer’s disease: associations with β-amyloid-PET, neurodegeneration and cognition

Associations of plasma phosphorylated tau181 and neurofilament light chain with brain amyloid burden and cognition in objectively defined subtle cognitive decline patients

Association of Kidney Function With Development of Alzheimer Disease and Other Dementias and Dementia-Related Blood Biomarkers

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