Neurodegenerative dementias: screening for major threats to healthy longevity with blood biomarkers
Authors: Henrik Zetterberg, Barbara B Bendlin
Journal: The Lancet Healthy Longevity (2021)

Clinical screening tests are readily available for most major age-associated diseases, including cardiovascular disease, type 2 diabetes, and common cancers. However, one of the most common causes of death in older adults—dementia—lacks a readily available early screening test that can be used in primary care. According to WHO, approximately 50 million people currently have dementia, and it is a leading cause of disability, dependency, and death among older people worldwide, making it a major threat to healthy human longevity. Reducing dementia prevalence and ensuring appropriate care will require access to readily implemented tools for detecting the disease processes underlying dementia in older adults. In The Lancet Healthy Longevity, Inge M W Verberk and colleagues provide evidence that such tools might be available in the form of blood biomarkers that can predict future dementia and disease progression among individuals who were free of dementia at the time of blood sampling.1Verberk IMW Laarhuis MB van den Bosch KA et al.Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study.Lancet Healthy Longev. 2021; 2: e87-e95Summary Full Text Full Text PDF Scopus (16) Google Scholar A major challenge to dementia screening has been the lack of easily deployed tests that are capable of early disease detection. Accordingly, biomarker development efforts have focused on developing assays for specific disease pathologies that can be detected before cognitive decline. Alzheimer's disease—by far the most common cause of dementia—has been a major focus of biomarker development. In Alzheimer's disease, the first detectable pathology occurs two to three decades before clinical symptom onset2Jansen WJ Ossenkoppele R Knol DL et al.Prevalence of cerebral amyloid pathology in persons without dementia: a meta-analysis.JAMA. 2015; 313: 1924-1938Crossref PubMed Scopus (812) Google Scholar and involves accumulation of extracellular amyloid plaques, which have a 42 amino acid-long amyloid β protein (Aβ42) as their core. This pathology can be detected in living humans by use of amyloid PET imaging and by measuring aggregation-prone Aβ42 (alone or as a ratio with water-soluble 40 amino acid-long Aβ) in cerebrospinal fluid (CSF) and blood.3Zetterberg H Bendlin BB Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.Mol Psychiatry. 2020; (published online April 6.)https://doi.org/10.1038/s41380-020-0721-9Crossref Scopus (76) Google Scholar Phosphorylation and secretion of tau, a microtubule-associated axonal protein that is highly expressed in cortical neurons, follows amyloid pathology in Alzheimer's disease, and this process is reflected in CSF and blood concentrations of phosphorylated tau and by the eventual development of neurofibrillary tangles, which can be assessed by use of tau PET.3Zetterberg H Bendlin BB Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.Mol Psychiatry. 2020; (published online April 6.)https://doi.org/10.1038/s41380-020-0721-9Crossref Scopus (76) Google Scholar Although these tools represent major advances in the field, they only reflect one cause of dementia; biomarkers for neurodegenerative dementias other than Alzheimer's disease, characterised by proteins such as TAR DNA-binding protein 43 and misfolded α-synuclein,4Jucker M Walker LC Propagation and spread of pathogenic protein assemblies in neurodegenerative diseases.Nat Neurosci. 2018; 21: 1341-1349Crossref PubMed Scopus (162) Google Scholar are still in development. Likewise, cerebrovascular disease, which is a common primary cause of dementia, does not have a biomarker that could be easily implemented in primary care. Therefore, although disease-specific features have often been the primary targets for biomarker development, these might not be the clinical tools of choice when an individual first presents to primary care with a memory complaint. In their study, Verberk and colleagues1Verberk IMW Laarhuis MB van den Bosch KA et al.Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study.Lancet Healthy Longev. 2021; 2: e87-e95Summary Full Text Full Text PDF Scopus (16) Google Scholar tested the utility of blood biomarkers that reflect processes common to most causes of dementia. Per definition, neurodegenerative diseases show progressive neuroaxonal loss, a process captured by the blood biomarker for neurofilament light (NfL),3Zetterberg H Bendlin BB Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.Mol Psychiatry. 2020; (published online April 6.)https://doi.org/10.1038/s41380-020-0721-9Crossref Scopus (76) Google Scholar which was assessed by Verberk and colleagues. Additionally, given that a broad range of neurodegenerative diseases are also characterised by the activation of astrocytes—abundant support cells that ensure homeostasis of the CNS5Liddelow SA Barres BA Reactive astrocytes: production, function, and therapeutic potential.Immunity. 2017; 46: 957-967Summary Full Text Full Text PDF PubMed Scopus (853) Google Scholar—Verberk and colleagues examined blood levels of glial fibrillary acidic protein (GFAP) that is expressed and released by activated astrocytes.3Zetterberg H Bendlin BB Biomarkers for Alzheimer's disease-preparing for a new era of disease-modifying therapies.Mol Psychiatry. 2020; (published online April 6.)https://doi.org/10.1038/s41380-020-0721-9Crossref Scopus (76) Google Scholar While these biomarkers are not indicators of any specific neurodegenerative disease, both NfL and GFAP are specific to the nervous system and represent minimally invasive tools for assessing brain health that might further inform risk of progression to dementia. In Verberk and colleagues’ study, NfL and GFAP were measured in 300 individuals without cognitive impairment who were controls in a memory clinic-based study of neurodegenerative dementias.1Verberk IMW Laarhuis MB van den Bosch KA et al.Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort study.Lancet Healthy Longev. 2021; 2: e87-e95Summary Full Text Full Text PDF Scopus (16) Google Scholar These individuals received extensive screening for dementia at first visit and annual follow-up visits, and serum GFAP and NfL levels were measured at baseline for all participants and at follow-up for a subset of participants. Mean baseline age was 61 years (SD 9), 125 (42%) of participants were women, and mini-mental state examination was 29 (IQR 27–29). Median follow-up time was 3·0 years (IQR 1·9–4·2), and and 27 (9%) of the 300 participants developed dementia. Already at baseline, GFAP levels were approximately 1·7-times higher and NfL levels approximately 1·4-times higher in individuals who developed dementia during follow-up than in those who did not (age and sex adjusted p<0·0001 GFAP, p=0·0031 NfL). After testing for independent associations, only GFAP remained associated with an increased risk of dementia (hazard ratio 3·3, 95% CI 1·9–5·5; p<0·0001). Additionally, GFAP performed well in predicting dementia prognosis when used simultaneously with Aβ42/40, suggesting that it might be useful in combination with disease-specific biomarkers. Both neurodegeneration and astrocytic activation appear to differentiate patients who are more or less susceptible to Aβ and tau pathology regarding clinical expression of Alzheimer's disease.6Perez-Nievas BG Stein TD Tai HC et al.Dissecting phenotypic traits linked to human resilience to Alzheimer's pathology.Brain. 2013; 136: 2510-2526Crossref PubMed Scopus (202) Google Scholar NfL was not as sensitive as GFAP, but in a subgroup of individuals with repeated sampling, the slope of NfL increase was higher in participants with cognitive deterioration than in those with preserved cognition. This finding resembles the pattern observed in familial Alzheimer's disease and Huntington's disease, where NfL change appears to be a more sensitive marker of eventual disease progression than baseline NfL alone.7Preische O Schultz SA Apel A et al.Serum neurofilament dynamics predicts neurodegeneration and clinical progression in presymptomatic Alzheimer's disease.Nat Med. 2019; 25: 277-283Crossref PubMed Scopus (323) Google Scholar, 8Rodrigues FB Byrne LM Tortelli R et al.Mutant huntingtin and neurofilament light have distinct longitudinal dynamics in Huntington's disease.Sci Transl Med. 2020; 12eabc2888Crossref PubMed Scopus (20) Google Scholar Neurodegenerative dementias are common, and disease-modifying treatments and other effective interventions are urgently needed to ensure healthy ageing. With access to such treatments, careful history-taking and clinical examination need to be enhanced by tests that alert a clinician to the potential presence of neurodegenerative processes. The results presented by Verberk and colleagues suggest that such generic blood-based biomarkers with potential for use in clinical practice might be close at hand. HZ has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, Siemens Healthineers, Pinteon Therapeutics, Nervgen, AZTherapies, and CogRx; has given lectures in symposia sponsored by Cellectricon, Fujirebio, Alzecure, and Biogen; and is a co-founder of Brain Biomarker Solutions in Gothenburg AB, which is a part of the GU Ventures Incubator Program. BBB declares no competing interests. HZ is a Wallenberg Scholar supported by grants from the Swedish Research Council (#2018–02532), the European Research Council (#681712), Swedish State Support for Clinical Research (#ALFGBG-720931), the Alzheimer Drug Discovery Foundation (ADDF), USA (#201809–2016862), the AD Strategic Fund and the Alzheimer's Association (#ADSF-21–831376-C, #ADSF-21–831381-C, and #ADSF-21–831377-C), the Olav Thon Foundation, the Erling-Persson Family Foundation, Stiftelsen för Gamla Tjänarinnor, Hjärnfonden, Sweden (#FO2019–0228), EU's Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no 860197 (MIRIADE), and the UK Dementia Research Institute at UCL. BBB is supported by funding from the National Institute on Aging, including R01AG062285, R01AG059312, RF1AG057784, R01AG037639, and P30AG062715. Serum markers glial fibrillary acidic protein and neurofilament light for prognosis and monitoring in cognitively normal older people: a prospective memory clinic-based cohort studyOur results suggest that, while serum NfL seems to have potential as monitoring biomarker, GFAP might be a valuable prognostic biomarker, predicting incident dementia. Full-Text PDF Open Access