Biomarker Discovery: Amyotrophic Lateral Sclerosis and Frontotemporal Dementia

Human brain, illustration.
A biomarker for both ALS and FTD, 2 neurological disorders that share clinical, genetic, and pathological traits, can help signal disease onset and the progression of degeneration.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) were traditionally considered 2 different neurologic disorders with discordant clinical features. However, research has shown ALS, both a neurodegenerative and a neuromuscular disease, and FTD, share common pathological mechanisms that drive the disease state.1

Mutational research has revealed the coincidence of mutated alleles that are common causative factors between the 2 diseases. These findings, together with shared pathological and clinical features, gave rise to the notion of an ALS/FTD spectrum and the oligogenic model of disease. In addition, the lack of sensitive and specific diagnostic and disease biomarkers for ALS and FTD prompted the exploration of biofluid biomarker discovery to improve disease monitoring and develop targeted drug therapies.

Evidence of a Disease Spectrum

Clinical similarities between the 2 diseases are striking and suggest that 50% of ALS cases show evidence of FTD-like cognitive changes, according to a 2017 study published in the Lancet.2 Furthermore, a 2015 study in Trends and Genetics found that approximately 15–18% of ALS cases exhibit FTD symptoms and 15% of FTD cases exhibit motor symptoms.3

The pathophysiology underpinning ALS and FTD show that abnormal clusters of TAR DNA-binding protein 43 (TDP-43) are present in approximately 50% of FTD cases and 95% of ALS cases4 and that these are associated with the C9orf72 repeat expansion in both diseases.5,6 Thus, the concept of a spectrum can aid in the identification of new genes and common pathways that influence these disease phenotypes. When combined with clinical assessment and genetics, biomarker development can empower clinicians to distinguish molecular signatures in patients presenting with similar symptomology.

Gene-Based Biomarkers

Biomarkers based on the presence of mutations show promise in determining disease susceptibility and the determination of early-stage vs late-stage disease. ALS and FTD both exhibit mutations in the TAR DNA-binding protein (TARDBP), chromosome 9 open reading frame 72 (C9orf72), microtubule-associated protein tau (MAPT), and superoxide dismutase 1 (SOD1) genes, together with correlating pathological subtypes.1


The TARDBP gene that encodes TDP-43 has been assessed for its efficacy as a biomarker in serum, plasma, and cerebrospinal fluid (CSF). In a 2017 systematic review and meta-analysis published in BMC Neurology, researchers evaluated the diagnostic utility of TDP-43 in the CSF of patients with FTD-ALS spectrum disorder. They found patients with ALS had a statistically significantly higher level of TDP-43 in CSF (effect size, 0.64; 95% CI, 0.1–1.19, P =.02).7

However, concerns have been raised with regards to the biological form of TDP-43 to be measured and methods to accurately differentiate between tissue-specific forms of the protein. Specifically, methods are required that can effectively differentiate brain-derived TDP-43 from other tissue sources.8 Additionally, an agreement as to whether full-length TDP-43, pTDP-43, or truncated variants would be the most effective measurement has not been reached.8


The MAPT gene encodes the tau protein which, under normal physiological conditions, stabilizes microtubules within cells through a fine-tuned phosphorylation/dephosphorylation mechanism. However, in ALS and FTD, abnormally phosphorylated tau aggregates are a common feature of the disease spectrum. Efforts to assess phosphorylated tau (p-tau181) and total tau (t-tau) ratios, and/or plasma p-tau181 levels as specific biomarkers of ALS and FTD, have been unable to distinguish FTD and Alzheimer disease. This suggests that tau is unlikely to be a disease-specific biomarker on its own.9


The C9orf72 gene shows remarkable differences in the G4C2 hexanucleotide repeat sequences between healthy and behavioral-variant FTD and ALS. There are usually 2–20 repeats in healthy individuals, whereas hundreds to thousands can be found in patients with ALS and FTD. One protein product of the repeat sequences, known as poly-glycine-proline (GP), has garnered attention as a potential biomarker in both behavioral-variant FTD and ALS.

A 2018 study published in the Annals of Clinical and Translational Neurology assessed the efficacy of a poly-GP immunoassay in testing CSF from patients with C9orf72 mutations and cohorts of healthy control individuals and other neurodegenerative diseases. The researchers found that poly-GP levels in asymptomatic individuals were similar to symptomatic ALS/FTD cases.10 Thus, presymptomatic expression of poly-GP could contribute to disease onset, representing a potential therapeutic target.

Neurofilament-Related Biomarkers

Neurofilaments, which consist of neurofilament heavy, medium, and light chains (NfH, NfM, and NfL) in the CSF, have been used as a general marker of neurodegeneration. In particular, NfL has been found useful as a neurodegenerative disease-differentiating biomarker as plasma levels appear to be significantly higher in FTD and ALS compared to atypical parkinsonism and various dementias.11

Interestingly, NfL is currently considered the most effective ALS biomarker for diagnosis and predicting survival time,12 and is shown to be approximately 20-fold higher in ALS CSF and 3-fold higher in FTD CSF in comparison to healthy individuals.13 Despite its overlapping presence across several neurodegenerative diseases, overall, NfL is currently the most established biomarker in FTD and ALS.

Matthew Disney, PhD, chemistry professor, department of chemistry, Scripps Research Institute in Jupiter, Florida, who is working on developing treatments for AD, Parkinson, ALS, and FTD, believes in looking for a general biomarker for ALS and FTD. “There is a large push for NfL to be an end point in all [central nervous system] diseases. This is where I would look for a general ALS and [FTD] biomarker. It is this marker that is helping to push the SOD antisense oligonucleotide through to trials.” SOD is an enzyme found in all living cells and has been found to be mutated in ALS.

Emerging Biomarkers

The significant and progressive reduction in the number of T regulatory cells in ALS has been shown to correlate with rates of disease progression and patient survival, making it a promising therapeutic target for neuroprotection in ALS.14

Another emerging biomarker for ALS is the urinary neurotrophin receptor p75 extracellular domain (p75ECD), which has been found to be significantly higher in patients with ALS compared to nonneurological control individuals.15 These findings and others16 support further investigation of p75ECD as a potential biomarker and progression indicator for ALS.

The polygenic risk score (PRS), which is a computational algorithm combining genome-wide genetic data to predict disease susceptibility, is testing its effectiveness in analyzing ALS and FTD. So far, PRS has shown that polygenic risk for FTD is associated with executive functioning, whereas polygenic risk for ALS is associated with verbal-numeric reasoning.17 The hope is that PRS, together with pathway analysis, will enable the determination of more enhanced therapeutic measures for ALS and FTD.

Biomarker Discovery

Genetic biomarkers relating to ALS/FTD brain pathology show the most promise in regard to specificity. Still, biomarker development will require the integration of genetics and multi-level omics approaches that can be conducted on biofluids that are less invasive, such as urine and blood. Ideally, the use of machine learning and artificial intelligence (AI) technologies to identify overlapping proteins, pathways, or molecules is key to finding informed targets and streamlining biomarker discovery.


  1. Katzeff JS, Bright F, Phan K, et al. Biomarker discovery and development for frontotemporal dementia and amyotrophic lateral sclerosis. Brain. Published online February 24, 2022. doi:10.1093/brain/awac077
  2. Van Es MA, Hardiman O, Chio A, et al. Amyotrophic lateral sclerosis. Lancet. Published online May 24, 2017. doi:10.1016/S0140-6736(17)31287-4
  3. Lattante S, Ciura S, Rouleau GA, and Kabashi E. Defining the genetic connection linking amyotrophic lateral sclerosis (ALS) with frontotemporal dementia (FTD). Trends in Genetics. Published online April 10, 2015. doi:10.1016/j.tig.2015.03.005
  4. Neumann M, Sampathu DM, Kwong LK, et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science. Published online October 6, 2006. doi:10.1126/science.1134108
  5. DeJesus-Hernandez M, Mackenzie IR, Boeve BF, et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron. Published online October 20, 2011. doi:10.1016/j.neuron.2011.09.011
  6. Renton AE, Majounie E, Waite A, et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron. Published online September 21, 2021. doi:10.1016/j.neuron.2011.09.010.
  7. Majumder, V, Gregory, JM, Barria, Green A, and Pal, S. TDP-43 as a potential biomarker for amyotrophic lateral sclerosis: a systematic review and meta-analysis. BMC Neurology. Published online June 28, 2018. doi:10.1186/s12883-018-1091-7
  8. Feneberg E, Gray E, Ansorge O, Talbot K, and  Turner MR. Towards a TDP-43-based biomarker for ALS and FTLD. Mol Neurobiol. Published online February 19, 2018. doi:10.1007/s12035-018-0947-6
  9. Foiani MS, Cicognola C, Ermann N, et al. Searching for novel cerebrospinal fluid biomarkers of tau pathology in frontotemporal dementia: an elusive quest. J Neurol Neurosurg Psychiatry. Published online April 13, 2019. doi:10.1136/jnnp-2018-319266
  10. Meeter LHH, Gendron TF, Sias AC, et al. Poly (GP), neurofilament and grey matter deficits in C9orf72 expansion carriers. Ann Clin Transl Neurol. Published online April 6, 2018. doi:10.1002/acn3.559
  11. Ashton JN, Pascoal TA, Karikari TK, et al. Plasma p-tau231: a new biomarker for incipient alzheimer’s disease pathology. Acta Neuropathol. Published online February 14, 2021. doi:10.1007/s00401-021-02275-6
  12. Abu-Rumeileh S, Vacchiano V, Zenesini C, et al. Diagnostic-prognostic value and electrophysiological correlates of CSF biomarkers of neurodegeneration and neuroinflammation in amyotrophic lateral sclerosis. Journal of Neurology. Published online February 25, 2020. doi:10.1007/s00415-020-09761-z
  13. Gaetani L, Blennow K, Calabresi P, et al. Neurofilament light chain as a biomarker in neurological disorders. Journal of Neurology, Neurosurgery & Psychiatry. Published online April 9, 2019. doi:10.1136/jnnp-2018-320106
  14. Giovannelli I, Heath P, Shaw P and Kirby J. The involvement of regulatory T cells in amyotrophic lateral sclerosis and their therapeutic potential. Amyotroph Lateral Scler Frontotemporal Degener. Published online June 2, 2020. doi:10.1080/21678421.2020.1752246
  15. Shi G, Shao S, Zhou J, Huang K and B FF. Urinary p75ECD levels in patients with amyotrophic lateral sclerosis: a meta-analysis. Amyotroph Lateral Scler Frontotemporal Degener. Published online November 2, 2021. doi:10.1080/21678421.2021.1990345
  16. Shepheard SR, Chataway T, Schultz DW, Rush RA and Rogers ML. The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. PLoS One. Published online January 27, 2014. doi:10.1371/journal.pone.0087398
  17. Hagenaars SP, Radakovic R, Crockford C, et al. Genetic risk for neurodegenerative disorders, and its overlap with cognitive ability and physical function. PLoS One. Published online June 1, 2018. doi:10.1371/journal.pone.0198187