Neurological Diseases

Antibody profiling across the neuroimmune spectrum

In a substantial share of neurological and psychiatric disease, an unrecognized autoimmune process may be at work. iI2K profiles the antibody repertoire at scale to enable discovery, patient subgrouping, and therapy development for patients with an underlying autoimmune cause.

The opportunity: an undiscovered immune driver behind the non-responders

First-line therapy for depression, anxiety, and many neurological disorders targets neurotransmitters. For a large minority of patients, it does not work.

In a subset of these treatment-refractory patients, the underlying driver may be a humoral autoimmune process rather than a neurotransmitter deficit. Characterizing it is a discovery problem: delineate the autoantibody-defined subgroup, establish the pathogenic mechanism, and provide a rationale for mechanism-targeted immunotherapy.

Alden Scientific built ImmunoINSIGHTS™ iI2K as a discovery platform, and partners with pharma, biotech, academic and grant-funded groups to build a shared database of immune reactivities, the starting point for new disease subgroups.

~30%	of people with depression meet criteria for treatment resistance
~50%	of generalized anxiety disorder does not respond to first-line therapy

Hole et al., Cells 2025.

Proof of the model: one antibody can redraw a disease

For decades, neuromyelitis optica was treated as a severe form of multiple sclerosis. In 2004, a single serum autoantibody, later shown to target the aquaporin-4 (AQP4) water channel, set it apart from MS. That one immune reactivity defined a new disease entity, neuromyelitis optica spectrum disorder, which gained its own consensus diagnostic criteria and, within two decades, approved targeted therapies against complement, the IL-6 receptor, and CD19 B cells.

This is the opportunity across the neuroimmune spectrum. A discovered reactivity can split a broad, heterogeneous diagnosis into a mechanistically defined subgroup and seed a drug-development path. iI2K is built to run that discovery at scale.

Year	Milestone
2004	Serum autoantibody (NMO-IgG) distinguishes neuromyelitis optica from multiple sclerosis
2005	Target identified as the aquaporin-4 water channel
2015	International consensus diagnostic criteria define NMOSD as a distinct entity
2019+	Approved targeted therapies: anti-complement (C5), anti-IL-6 receptor, anti-CD19 B cell

Lennon et al. 2004 (NMO-IgG); Lennon et al. 2005 (aquaporin-4 target); Wingerchuk et al. 2015 (NMOSD criteria).

Resolving autoantibody roles across the neuroimmune spectrum

In the nervous system an autoantibody can be the cause of disease, a marker of it, or a bystander of tissue injury. The same array reads across the whole range and resolves which role applies.

Disease group	What drives it	Role of the antibody	Examples
Autoimmune neurology	Immunity against neural surface antigens	Driver: immune-mediated damage to the nervous system	NMOSD: AQP4. CIDP: nodal and paranodal proteins (NF155, CNTN1)
Neurodegenerative	Protein aggregation, neuroinflammation	Biomarker and modulator; natural antibodies may be protective	Toxic protein aggregates and structural components. Alzheimer’s: Aβ, tau. Parkinson’s: αSyn
Neuropsychiatric	Mixed; a subset may be autoimmune-mediated	Driver in a candidate subgroup	Autoimmune psychosis: CASPR2. Depression: GAD65
Motor neuron (ALS)	Neurodegeneration with immune overlay	Biomarker and surface-protein overlap	C9orf72, LRP4, SOD1

ALS sits across the border, a neurodegenerative disease with a surface-antibody and neuroinflammatory overlay. Prior infection leaves its mark too: viral antibody indices track with anti-neural autoimmunity, read from the same sample.

Built for the brain, on one standardized array

1,963

antigens read from one low-volume blood sample

764

human proteins expressed in brain and the nervous system

188

microbial antigens across 79 species, to test infection-to-autoimmunity

IgG · IgM

isotypes measured, with standardized quantitative readout

Localization across brain regions

Brain region / compartment	Antigens on iI2K
Cerebellum	126
Fetal brain cortex	97
Hippocampus	84
Thalamus	66
Cerebrospinal fluid	21
Spinal cord	15

Human antigens carrying each UniProt tissue annotation (annotations overlap, and all are subsets of the 764 brain-expressed proteins). More than 250 are additionally curated for neurological or neurodevelopmental disease relevance, spanning synaptic, axonal, cytoskeletal and ion-channel proteins. Source: DAVID UP_TISSUE enrichment of the iI2K v1.1 human antigen list.

CELL-SURFACE & SYNAPTIC LOCALIZATION

Driver candidates

Cell-surface channels, receptors and adhesion molecules where an antibody can directly cause disease: AQP4, MOG, CASPR2, CASPR1, contactin-1, neurofascin, IgLON5, MuSK, LRP4.

INTRACELLULAR & CYTOSKELETAL LOCALIZATION

Biomarker candidates

Axonal, cytoskeletal, nuclear and RNA-binding proteins that mark disease or exposure: tau, alpha-synuclein, and the paraneoplastic Hu, Ma and Yo antigens.

Supporting ARPA-H EVIDENT

SUPPORTING ARPA-H EVIDENT

The immune dimension of a national effort to end trial-and-error psychiatry

ARPA-H EVIDENT is an initiative of up to $139.4 million to replace subjective, trial-and-error treatment selection in mental health with objective, data-driven measures, and to learn who responds to which treatment.

Alden Scientific is one of the selected teams. ImmunoINSIGHTS iI2K was built for EVIDENT to supply the immune side of that signal: a blood-based readout of the autoantibody and anti-microbial antibody repertoire as candidate biomarkers of nervous-system and behavioral health. ARPA-H EVIDENT announcement

A shared database of immune reactivities

The aim is a standardized, growing database of immune reactivities, built together with partners. The same validated array runs across every cohort, so each study adds comparable data to a common resource, the raw material for new disease subgroups, mechanism, and therapy development.

DISCOVERY

Find the reactivities

Profile cohorts at scale to surface autoantibody and anti-microbial signals that standard workups miss.

SUBGROUPING

Define the subgroup

Resolve heterogeneous diagnoses into mechanistically defined, immune-based subgroups.

THERAPY DEVELOPMENT

Open the path

Give pharma, biotech, academic and grant-funded partners a rational basis and endpoints for immune-targeted therapies.

ImmunoINSIGHTS iI2K is a discovery and biomarker research platform for partnership, not a clinical diagnostic. Partner with Alden Scientific to profile a cohort and contribute to the shared database.

References

Prüss H. Autoantibodies in neurological disease. Nat Rev Immunol. 2021;21:798-813.
Fan S, Prüss H. Pathogenic mechanisms of autoantibodies in neurological autoimmune diseases. Curr Opin Immunol. 2025;95:102594.
Lennon VA, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364:2106-2112.
Lennon VA, et al. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202:473-477.
Wingerchuk DM, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177-189.
Knecht L, et al. Autoantibody profiles in Alzheimer’s, Parkinson’s, and dementia with Lewy bodies. J Neuroinflammation. 2024;21:317.
Chatanaka MK, et al. The role of autoantibodies in Alzheimer’s disease: pathogenetic connections or epiphenomena? Alzheimers Dement. 2025;21:e70484.
Tebartz van Elst L, et al. The Neuropsychiatric Checklist for Autoimmune Psychosis. Biol Psychiatry. 2025;98:654-669.
Endres D, et al. Immunological causes of obsessive-compulsive disorder: is it time for the concept of an autoimmune OCD subtype? Transl Psychiatry. 2022;12:5.
Jeppesen R, Benros ME. Autoimmune diseases and psychotic disorders. Front Psychiatry. 2019;10:131.
Hansen N, et al. Neural autoantibodies in psychiatric disorders are associated with antibodies against viral pathogens. J Neural Transm. 2025;132:1063-1074.
Hole C, et al. Immune dysregulation in depression and anxiety. Cells. 2025;14:607.