Autoimmunity targeting inositol 1,4,5-triphosphate receptor type 1 (ITPR1) was identified as a potential cause of cognitive decline resembling Alzheimer’s disease in a retrospective case study. The findings were reported by a research group from Norway and Germany in collaboration with Euroimmun.
Patient with acute deterioration
The study describes a 58-year-old patient who presented with acute confusion, rapidly progressive cognitive decline and hallucinations. Notably, he had a several-year history of mild cognitive impairment. Cerebrospinal fluid (CSF) analysis showed low amyloid beta-42 and elevated total tau protein, suggestive of Alzheimer’s disease. However, due to the atypical findings of pleocytosis, intrathecal IgG synthesis and blood-CSF barrier dysfunction, an evaluation for autoimmune aetiologies was undertaken.
Extensive autoantibody screening
Initial testing for established neural and paraneoplastic autoantibodies — as well as ANA, ANCA and rheumatoid factor — was negative. PCR-based screening for a range of viral and bacterial pathogens also showed no pathological findings. Due to continued clinical deterioration, an extended panel of novel and rare neural autoantibodies was tested at an external reference laboratory (Labor Stöcker, Groß Grönau, Germany).
IgG antibodies against ITPR1 were detected in the patient’s serum by indirect immunofluorescence assay (IFA) both on brain tissue sections and in a cell-based assay. The latter is a specialised IFA technique in which transfected cells expressing the target antigen are used as a monospecific antibody detection substrate. CSF samples from the patient were also positive for ITPR1-IgG in the cell-based assay. The anti-ITPR1 reactivity in serum was confirmed using independent assays at another laboratory.
Broad serological testing was otherwise negative for autoantibodies against the following: Hu, Yo, Ri, ANNA-3, Tr/DNER, myelin, Ma1, Ma2/Ta, GAD65, amphiphysin, AMPA type glutamate receptors, NMDA type glutamate receptors, GluRD2, mGluR1, mGluR5, GABAA/GABAB receptors, glycine receptors, LGI1, CASPR2, ZIC4, DPPX, CARPVIII, RhoGTPase-activating protein 26/anti-Ca, Homer-3, MOG, AQP4, recoverin, neurochondrin, flotillin-1/2, IgLON5, neurexin-3-alpha, ERC1, Sez6I2, AP3B2, contactin 1, neurofascin 155, neurofascin 186, AT1A3, KCNA2 and dopamine receptors 2.
Heterogeneous disease entity
In addition to cognitive decline, the patient also exhibited marked truncal instability with difficulty standing, as well as severe apraxia. ITPR1 autoimmunity has previously been associated with a wide range of neurological and neuropsychiatric symptoms, reflecting its widespread expression throughout the central and peripheral nervous system. It is considered a facultative paraneoplastic disease, although in this case no tumour was identified. Immunosuppressive treatment of the patient stabilised the disease course but did not produce any significant improvement in symptoms.
Summary
This case study underscores the importance of considering autoimmune encephalitis — including rare or emerging forms — in patients with known or suspected Alzheimer’s disease who exhibit rapid cognitive decline.
Read the full study in the Journal of Neuroimmunology:
Kunath N et al. ITPR1 autoantibody-associated autoimmunity as a cause of newly emerging cognitive decline mimicking Alzheimer’s disease: Case report and brief review of the literature. J Neuroimmunol. 2025 Dec 15;409:578774. doi: 10.1016/j.jneuroim.2025.578774.
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