MON-642 Beyond Diabetes: Extreme Anti-GAD65 and Neurological Damage

Abstract Disclosure: J. Tamayo Acosta: None. G. Rivera Rodriguez: None. R. Trinidad-Hernandez: None. High-titer anti-glutamic acid decarboxylase 65 (anti-GAD65) autoimmunity is emerging as a dual-threat phenomenon that challenges conventional diabetes classification and portends multisystem involvement. When anti-GAD65 titers exceed 25,000 IU/mL, they may unmask latent autoimmune diabetes in adults (LADA) and signal potential central nervous system (CNS) involvement. We present two illustrative cases of older adults originally managed as type 2 diabetes mellitus (T2DM) who were reclassified as LADA after the detection of anti-GAD65 titers >25,000 IU/mL.In the first case, a 61-year-old man with a decade-long presumed T2DM diagnosis and well-controlled hypothyroidism experienced recurrent, severe hypoglycemic episodes despite acceptable self-monitored glucose readings. Paradoxically low HbA1c values, combined with markedly elevated anti-GAD65 titers and positive thyroid autoantibodies, prompted reclassification to LADA. Subsequent neurological evaluation revealed subtle cognitive deficits and neuroimaging abnormalities—including cortical microhemorrhages and cerebellar lesions—raising concerns for CNS involvement and a broader multisystem autoimmune process.In the second case, a 69-year-old woman with historically stable glycemic control underwent abrupt metabolic decompensation, with her HbA1c rising to 12.5%. Further investigation confirmed anti-GAD65 titers exceeding 25,000 IU/mL with preserved C-peptide levels, establishing the diagnosis of LADA. Although overt neurological symptoms were minimal, cognitive screening and neuroimaging suggested early neurocognitive impairment consistent with subclinical CNS involvement. These cases provide critical teaching points: LADA may masquerade as T2DM in older adults, and unexpected hypoglycemia or sudden glycemic deterioration should prompt evaluation for autoimmune markers such as anti-GAD65. Exceptionally high anti-GAD65 titers may signal multisystem autoimmune involvement, including subtle neurological dysfunction. Comprehensive metabolic and neurological assessments, coupled with early interdisciplinary intervention, are essential to optimize outcomes and mitigate long-term complications. Recognizing high-titer anti-GAD65 autoimmunity as a dual threat to metabolic and neural health carries significant implications for contemporary clinical practice in endocrinology. Presentation: Monday, July 14, 2025