1518-P: Plasma Biomarker Concentrations of Alzheimer’s Disease Are Associated with Insulin Resistance—Results from a Pilot RCT in Adults with Diabetes Risk
Authors: HUBER HANNA , ASHTON NICHOLAS J. , WEINHOLD LEONIE , SCHMID MATTHIAS , COENEN MARTIN , STOFFEL-WAGNER BIRGIT , BLENNOW KAJ , STEHLE PETER , ZETTERBERG HENRIK , SIMON MARIE-CHRISTINE 
Published: June 2023

Background: Recent research confirms insulin resistance (IR) not only as risk factor for type 2 diabetes mellitus (T2DM) but also for Alzheimer’s disease (AD). Diet restrictions in patients with T2DM or obesity alone may, thus, not only improve insulin sensitivity (IS) of the CNS but may beneficially affect AD-related biomarkers known to early recognize long-term AD risks. To prove this hypothesis, we investigated the effects of a controlled, potentially health-promoting dietary intervention on both glucose metabolism (IR) and AD biomarkers in cognitively healthy, obese adults.
Methods: One-hundred-and-eleven adults (60±7y, BMI 31.1±3.5kg/m², 47 males) were randomized either to the intervention group consuming a plant-based diet or the control group maintaining their habitual Western diet. Both diets were isoenergetic to ensure a constant body weight. At baseline and after 6 weeks intervention, OGTT was performed and HOMA-IR and OGIS were calculated. Fasting plasma levels of AD biomarkers (neurofilament light chain, glial fibrillary acidic protein, amyloid-beta (Aβ) 42/40, and phosphorylated tau (p-tau) 181 and 231; Simoa assay), glucose, HbA1c and serum insulin were measured. Data were analyzed via linear mixed-effect models and regression analyses.
Results: Fasting glucose and insulin levels were in borderline high physiological ranges; a possible IR was indicated. After 6 weeks, there were no diet-induced differences in fasting levels of glucose, insulin, AD biomarkers, and IR measures (all p&gt;0.05). However, a positive association of fasting levels of p-tau181 and HOMA-IR (β=0.464, p=0.038) and p-tau231 and HbA1c (β=2.693, p=0.029) and a negative trend for Aβ40 and OGIS (β=−0.049; p=0.055) were found.
Conclusion: Impaired insulin sensitivity is associated with unfavorable changes in AD-related biomarker levels in adults with diabetes risk, highlighting the relevance of glucose metabolism in cognitive health.

Disclosure
H.Huber: None. M.Simon: None. N.J.Ashton: None. L.Weinhold: None. M.Schmid: None. M.Coenen: None. B.Stoffel-wagner: None. K.Blennow: Other Relationship; Acumen, BioArctic, Eisai, Biogen, Eisai Co., Ltd., Lilly, Novartis, Ono Pharmaceutical Co., Ltd., Prothena, Roche Diagnostics, Siemens, Brain Biomarker Solutions, Julius Clinical, ALZPath. P.Stehle: None. H.Zetterberg: None.

Funding
German Federal Ministry of Education and Research (01EA1707, 01EA1809A); Swedish Research Council (2017-00915, 2022-00732, 2022-01018); Swedish Alzheimer Foundation (AF-930351, AF-939721, AF-968270); Hjärnfonden, Sweden (FO2017-0243, ALZ2022-0006, FO2022-0270); Swedish State (ALFGBG-715986, ALFGBG-965240, ALFGBG-71320); European Union Joint Program for Neurodegenerative Disorders (JPND2019-466-236, JPND2021-00694); Alzheimer’s Association (ZEN-21-848495, SG-23-1038904 QC); European Union’s Horizon Europe Research and Innovation Programme (101053962, 860197); Alzheimer Drug Discovery Foundation (201809-2016862); AD Strategic Fund/Alzheimer's Association (ADSF-21-831376-C, ADSF-21-831381-C, ADSF-21-831377-C); Bluefield Project; Olav Thon Foundation; Erling-Persson Family Foundation; Stiftelsen för Gamla Tjänarinnor; UK Dementia Research Institute (UKDRI-1003)