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Principal Investigator: Sarah Ann Flowers
Organization: WINIFRED MASTERSON BURKE MED RES INST
Fiscal Year: 2024
Award: $1,018,953
Funding agency: National Institute on Aging
Experimental data linking thiamine (vitamin B1) deficiency to Alzheimer’s disease (AD) inspired our
clinical trial, which generated preliminary evidence that pharmacological thiamine produced by the drug
benfotiamine provides clinical benefit. We hypothesize that pharmacological thiamine is protective by diminishing
the formation of advanced glycation endproducts (AGE). AGE are proteins and lipids that become glycated and
harmful following exposure to reducing sugars. AGE cause irreversible damage to biological macromolecules by
altering their structural and functional integrity. Abundant evidence links AGE to AD. In AD animal models,
thiamine deficiency increases AGE and exacerbates plaques and tangle formation, while increased thiamine
diminishes AGE and pathology. In our pilot clinical trial, pharmacological thiamine levels diminished global
plasma AGE levels and improved symptoms in patients with AD. Interestingly, in AD patients, the effects of high
thiamine are diminished in patients carrying the APOE4 genotype, the most significant genetic risk factor for
sporadic AD. We postulate that this is because APOE4 increases unique AGE at earlier stages.
Optimizing this therapeutic approach requires a better understanding of the mechanism underlying the
action of benfotiamine. All previous related AD and thiamine studies have utilized AGE antibody surveys. This
data is limited to a small range of AGE and provides no data on the proteins and specific sites modified with
glycation. We will provide this critical data by using multiple state-of-the-art mass spectrometric measures of
AGE. Global glycaproteomics will identify glycated proteins and specific sites of AGE modifications and AGE-
omics will identify a broad range of crosslinking and non-crosslinking AGE. A second major gap is the lack of
our understanding on how APOE4 modifies the response to thiamine. Novel APOE3 and APOE4 humanized
APP mouse models will allow us to test these interactions. We will test our hypotheses: (1) In AD autopsy
brains at different stages of the disease, AGE modifications are critical to the pathophysiology of AD in
an APOE-dependent manner. (2) In mouse models of AD, thiamine deficiency drives AD-like pathology
and memory loss by causing specific brain and blood AGE modifications which are modified by APOE
genotype. (3) In mouse models, benfotiamine is beneficial by diminishing specific AGE and the treatment
must be initiated at an earlier stage of disease in APOE4 mice.
These studies will dramatically improve our understanding of the role of AGE in AD and its link to a treatment
of pharmacological thiamine levels. Defining the interaction of AGE and thiamine in the etiology and progression
of AD will enable the development of specific AGE signatures for targets of engagement for therapeutic trials
and as AD diagnostic and prognostic biomarkers. These studies will define the differential effectiveness of
thiamine by APOE genotype and define the most effective therapeutic approach for APOE3 and consistently
hard to treat APOE4 carriers. We therefore expect this study will have a high impact on translational AD medicine.
Terms: <AD dementia><AD diagnostic><AD model><APOE e4><APOE-ε4><APOEε4><Advanced Glycation End Products><Advanced Glycosylation End Products><Alleles><Allelomorphs><Alzheimer Type Dementia><Alzheimer disease dementia><Alzheimer like pathology><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Disease><Alzheimer's diagnostic><Alzheimer's disease diagnostic><Alzheimer's disease like pathology><Alzheimer's disease model><Alzheimer's disease patient><Alzheimer's disease therapy><Alzheimer's patient><Alzheimer's therapy><Alzheimers Dementia><Aneurin><Animal Disease Models><Antibodies><Attenuated><Autopsy><BTMP-benfo><Beri Beri><Beriberi><Biological><Biological Markers><Blood><Blood Plasma><Blood Reticuloendothelial System><Blood Sample><Blood specimen><Brain><Brain Nervous System><Brain region><Causality><Clinical><Clinical Trials><Clinical dementia rating scale><Cocarboxylase><D-Glucose><Data><Dementia rating scale><Development><Dextrose><Diabetes Mellitus><Disease><Disorder><Dose><Drugs><Dysfunction><Effectiveness><Encephalon><Etiology><Exposure to><Functional disorder><Funding><Genetic predisposing factor><Genotype><Glucose><Glycohemoglobin A><Glycosylated hemoglobin A><Goals><Hb A1><Hb A1a+b><Hb A1c><HbA1><HbA1c><Hemoglobin A(1)><KI mice><Knock-in Mouse><Link><Lipids><Location><Measures><Medication><Medicine><Memory><Memory Loss><Metabolic><Metabolic dysfunction><Mice><Mice Mammals><Modification><Multi-center trial><Multicenter Trials><Murine><Mus><Nature><Neurofibrillary Tangles><Participant><Pathology><Patients><Pattern><Pharmaceutical Preparations><Pharmacological Treatment><Physiopathology><Plasma><Plasma Serum><Prediabetes><Prediabetes syndrome><Prediabetic State><Primary Senile Degenerative Dementia><Process><Prognostic Marker><Proteins><Proteomics><Publishing><Research><Reticuloendothelial System, Serum, Plasma><Role><Severity of illness><Signal Pathway><Site><Survey Instrument><Surveys><Testing><Therapeutic><Therapeutic Trials><Thiamine><Thiamine Deficiency><Thiamine Diphosphate><Thiamine Pyrophosphate><Trust><Vit B1><Vitamin B 1><Vitamin B1><advanced glycation endproduct><advanced glycosylation endproduct><alzheimer model><apo E-3><apo E-4><apo E3><apo E4><apo epsilon4><apoE epsilon 4><apoE-3><apoE-4><apoE3><apoE4><apolipoprotein E epsilon 4><apolipoprotein E-3><apolipoprotein E-4><apolipoprotein E3><apolipoprotein E4><attenuate><attenuates><benfothiamine><benfotiamine><benphothiamine><bio-markers><biologic><biologic marker><biomarker><causation><crosslink><developmental><diabetes><diagnostic biomarker><diagnostic marker><disease causation><disease prognostic><disease severity><dosage><drug/agent><genetic risk factor><glucose metabolism><glycation><hemoglobin A1c><improve symptom><improved><inherited factor><knockin mice><macromolecule><memory decline><mouse model><murine model><necropsy><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurofibrillary tangle formation><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><non-enzymatic glycosylation><nonenzymatic glycosylation><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><patient living with Alzheimer's disease><patient suffering from Alzheimer's disease><patient with Alzheimer's><patient with Alzheimer's disease><pharmacologic><postmortem><pre-diabetes><pre-diabetic><prediabetic><primary degenerative dementia><prognostic biomarker><response><senile dementia of the Alzheimer type><sex><social role><success><sugar><symptom improvement><symptomatic improvement><tangle><tangle formation><therapeutically effective><thiamin><translational medicine>