Neuroprotective Effects of Oleanolic Acid and Erythrodiol in Prodromal Alzheimer's Disease (NEUROLEA)
Alzheimer's disease begins many years before memory problems become obvious. People in the early ("prodromal") stage have memory complaints but are still independent in daily life. At present there is no treatment that prevents this stage from progressing to dementia.
Olive oil contains two natural compounds, oleanolic acid and erythrodiol. Earlier work by this research team suggests that these compounds may reduce inflammation and oxidative stress and may improve the way the body handles sugars and fats, processes that are also altered in Alzheimer's disease.
This study will test whether consuming olive oils that contain these compounds delays the progression from prodromal Alzheimer's disease to dementia.
A total of 120 adults aged 50 to 80 years with prodromal Alzheimer's disease will take part at three public hospitals in southern Spain. Participants will be assigned by chance to one of three groups and will consume 55 mL per day of one of three oils for 12 months: olive oil enriched with oleanolic acid, pomace olive oil (which naturally contains both compounds), or a standard commercial olive oil with very low levels of these compounds. Neither the participants nor the staff assessing them will know which oil each person is receiving.
Participants will attend study visits at the start of the study and after 6 and 12 months. At these visits they will complete memory and thinking tests, a physical and nutritional assessment, and blood and urine tests.
Visão geral do estudo
Status
Descrição detalhada
NEUROLEA is a multicenter, randomized, double-blind, controlled dietary intervention trial coordinated by the Instituto de la Grasa (CSIC). Participants will be recruited at the Neurology Units of Hospital Universitario Virgen del Rocío, Hospital Universitario Reina Sofía and Hospital Universitario de Valme.
Study oils. High-purity crystalline oleanolic acid (>95%) will be obtained from olive leaves following a procedure developed by the research team (Spanish Patent ES2160553) and used to prepare an oleanolic acid-enriched olive oil (600 mg/kg) according to European Patent EP18382510. A commercial olive oil 0.4° will serve as the control oil, as it has the same fatty acid composition as the other oils but a very low content of minor bioactive components. Pomace olive oil, which naturally contains oleanolic acid and erythrodiol, will be purchased from local markets. Oil composition will be verified by gas chromatography and differential scanning calorimetry before the intervention begins.
Randomization and blinding. Allocation will follow computer-generated random numbers prepared by the trial coordinator. Participants, clinical and nutritional research staff, and the neuropsychologists scoring the cognitive assessments will be blinded to group assignment.
Sample size. Thirty-four participants per arm are required for 90% power to detect a 10% reduction in dementia incidence in the functional oil arms compared with a 25% incidence in the control arm over 12 months (alpha 0.05). Allowing for up to 15% attrition in a long-term dietary intervention, the target is 40 participants per arm (120 in total).
Intervention and follow-up. Participants will consume 55 mL/day of the assigned oil, preferably raw and distributed across the three main meals, for 12 months. Adherence will be assessed with the self-reported Haynes-Sackett compliance test and by return of empty bottles, methods previously used by this team in the PREDIABOLE and OLTRAD trials. Participants and their caregivers will receive general healthy-eating guidance throughout the study.
Assessments. Evaluations will be performed at baseline and after 6 and 12 months, and will include a comprehensive neuropsychological battery, clinical examination, anthropometry and body composition by bioimpedance, dietary intake and diet quality questionnaires, and fasting blood and urine sampling. Serum concentrations of oleanolic acid and erythrodiol will be measured by HPLC-MS to verify exposure.
Mechanistic analyses. Beyond the clinical endpoints, the trial will examine circulating markers of lipid and glucose metabolism, oxidative stress and inflammation, and advanced glycation end product metabolism, together with the expression of related genes in peripheral blood mononuclear cells. Blood-based markers of Alzheimer's disease pathology (p-tau 217, neurofilament light chain, glial fibrillary acidic protein, and the amyloid beta 42/40 ratio) will be quantified at baseline and 12 months.
Data will be managed in REDCap and stored in pseudonymized form in accordance with the General Data Protection Regulation.
Tipo de estudo
Inscrição (Estimado)
Estágio
- Não aplicável
Contactos e Locais
Contato de estudo
- Nome: Elena M Yubero-Serrano, PhD.
- Número de telefone: +34687848695
- E-mail: elena.yubero@ig.csic.es
Locais de estudo
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Seville, Espanha, 41013
- Instituto de la Grasa, CSIC
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Contato:
- Elena M Yubero-Serrano, PhD.
- Número de telefone: +34687848695
- E-mail: elena.yubero@ig.csic.es
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
Aceita Voluntários Saudáveis
Gêneros Elegíveis para o Estudo
Descrição
Inclusion Criteria:
Men and women aged 50 to 80 years Diagnosis of prodromal Alzheimer's disease, meeting all of the following: memory complaints corroborated by a reliable informant; Mini-Mental State Examination (MMSE) total score between 22 and 30; Free and Cued Selective Reminding Test (FCSRT, picture version) total recall score of 46 or less; Clinical Dementia Rating Global Score (CDR-GS) of 0.5; functional independence in activities of daily living (Functional Activities Questionnaire total score of 8 or less); plasma p-tau 217 above 0.45 pg/mL measured by the Lumipulse method Ability and willingness to attend scheduled visits at the study center Adequate visual and auditory capacity to complete study evaluations Educational level sufficient to read and write Written informed consent
Exclusion Criteria:
Absence of a reliable informant Evidence, based on medical history or clinical evaluation, of a neurological condition other than Alzheimer's disease that could account for the cognitive impairment Clinically significant, advanced or unstable systemic disease that may interfere with cognitive evaluation Severe psychiatric disorders, including schizophrenia, bipolar disorder or active major depression History of alcohol or psychotropic substance abuse Pre-existing intellectual disability that precludes neuropsychological evaluation
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Prevenção
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Quadruplicar
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
|
Experimental: OA-enriched Olive Oil
Participants will consume 55 mL/day of olive oil enriched with oleanolic acid (600 mg/kg) for 12 months, preferably raw and distributed across the three main meals. |
Olive oil enriched with oleanolic acid (600 mg/kg), 55 mL/day for 12 months, consumed preferably raw and distributed across the three main meals. |
|
Experimental: Pomace Olive Oil
Participants will consume 55 mL/day of commercial pomace olive oil, which naturally contains oleanolic acid (180 mg/kg) and erythrodiol (670 mg/kg), for 12 months, preferably raw and distributed across the three main meals. |
Commercial pomace olive oil, naturally containing oleanolic acid (180 mg/kg) and erythrodiol (670 mg/kg), 55 mL/day for 12 months, consumed preferably raw and distributed across the three main meals. |
|
Comparador de Placebo: Control Olive Oil
Participants will consume 55 mL/day of commercial olive oil 0.4°, which has the same fatty acid composition but a very low content of minor bioactive components, for 12 months, preferably raw and distributed across the three main meals. |
Commercial olive oil 0.4°, with the same fatty acid composition but a very low content of minor bioactive components, 55 mL/day for 12 months, consumed preferably raw and distributed across the three main meals. |
O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Conversion from prodromal Alzheimer's disease to dementia
Prazo: Baseline to 12-months
|
Proportion of participants converting to dementia, defined as a change in the Clinical Dementia Rating Global Score (CDR-GS) from 0.5 at baseline to 1 or higher. The CDR-GS ranges from 0 to 3, with higher scores indicating greater dementia severity |
Baseline to 12-months
|
Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Change in Clinical Dementia Rating Sum of Boxes (CDR-SB)
Prazo: Baseline to 12-months
|
CDR-SB total score ranges from 0 to 18, with higher scores indicating more severe cognitive impairment. |
Baseline to 12-months
|
|
Change in Mini-Mental State Examination (MMSE) score
Prazo: Baseline to 12-months
|
MMSE total score ranges from 0 to 30, with higher scores indicating better global cognitive performance |
Baseline to 12-months
|
|
Change in Mild Behavioral Impairment Checklist (MBI-C) score
Prazo: Baseline to 12-months
|
MBI-C assesses behavioral and psychological symptoms; higher scores indicate more severe symptoms |
Baseline to 12-months
|
|
Change in Functional Activities Questionnaire (FAQ) score
Prazo: Baseline to 12-months
|
FAQ total score ranges from 0 to 30, with higher scores indicating greater functional impairment |
Baseline to 12-months
|
Outras medidas de resultado
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
|
Change in lipid metabolism biomarkers
Prazo: Baseline, 6 months and 12 months
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Serum concentrations of total triglycerides, total cholesterol, LDL cholesterol, HDL cholesterol, apolipoprotein A1 and apolipoprotein B |
Baseline, 6 months and 12 months
|
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Change in glucose metabolism and insulin sensitivity biomarkers
Prazo: Baseline, 6 months and 12 months
|
Plasma glucose, insulin, glycated hemoglobin (HbA1c), HOMA-IR index and Quantitative Insulin Sensitivity Check Index (QUICKI) |
Baseline, 6 months and 12 months
|
|
Change in plasma lipid classes
Prazo: Baseline and 12 months
|
Cholesterol esters, triglycerides, diglycerides, free cholesterol, monoglycerides, phospholipids and ceramides determined by HPLC-MS. |
Baseline and 12 months
|
|
Change in oxidative stress markers
Prazo: Baseline, 6 months and 12 months
|
Reduced and oxidized glutathione (GSH, GSSG), Nrf2 levels, activities of superoxide dismutase, catalase and heme oxygenase-1, reactive oxygen species production and malondialdehyde. |
Baseline, 6 months and 12 months
|
|
Change in inflammation markers
Prazo: Baseline, 6 months and 12 months
|
NF-kB p65 and proinflammatory cytokines (TNF-alpha and IL-1beta) measured in plasma or serum. |
Baseline, 6 months and 12 months
|
|
Change in circulating advanced glycation end products and dicarbonyl compounds and parameters related to their metabolism
Prazo: Baseline, 6 months and 12 months
|
Baseline, 6 months and 12 months
|
|
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Change in blood biomarkers of Alzheimer's disease pathology
Prazo: Baseline and 12 months
|
Plasma p-tau 217, neurofilament light chain (NFL), glial fibrillary acidic protein (GFAP), and the amyloid beta 42/40 ratio. |
Baseline and 12 months
|
|
Serum concentrations of oleanolic acid and erythrodiol
Prazo: Baseline, 6 months and 12 months
|
Baseline, 6 months and 12 months
|
Colaboradores e Investigadores
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Estimado)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Outros números de identificação do estudo
- PID2024-161189OB-I00
Plano para dados de participantes individuais (IPD)
Planeja compartilhar dados de participantes individuais (IPD)?
Descrição do plano IPD
De-identified individual participant data underlying published results will be made available in institutional repositories, in accordance with the data management plan of the project and with international standards for the documentation of clinical study data.
Prazo de Compartilhamento de IPD
Data will become available after completion of the project and publication of the main results, and will remain accessible for at least five years thereafter.
Critérios de acesso de compartilhamento IPD
Requests for access should be submitted to the principal investigator by e-mail, including a description of the proposed research question and analysis plan. Requests will be evaluated by the study investigators. Access to de-identified individual participant data and to the supporting documents will be granted to researchers whose proposal is considered methodologically sound and consistent with the consent given by study participants, subject to a signed data access agreement.
Tipo de informação de suporte de compartilhamento de IPD
- PROTOCOLO DE ESTUDO
- CIF
Informações sobre medicamentos e dispositivos, documentos de estudo
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