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Exercise in Alzheimer's Disease: Functional Biomarkers (AD-GUT-EX)

30. oktober 2026 oppdatert av: European University Miguel de Cervantes

Physical Exercise in Alzheimer's Disease: Impact on Functional Biomarkers and the Muscle-Gut-Brain Axis

Alzheimer's disease (AD) is the leading cause of dementia worldwide and involves systemic alterations beyond the brain, such as loss of muscle strength, chronic low-grade inflammation, and gut microbiome dysbiosis. Physical exercise is a promising non-pharmacological therapy, and velocity-based resistance training has proven safe and effective in older adults. However, the effects of performing resistance exercises at high versus moderate velocity in people with AD remain unknown, and human evidence on how exercise modulates the gut microbiome in AD is very limited. This study aims to assess and compare the effects of two velocity-based resistance training modalities (high load at moderate velocity and moderate load at high velocity) versus usual care on the gut microbiome, systemic inflammation, plasma biomarkers, biological age, and intrinsic capacity in older adults with mild-to-moderate AD, using cognitively healthy older adults as a reference group.

Studieoversikt

Status

Har ikke rekruttert ennå

Forhold

Intervensjon / Behandling

Detaljert beskrivelse

Alzheimer's disease (AD) is the leading cause of dementia worldwide, affecting more than 50 million people, a figure projected to exceed 150 million by 2050, with a high economic and social burden that increases with disease severity. Beyond the accumulation of amyloid-β and hyperphosphorylated tau in the brain, AD involves systemic alterations even in early stages, including the progressive loss of muscle mass and strength (sarcopenia), chronic low-grade inflammation and disruption of the gut-brain axis. In this context, physical exercise has emerged as a high-impact adjuvant therapy capable of inducing relevant neurobiological and systemic adaptations. Among the available training modalities, velocity-based resistance training (i.e., controlling the execution velocity of each repetition to individualize the training load) has been shown to be safe and effective in older adults. However, the effects of executing resistance exercises at high velocity with moderate loads (e.g., 40-60% of one-repetition maximum [1RM]) versus moderate velocity with high loads (e.g., 60-80% 1RM) remain unexplored in people with AD. These exercise-induced adaptations can be monitored through circulating biomarkers that capture different biological responses: brain-derived neurotrophic factor (BDNF), a key mediator of neuronal survival and synaptic plasticity; the testosterone/cortisol ratio, an indicator of anabolic-catabolic balance; phosphorylated tau 217 (p-tau217), one of the most specific plasma markers of AD pathology; and Klotho, a protein linked to healthy aging with neuroprotective and anti-inflammatory functions. In parallel, the gut microbiome has gained prominence as a key modulator of the muscle-gut-brain axis. People with AD show reduced microbial diversity, an expansion of pro-inflammatory species and a reduction of short-chain fatty acid-producing bacteria, which compromise intestinal and blood-brain barrier integrity and amplify systemic inflammation. Although animal models consistently show that exercise promotes beneficial taxa and is associated with cognitive improvements, human studies have focused mainly on healthy older adults, and evidence in people diagnosed with AD is very limited. Moreover, molecular changes should translate into clinically relevant benefits. The World Health Organization's intrinsic capacity framework (cognition, locomotion, vitality, psychological and sensory domains) offers an integrative approach linking biological mechanisms with functional outcomes, together with sarcopenia, frailty, functional independence and caregiver burden. Therefore, this randomized controlled trial will compare two velocity-based resistance training modalities with usual care in older adults with mild-to-moderate AD, including a cognitively healthy reference group, to determine which modality has the greatest impact on the muscle-gut-brain axis, biological aging and intrinsic capacity, and whether these effects persist after detraining.

Studietype

Intervensjonell

Registrering (Antatt)

48

Fase

  • Ikke aktuelt

Kontakter og plasseringer

Denne delen inneholder kontaktinformasjon for de som utfører studien, og informasjon om hvor denne studien blir utført.

Studiekontakt

  • Navn: Alejandro Santos-Lozano, PhD
  • Telefonnummer: 22292 +34983001000
  • E-post: asantos@uemc.es

Studer Kontakt Backup

  • Navn: Fabrzio Evangelista, Nurse

Studiesteder

  • Spania
    • Valladolid
      • Valladolid, Valladolid, Spania, 47012
        • Miguel de Cervantes European University
        • Underetterforsker:
          • María Merino País, MSc, PhD student
        • Underetterforsker:
          • Susana López Ortiz, PhD
        • Underetterforsker:
          • Celia García Chico, PhD
        • Ta kontakt med:
          • Francisco Javier Gutiérrez Pecharrómán
          • Telefonnummer: 22293 +34 983 001 000
          • E-post: dit@uemc.es
        • Hovedetterforsker:
          • Alejandro Santos Lozano, PhD
        • Hovedetterforsker:
          • Fabrizio Evangelista, MSc
        • Underetterforsker:
          • Alba Canteli Diez, MSc, PhD student
        • Underetterforsker:
          • Virginia Carbajosa Rodríguez, PhD
        • Underetterforsker:
          • Sara del Amo Ramos, MD
        • Underetterforsker:
          • Daniel Arévalo Sillero, MSc
        • Underetterforsker:
          • Mónica Álvarez Muñoz, MD
        • Underetterforsker:
          • Javier Guitiérrez Redondo
        • Underetterforsker:
          • Francisco Javier Iruzubieta Barragan, PhD

Deltakelseskriterier

Forskere ser etter personer som passer til en bestemt beskrivelse, kalt kvalifikasjonskriterier. Noen eksempler på disse kriteriene er en persons generelle helsetilstand eller tidligere behandlinger.

Kvalifikasjonskriterier

Alder som er kvalifisert for studier

60 år og eldre (Voksen, Eldre voksen)

Tar imot friske frivillige

Ja

Kjønn som er kvalifisert for studier

Alle

Beskrivelse

Inclusion Criteria - participants with Alzheimer's Disease

  • Age ≥ 60 years
  • Medical diagnosis of mild or moderate Alzheimer's disease based on clinical criteria and plasma biomarkers.
  • Able to perform physical activity according to medical assessment
  • Written informed consent from the participant or, when capacity is insufficient, from the legal representative

Inclusion Criteria - cognitively healthy reference group

  • Age ≥ 60 years
  • No medical diagnosis of Alzheimer's disease or cognitive impairment according to clinical criteria
  • Preserved functional autonomy
  • Able to perform physical activity according to medical assessment
  • Written informed consent

Exclusion Criteria:

  • Major surgery in the previous 3 months
  • Total functional dependence
  • Uncontrolled neuromuscular disease or severe heart disease
  • Antibiotic, probiotic or corticosteroid treatment in the 4 weeks before biological sample collection

Studieplan

Denne delen gir detaljer om studieplanen, inkludert hvordan studien er utformet og hva studien måler.

Hvordan er studiet utformet?

Designdetaljer

  • Primært formål: Helsetjenesteforskning
  • Tildeling: Randomisert
  • Intervensjonsmodell: Parallell tildeling
  • Masking: Enkelt

Våpen og intervensjoner

Deltakergruppe / Arm
Intervensjon / Behandling
Eksperimentell: Alzheimer's disease - High load

Participants with mild-to-moderate AD perform 12 weeks of supervised based resistance training at 60-80% 1RM, 3 sessions/week, plus usual care. Followed by 12 weeks of detraining.
Annen: High load

Supervised resistance training programme lasting 12 weeks, with 3 sessions per week of 60 minutes each. Each session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 60-80% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. Training volume will be progressively increased throughout the programme by increasing the number of repetitions and sets per exercise.
Eksperimentell: Alzheimer's disease - Moderate load

Participants with mild-to-moderate AD perform 12 weeks of supervised based resistance training at 40-60% 1RM, 3 sessions/week, plus usual care. Followed by 12 weeks of detraining.
Annen: Moderate load

Supervised resistance training programme lasting 12 weeks, with 3 sessions per week of 60 minutes each. Each session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 40-60% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises. Training volume will be progressively increased throughout the programme by increasing the number of repetitions and sets per exercise.
Ingen inngripen: Alzheimer's disease - Usual care

Participants with mild-to-moderate AD continue their usual care only (cognitive therapy, music therapy or other routine therapies).
Annen: Healthy reference group

Cognitively healthy adults aged ≥ 60 years, not randomized for the longitudinal phase and not undergoing structured exercise. At week 1 they will be randomized to a single high-load session, a single moderate-load session or no exercise for the acute sub-study.
Annen: Healthy adults - High load

One acute session of 60 minutes each. The session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 60% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises.

Annen: Healthy adults - Moderate load

One acute session of 60 minutes each. The session consists of a 15-minute mobility warm-up, in which one set of 10 repetitions with a load of 10% of body weight is performed for each exercise; a 35-minute main part with five exercises performed on guided resistance machines (leg press, leg extension, leg curl, chest press and seated row) in circuit format at 40% of one-repetition maximum (1RM); and a 10-minute cool-down with mobility and flexibility exercises.

Hva måler studien?

Primære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Gut microbiome
Tidsramme: Baseline, week 12 of intervention

Participants will collect a stool sample at home using a commercial collection kit (REAL Stool Sample Collection Microbiome kit, Durviz S.L., Valencia, Spain). Samples will be divided into three aliquots and stored at -80ºC within 2 hours of collection. Microbial DNA will be extracted and the gut microbiome will be analysed by next-generation sequencing of the 16S rRNA gene.
Baseline, week 12 of intervention
Inflammation indices - Systemic Inflammation Response Index
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and complete blood count will be assessed by flow cytometry to assess the Systemic Inflammation Response Index (SIRI) .

SIRI = (neutrophils × monocytes) / lymphocytes

All cell counts will be expressed as ×10⁹ cells/L or equivalent.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Plasma biomarkers - Brain-derived neurotrophic factor
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Plasma concentrations of Brain-derived neutrophic factor (BDNF) will be measured by Enzyme-Linked ImmunoSorbent Assay (ELISA). Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Inflammation indices - Aggregate Index of Systemic Inflammation
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and complete blood count will be assessed by flow cytometry to assess the Aggregate Index of Systemic Inflammation (AISI).

AISI = (neutrophils × monocytes × platelets) / lymphocytes

All cell counts will be expressed as ×10⁹ cells/L or equivalent.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Plasma biomarkers - p-tau217
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Plasma concentrations of p-tau217 will be measured by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Plasma biomarkers - Klotho
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Plasma concentrations of klotho will be measured by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Plasma biomarkers - Testosterone/cortisol ratio
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Plasma ratio of testosterone/cortisol will be assessed by ELISA. Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein into EDTA-treated vacutainers and centrifuged at 1500g for 10 minutes. Plasma will then undergo a second centrifugation at 2500g for 15 minutes and be stored in cryogenic vials at -80ºC. Results will be expressed in pg/mL or ng/mL.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining
Biological age
Tidsramme: Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Fasting venous blood samples will be collected by a qualified nurse from the antecubital vein and analysed at the Hospital Universitario Río Hortega laboratory. PhenoAge clock based on crhonological age and nine blood biomarkers: albumin, creatinine, glucose, C-reactive protein, lymphocyte %, mean corpuscular volume, red blood cell distribution width, alkaline phosphatase and white blood count).

PhenoAge acceleration (years) will be computed as the residual from regression PhenoAge on chronological age.
Baseline, week 1 of intervention, week 12 of intervention and week 12 of detraining

Sekundære resultatmål

Resultatmål
Tiltaksbeskrivelse
Tidsramme
Intrinsic capacity - Cognition
Tidsramme: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining

Cognition will be measured by Mini-Mental State Examination (0-35 points).
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
Intrinsic capacity - Cognition
Tidsramme: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining

Cognition will also be measured by Clock Drawing Test (0-10 points)
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
Intrinsic capacity - Cognition
Tidsramme: Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining

Cognition will also be measured verbal fluency (words/min).
Baseline, week 1 of intervention (only verbal fluency), week 12 of intervention and week 12 of detraining
Intrinsic capacity - Locomotion
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Locomotion will be assessed using the Short Physical Performance Battery (0-12 points).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Locomotion
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Locomotion will be also assessed using the sit-to-stand muscle power (W) measured by PowerFrail app.
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Vitality
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Vitality will be measured by Mini-Nutritional Assessment (0-30 points).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Vitality
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Vitality will also be measured by peak expiratory peak flow (L/min).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Vitality
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Vitality will also be measured by handgrip strength (kg).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Psychological
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Psychological domain will be assessed using the Cornell Scale for Depression in Dementia (0-38 points).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Psychological
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Psychological domain will also be assessed using the Geriatric Depression Scale-10 (0-10 points).
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Psychological
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Psychological domain will also be assessed using the Neuropsychiatric inventory.
Baseline, week 12 of intervention and week 12 of detraining
Intrinsic capacity - Sensory capacity
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Sensory domain will be assessed by self-, clinician- or caregiver-reported vision and hearing problems
Baseline, week 12 of intervention and week 12 of detraining
Quadriceps muscle thickness
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Rectus femoris and vastus lateralis thickness (cm) will be measured with a real-time B-mode ultrasound (MyLab Gamma, Esaote, Genoa, Italy) and a linear transducer (SL 1543, 3-13 MHz; Esaote)
Baseline, week 12 of intervention and week 12 of detraining
Functional outcomes - Functional capacity
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Functional capacity will be assessed using the 6-Minute walking test (6MWT). Participants will walk along a 30-metre corridor marked every 10 metres to cover the maximum distance possible in six minutes. Total distance will be recorded (in meters). r.
Baseline, week 12 of intervention and week 12 of detraining
Functional outcomes - Functional independence in basic activities of daily living
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

The Barthel Index assesses ten basic activities of daily living. The score ranges from 0 to 100 points, with higher scores indicating greater independence: total dependence (0-20), severe (21-60), moderate (61-90), mild dependence (91-99) and independence (100).
Baseline, week 12 of intervention and week 12 of detraining
Functional outcomes - Heart rate recovery
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Additionally to the distance, heart rate recovery (bpm) will be calculated as the difference between heart rate at the end of the test (6MWT) and one minute after
Baseline, week 12 of intervention and week 12 of detraining
Functional outcomes - Functional independence in instrumental activities of daily living
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

The Lawton and Brody Scale evaluates eight instrumental activities of daily living. The score ranges from 0 to 8 points, with lower scores indicating greater dependence.
Baseline, week 12 of intervention and week 12 of detraining
Clinical outcomes - Bioimpedance
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

The NUTRILAB bioimpedance device (AKERN Srl, Florence, Italy) will be used. This non-invasive method measures the body's resistance and reactance of the body to the passage of a low-intensity electric current and enables the determination of various body parameters. Bioimpedance provides accurate data on body fat percentage, muscle mass, total body water and other relevant indicators such as phase angle and Z-score. Users will be instructed to remove all metal-containing objects and remain in a supine position on a couch during the measurements, with the legs in 45° abduction, the shoulders in 30° abduction relative to the center of the body and the hands in pronation. After cleaning the skin with alcohol, two adhesive electrodes (Biatrodes Akern Srl, Florence, Italy) will be placed on the surface of the right hand and two on the right foot.

The measurement results will be given in different unit measures depending on the specific variable assessed
Baseline, week 12 of intervention and week 12 of detraining
Clinical outcomes - Risk of sarcopenia
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Sarcopenia will be assessed following the European Working Group on Sarcopenia in Older People (EWGSOP2) algorithm.
Baseline, week 12 of intervention and week 12 of detraining
Clinical outcomes - Comorbidities
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Comorbidities will be recorded through the Charlson Comorbidity Index. Score is given in points, ith higher scores indicating greater comorbidity burden.
Baseline, week 12 of intervention and week 12 of detraining
Pyschosocial outcomes - Caregiver burden
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

Caregiver burden will be assessed by the Zarit Burden Interview. It consists of 22 items on the caregiver's psychosocial, economic and emotional well-being. The score ranges from 0 to 88 points, with higher scores indicating greater caregiver burden.
Baseline, week 12 of intervention and week 12 of detraining
Pyschosocial outcomes - Socio-familial situation
Tidsramme: Baseline, week 12 of intervention and week 12 of detraining

The Gijón Socio-Familial Assessment will be used. It evaluates five dimensions: personal situation, economic situation, housing, social relationships and support from the social network. The score ranges from 5 to 25 points, with higher scores indicating greater social risk (15 or more indicates a social problem).
Baseline, week 12 of intervention and week 12 of detraining

Samarbeidspartnere og etterforskere

Det er her du vil finne personer og organisasjoner som er involvert i denne studien.

Sponsor

European University Miguel de Cervantes

Samarbeidspartnere

Hospital Rio Hortega

Studierekorddatoer

Disse datoene sporer fremdriften for innsending av studieposter og sammendragsresultater til ClinicalTrials.gov. Studieposter og rapporterte resultater gjennomgås av National Library of Medicine (NLM) for å sikre at de oppfyller spesifikke kvalitetskontrollstandarder før de legges ut på det offentlige nettstedet.

Studer hoveddatoer

Studiestart (Antatt)

10. november 2026

Primær fullføring (Antatt)

31. oktober 2027

Studiet fullført (Antatt)

1. desember 2027

Datoer for studieregistrering

Først innsendt

26. oktober 2026

Først innsendt som oppfylte QC-kriteriene

30. oktober 2026

Først lagt ut (Faktiske)

5. november 2026

Oppdateringer av studieposter

Sist oppdatering lagt ut (Faktiske)

5. november 2026

Siste oppdatering sendt inn som oppfylte QC-kriteriene

30. oktober 2026

Sist bekreftet

1. oktober 2026

Mer informasjon

Begreper knyttet til denne studien

Nøkkelord

Ytterligere relevante MeSH-vilkår

Andre studie-ID-numre

  • PI-DOC013-ADD-GUT-EXERCISE

Legemiddel- og utstyrsinformasjon, studiedokumenter

Studerer et amerikansk FDA-regulert medikamentprodukt

Nei

Studerer et amerikansk FDA-regulert enhetsprodukt

Nei

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