Subjective Cognitive DeclineAHEADNCT07652931
Using Artificial Intelligence to Detect Early Signs of Alzheimer's Disease in People With Memory Concerns
A study testing High-frequency Transcranial Magnetic Stimulation (TMS), Digital Cognitive Training and Structured Physical Exercise in people with Subjective Cognitive Decline and Alzheimer Disease, run by IRCCS San Raffaele at 1 site in Italy.
Trial summary
AHEAD is a prospective, longitudinal, risk-stratified single-arm interventional study enrolling 300 patients with Subjective Cognitive Decline (SCD) at IRCCS San Raffaele Hospital, Milan, Italy. Read more about this study
- Who is it for?
- Ages 40 years and older
- Conditions the study is for
- Subjective Cognitive Decline, Alzheimer Disease, Mild Cognitive Impairment
- What is being tested?
- High-frequency Transcranial Magnetic Stimulation (TMS), Digital Cognitive Training and Structured Physical Exercise
- Type of treatment
- Medical device, Lifestyle or therapy programme
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 300 participants
- Where
- 1 siteItaly
- Study dates
- 1 Aug 2026to 1 Aug 2029
- Phase
- Interventional
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 40 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Diagnosis of Subjective Cognitive Decline (SCD) according to international diagnostic criteria (Jessen et al., 2014).
- Self-experienced persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event.
- Normal age-, gender-, and education-adjusted performance on standardized cognitive tests used to classify mild cognitive impairment (MCI) or prodromal AD.
- Age greater than or equal to 40 years.
- Native Italian Speaker.
- Stable pharmacological treatment for at least 4 weeks prior to enrollment.
- Provision of oral and written informed consent to study participation.
Who cannot join
- Presence of MCI, prodromal AD, or dementia.
- Any major systemic, psychiatric, or neurological disturbance.
- Medical conditions or substance abuse that could interfere with cognition.
- Pacemaker and/or other implanted neurostimulation devices in the head/neck district.
- Contraindications to undergoing MRI examination.
- Brain damage at routine MRI, including extensive cerebrovascular disorders.
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- Traumatic or surgical wounds that could determine a risk of infection at the site of non-invasive stimulation.
- Scalp alterations that could determine the spread of excessive current from the device.
- Known history of epilepsy (due to small risk of seizure induction from rTMS in epileptic patients).
- Denial of oral and written informed consent to study participation.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Italy1 site
San Raffaele Neurology Unit
Milan, Milano, 20132
Federica Agosta, MD, 0226433051, agosta.federica@hsr.it
Elisa EC Canu, PhD, 0226433033, canu.elisa@hsr.it
About this study
Official title: AHEAD: AI-driven Brain Health for Early Alzheimer's Disease Detection in Individuals With Subjective Cognitive Decline
AHEAD is a prospective, longitudinal, risk-stratified single-arm interventional study enrolling 300 patients with Subjective Cognitive Decline (SCD) at IRCCS San Raffaele Hospital, Milan, Italy.
The study uses artificial intelligence (AI) to integrate multimodal data - including MRI, EEG, Optical Coherence Tomography (OCT), neuropsychological assessments, and plasma biomarkers - to identify individuals with underlying Alzheimer's disease (AD) biology and predict cognitive progression.
Only participants found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up at 12 and 24 months. Participants classified as high risk additionally receive a 6-month personalized multidisciplinary intervention combining high-frequency transcranial magnetic stimulation (TMS), digital cognitive training, structured physical exercise, and targeted management of modifiable vascular and behavioral risk factors.
Read the detailed description
Subjective Cognitive Decline (SCD) refers to the self-perception of worsening cognitive abilities despite normal performance on standardized neuropsychological testing. It affects approximately 10% of the general population and 20-35% of patients attending memory clinics. Although the majority of individuals with SCD do not progress to clinical forms of Alzheimer's disease (AD), they show a higher prevalence of AD-related pathological biomarkers compared with individuals without subjective cognitive complaints, with rates of cognitive decline estimated at approximately 20% per 1,000 person-years in memory clinic patients.
Plasma biomarkers for AD represent minimally invasive and easily accessible diagnostic tools; however, their large-scale implementation in the broad SCD population is neither economically nor ethically sustainable because of costs, the risk of overdiagnosis, and the associated psychological burden. Artificial intelligence (AI) may represent a transformative tool for addressing the complexity of SCD management. By integrating multimodal data including cognitive assessments, MRI, EEG, and OCT, AI may help identify those individuals with SCD most likely to benefit from further diagnostic investigations, including plasma biomarker assessment.
At baseline (T0), all participants undergo a minimum assessment dataset including clinical evaluation, standard neuropsychological assessment, structural MRI, and blood sampling. A subset additionally undergoes a comprehensive risk assessment, extended neuropsychological evaluation including digital cognitive testing and the Preclinical Alzheimer Cognitive Composite (PACC), resting-state EEG, and retinal imaging through Optical Coherence Tomography (OCT).
Only patients found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up visits at 12 months (M12) and 24 months (M24), including clinical evaluation, neuropsychological assessments, and blood sampling to monitor cognitive and biological progression.
Participants stratified as high risk - defined as plasma p-tau217 greater than 0.1325 pg/mL, and/or APOE epsilon4 carrier, and/or elevated CAIDE Dementia Risk Score - enter a 6-month single-arm multidisciplinary intervention comprising: (1) targeted management of modifiable vascular and behavioral risk factors with monthly remote follow-up; (2) high-frequency TMS during the first 4 weeks (2-3 sessions per week); (3) home-based digital cognitive training, 2 sessions per week of 30 minutes each over 5 months; (4) structured physical exercise (walking, cycling, resistance training), 2 sessions per week of 30 minutes each.
A retrospective SCD cohort (rSCD), comprising patients who underwent the minimum assessment dataset within one year prior to enrollment and were found to be AD plasma biomarker positive, undergoes follow-up at M12 and M24 according to the same longitudinal protocol, with the intervention starting at M12.
AI models will integrate multimodal baseline data using machine learning (logistic regression, random forest), deep learning (CNNs for MRI/OCT, RNNs/Transformers for EEG), and survival analysis (Cox proportional hazards, DeepSurv). All models will be validated using k-fold cross-validation with performance metrics including AUC, sensitivity, specificity, balanced accuracy, and positive and negative predictive values.
- Conditions
- Subjective Cognitive Decline, Alzheimer Disease, Mild Cognitive Impairment, Cognitive Decline
- Being tested
- High-frequency Transcranial Magnetic Stimulation (TMS), Digital Cognitive Training, Structured Physical Exercise, Management of Modifiable Vascular and Behavioral Risk Factors
- Keywords
- Subjective Cognitive Decline, Alzheimer's disease, Artificial Intelligence, Transcranial Magnetic Stimulation, Plasma biomarkers, p-tau217, MRI, EEG, Optical Coherence Tomography, Cognitive Training, Physical Exercise, Brain Health, APOE, Machine Learning, Deep Learning
- Medical subject headings
- Alzheimer Disease, Cognitive Dysfunction, Motor Activity
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
High-frequency Transcranial Magnetic Stimulation (TMS)Device
High-frequency repetitive TMS (rTMS) delivered according to an intensive protocol during the first 4 weeks of the intervention period (2-3 sessions per week). Applied to brain regions associated with cognitive function to optimize brain health and reduce risk of cognitive decline. Administered by trained professionals following international safety guidelines (Rossi et al., 2009).
Digital Cognitive TrainingBehavioural
Home-based cognitive training delivered via digital platform over 5 months: 2 sessions per week of 30 minutes each. Targets perceived cognitive deficits and related domains (memory, executive functions, attention, visuospatial abilities, language) with progressive adaptation to individual performance level. Compliance monitored via dedicated applications and/or activity diaries. Monthly remote meetings with neuropsychologists to monitor progress.
Structured Physical ExerciseBehavioural
Home-based structured physical exercise program over 5 months: 2 sessions per week of 30 minutes each. Activities include walking, cycling, and global resistance training. An in-person familiarization session is conducted before program start. Monthly remote meetings with physiotherapists to monitor progress and adapt the program. Compliance remotely monitored via dedicated applications and/or activity diaries.
Management of Modifiable Vascular and Behavioral Risk FactorsOther
Personalized pharmacological and non-pharmacological interventions targeting modifiable vascular and behavioral risk factors including blood pressure, cholesterol, BMI, physical inactivity, dietary habits, sleep quality, and social isolation. Monthly remote follow-up visits over 6 months to monitor treatment adherence and optimize risk factor control.
| Study group | Role | What they receive |
|---|---|---|
| SCD Participants | Experimental | All 300 SCD participants undergo baseline multimodal assessment. Those found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up at M12 and M24. Those classified as high risk (plasma p-tau217 greater than 0.1325 pg/mL, and/or APOE epsilon4 carrier, and/or elevated CAIDE Dementia Risk Score) additionally receive a 6-month multidisciplinary personalized intervention combining high-frequency TMS, digital cognitive training, structured physical exercise, and targeted vascular and behavioral risk factor management. Receives: Device: High-frequency Transcranial Magnetic Stimulation (TMS); Behavioral: Digital Cognitive Training; Behavioral: Structured Physical Exercise; Other: Management of Modifiable Vascular and Behavioral Risk Factors |
What is being measured
The primary outcome is the main question the study is designed to answer.
Diagnostic accuracy of AI models in identifying AD biomarker-positive SCD subjects (AUC)
Area under the ROC curve (AUC), sensitivity, and specificity of AI models in discriminating between plasma AD biomarker-positive and biomarker-negative SCD subjects, assessed at study entry.
Measured: Baseline (study entry)
Secondary outcomes (1)
Predictive accuracy of AI models for cognitive progression (AUC)
Area under the ROC curve (AUC), sensitivity, and specificity of AI models in discriminating between SCD progressors and non-progressors (conversion to Mild Cognitive Impairment or dementia) over a 24-month follow-up period.
Measured: Baseline, 12 months (M12), and 24 months (M24)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted17 Jun 2026
- Study start1 Aug 2026 (estimated)
- Primary completion1 Aug 2028 (estimated)
- Study completion1 Aug 2029 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Subjective Cognitive DeclineStudies of the same condition, open and under way.
- More trials run by IRCCS San RaffaeleThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Model description
- Prospective, longitudinal, risk-stratified single-arm interventional study. Not all participants receive the intervention: only those classified as high risk based on plasma biomarkers (p-tau217), APOE genotype, and/or cardiovascular risk profile (CAIDE score) receive the 6-month multidisciplinary intervention program.
- Masking
- None (open label)
- Enrolment
- 300 participants (estimated)
Sponsor and investigators
- Lead sponsor
- IRCCS San Raffaele
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Massimo Filippi, IRCCS San Raffaele
- Investigators
- Massimo Filippi, Prof, Principal investigator, IRCCS San Raffaele
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT07652931
- Sponsor's protocol ID
- RF-2024-12380444
- Acronym
- AHEAD
- Status last verified
- Jun 2026
- First submitted
- 8 Jun 2026
- Last updated
- 17 Jun 2026
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 17 Jun 2026. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- AHEAD: AI-driven Brain Health for Early Alzheimer's Disease Detection in Individuals With Subjective Cognitive Decline
- ClinicalTrials.gov ID
- NCT07652931
- Acronym / sponsor ID
- AHEAD / RF-2024-12380444
- Conditions
- Subjective Cognitive Decline, Alzheimer Disease, Mild Cognitive Impairment, Cognitive Decline
- Keywords
- Subjective Cognitive Decline, Alzheimer's disease, Artificial Intelligence, Transcranial Magnetic Stimulation, Plasma biomarkers, p-tau217, MRI, EEG
- Study type
- Interventional
- Recruitment status
- Not yet recruiting
- Enrolment
- 300 participants (estimated)
- Lead sponsor
- IRCCS San RaffaeleUniversity, hospital or other
- Study start
- 1 Aug 2026 (estimated)
- Primary completion
- 1 Aug 2028 (estimated)
- Study completion
- 1 Aug 2029 (estimated)
- First posted
- 17 Jun 2026 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
AHEAD is a prospective, longitudinal, risk-stratified single-arm interventional study enrolling 300 patients with Subjective Cognitive Decline (SCD) at IRCCS San Raffaele Hospital, Milan, Italy.
The study uses artificial intelligence (AI) to integrate multimodal data - including MRI, EEG, Optical Coherence Tomography (OCT), neuropsychological assessments, and plasma biomarkers - to identify individuals with underlying Alzheimer's disease (AD) biology and predict cognitive progression.
Only participants found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up at 12 and 24 months. Participants classified as high risk additionally receive a 6-month personalized multidisciplinary intervention combining high-frequency transcranial magnetic stimulation (TMS), digital cognitive training, structured physical exercise, and targeted management of modifiable vascular and behavioral risk factors.
Detailed description
Subjective Cognitive Decline (SCD) refers to the self-perception of worsening cognitive abilities despite normal performance on standardized neuropsychological testing. It affects approximately 10% of the general population and 20-35% of patients attending memory clinics. Although the majority of individuals with SCD do not progress to clinical forms of Alzheimer's disease (AD), they show a higher prevalence of AD-related pathological biomarkers compared with individuals without subjective cognitive complaints, with rates of cognitive decline estimated at approximately 20% per 1,000 person-years in memory clinic patients.
Plasma biomarkers for AD represent minimally invasive and easily accessible diagnostic tools; however, their large-scale implementation in the broad SCD population is neither economically nor ethically sustainable because of costs, the risk of overdiagnosis, and the associated psychological burden. Artificial intelligence (AI) may represent a transformative tool for addressing the complexity of SCD management. By integrating multimodal data including cognitive assessments, MRI, EEG, and OCT, AI may help identify those individuals with SCD most likely to benefit from further diagnostic investigations, including plasma biomarker assessment.
At baseline (T0), all participants undergo a minimum assessment dataset including clinical evaluation, standard neuropsychological assessment, structural MRI, and blood sampling. A subset additionally undergoes a comprehensive risk assessment, extended neuropsychological evaluation including digital cognitive testing and the Preclinical Alzheimer Cognitive Composite (PACC), resting-state EEG, and retinal imaging through Optical Coherence Tomography (OCT).
Only patients found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up visits at 12 months (M12) and 24 months (M24), including clinical evaluation, neuropsychological assessments, and blood sampling to monitor cognitive and biological progression.
Participants stratified as high risk - defined as plasma p-tau217 greater than 0.1325 pg/mL, and/or APOE epsilon4 carrier, and/or elevated CAIDE Dementia Risk Score - enter a 6-month single-arm multidisciplinary intervention comprising: (1) targeted management of modifiable vascular and behavioral risk factors with monthly remote follow-up; (2) high-frequency TMS during the first 4 weeks (2-3 sessions per week); (3) home-based digital cognitive training, 2 sessions per week of 30 minutes each over 5 months; (4) structured physical exercise (walking, cycling, resistance training), 2 sessions per week of 30 minutes each.
A retrospective SCD cohort (rSCD), comprising patients who underwent the minimum assessment dataset within one year prior to enrollment and were found to be AD plasma biomarker positive, undergoes follow-up at M12 and M24 according to the same longitudinal protocol, with the intervention starting at M12.
AI models will integrate multimodal baseline data using machine learning (logistic regression, random forest), deep learning (CNNs for MRI/OCT, RNNs/Transformers for EEG), and survival analysis (Cox proportional hazards, DeepSurv). All models will be validated using k-fold cross-validation with performance metrics including AUC, sensitivity, specificity, balanced accuracy, and positive and negative predictive values.
Study design
- Primary purpose
- Other
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
- Model description
- Prospective, longitudinal, risk-stratified single-arm interventional study. Not all participants receive the intervention: only those classified as high risk based on plasma biomarkers (p-tau217), APOE genotype, and/or cardiovascular risk profile (CAIDE score) receive the 6-month multidisciplinary intervention program.
| Arm | Type | Receives |
|---|---|---|
| SCD Participants | Experimental | Device: High-frequency Transcranial Magnetic Stimulation (TMS), Behavioral: Digital Cognitive Training, Behavioral: Structured Physical Exercise, Other: Management of Modifiable Vascular and Behavioral Risk FactorsAll 300 SCD participants undergo baseline multimodal assessment. Those found to be AD plasma biomarker positive (SCD+) undergo longitudinal follow-up at M12 and M24. Those classified as high risk (plasma p-tau217 greater than 0.1325 pg/mL, and/or APOE epsilon4 carrier, and/or elevated CAIDE Dementia Risk Score) additionally receive a 6-month multidisciplinary personalized intervention combining high-frequency TMS, digital cognitive training, structured physical exercise, and targeted vascular and behavioral risk factor management. |
Who may qualify
- Ages
- 40 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (7 listed)
- Diagnosis of Subjective Cognitive Decline (SCD) according to international diagnostic criteria (Jessen et al., 2014).
- Self-experienced persistent decline in cognitive capacity in comparison with a previously normal status and unrelated to an acute event.
- Normal age-, gender-, and education-adjusted performance on standardized cognitive tests used to classify mild cognitive impairment (MCI) or prodromal AD.
- Age greater than or equal to 40 years.
- Native Italian Speaker.
Key exclusion criteria (10 listed)
- Presence of MCI, prodromal AD, or dementia.
- Any major systemic, psychiatric, or neurological disturbance.
- Medical conditions or substance abuse that could interfere with cognition.
- Pacemaker and/or other implanted neurostimulation devices in the head/neck district.
- Contraindications to undergoing MRI examination.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| High-frequency Transcranial Magnetic Stimulation (TMS)High-frequency repetitive TMS (rTMS) delivered according to an intensive protocol during the first 4 weeks of the intervention period (2-3 sessions per week). Applied to brain regions associated with cognitive function to optimize brain health and reduce risk of cognitive decline. Administered by trained professionals following international safety guidelines (Rossi et al., 2009). | Device | SCD Participants |
| Digital Cognitive TrainingHome-based cognitive training delivered via digital platform over 5 months: 2 sessions per week of 30 minutes each. Targets perceived cognitive deficits and related domains (memory, executive functions, attention, visuospatial abilities, language) with progressive adaptation to individual performance level. Compliance monitored via dedicated applications and/or activity diaries. Monthly remote meetings with neuropsychologists to monitor progress. | Behavioural | SCD Participants |
| Structured Physical ExerciseHome-based structured physical exercise program over 5 months: 2 sessions per week of 30 minutes each. Activities include walking, cycling, and global resistance training. An in-person familiarization session is conducted before program start. Monthly remote meetings with physiotherapists to monitor progress and adapt the program. Compliance remotely monitored via dedicated applications and/or activity diaries. | Behavioural | SCD Participants |
| Management of Modifiable Vascular and Behavioral Risk FactorsPersonalized pharmacological and non-pharmacological interventions targeting modifiable vascular and behavioral risk factors including blood pressure, cholesterol, BMI, physical inactivity, dietary habits, sleep quality, and social isolation. Monthly remote follow-up visits over 6 months to monitor treatment adherence and optimize risk factor control. | Other | SCD Participants |
Primary outcome
Diagnostic accuracy of AI models in identifying AD biomarker-positive SCD subjects (AUC)
Time frame: Baseline (study entry)
Area under the ROC curve (AUC), sensitivity, and specificity of AI models in discriminating between plasma AD biomarker-positive and biomarker-negative SCD subjects, assessed at study entry.
1 secondary outcome
Predictive accuracy of AI models for cognitive progression (AUC)
Time frame: Baseline, 12 months (M12), and 24 months (M24)
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 17 Jun 2026.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Massimo Filippi, Prof principal investigator
IRCCS San Raffaele
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing High-frequency Transcranial Magnetic Stimulation (TMS), Digital Cognitive Training and Structured Physical Exercise in people with Subjective Cognitive Decline and Alzheimer Disease, run by IRCCS San Raffaele at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 7 inclusion and 10 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: opening soon, as of the sponsor's last update on 17 Jun 2026. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Federica FA Agosta, MD (0226433051, agosta.federica@hsr.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Diagnostic accuracy of AI models in identifying AD biomarker-positive SCD subjects (AUC) (time frame: Baseline (study entry)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 17 Jun 2026.