Trial Outcomes & Findings for The Synapse Project (NCT NCT04871074)

Last Updated: 2025-08-12

Results Overview

DeLong's method will test whether the MTL UCB-J receiver-operator characteristic (ROC) area under the curve (AUC) has better mild cognitive impairment/probable AD dementia (MCI/AD) prediction accuracy than the hippocampal volume ROC AUC. ROC AUC is a measure of the correctness of group (where group is MCI/AD and cognitively unimpaired) classification using a continuous predictor, in this case, the medial temporal lobe UCB-J uptake (11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density). This ROC AUC was compared to that of the comparator continuous predictor, hippocampal volume.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

100 participants

Primary outcome timeframe

Baseline

Results posted on

2025-08-12

Participant Flow

The intent of the study was observational, to characterize synaptic density across disease stages, the groups shown in the Baseline Characteristic Section are non-randomized subgroups within a single study arm.

Participant milestones

Participant milestones
Measure	Cognitively Impaired Plus Cognitive Unimpaired Participants Participants include both cognitively impaired and unimpaired populations to populate a single model to examine variables within the group as a whole. * Cognitively impaired participants have abnormal cognitive status of MCI or dementia as judged by consensus or expert review using National Institute of Aging and Alzheimer's Association (NIA-AA) 2018 criteria. * Cognitively unimpaired participants: results of most recent testing with the source cohort indicate the participant is cognitively unimpaired as judged by consensus or expert review.
Overall Study STARTED	100
Overall Study Cognitively Unimpaired Subgroup	65
Overall Study Cognitively Impaired Subgroup	35
Overall Study COMPLETED	100
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Not applicable to this group

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Cognitively Unimpaired n=65 Participants Results of most recent testing with the source cohort indicate the participant is cognitively unimpaired as judged by consensus or expert review.	Cognitively Impaired n=35 Participants Abnormal cognitive status of MCI and Dementia as judged by consensus or expert review using National Institute of Aging and Alzheimer's Association (NIA-AA) 2018 criteria.	Total n=100 Participants Total of all reporting groups
Age, Continuous	68.9 years n=65 Participants	75.2 years n=35 Participants	71.1 years n=100 Participants
Sex: Female, Male Female	45 Participants n=65 Participants	11 Participants n=35 Participants	56 Participants n=100 Participants
Sex: Female, Male Male	20 Participants n=65 Participants	24 Participants n=35 Participants	44 Participants n=100 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	65 Participants n=65 Participants	35 Participants n=35 Participants	100 Participants n=100 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Race (NIH/OMB) American Indian or Alaska Native	4 Participants n=65 Participants	1 Participants n=35 Participants	5 Participants n=100 Participants
Race (NIH/OMB) Asian	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Race (NIH/OMB) Black or African American	7 Participants n=65 Participants	3 Participants n=35 Participants	10 Participants n=100 Participants
Race (NIH/OMB) White	54 Participants n=65 Participants	31 Participants n=35 Participants	85 Participants n=100 Participants
Race (NIH/OMB) More than one race	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=65 Participants	0 Participants n=35 Participants	0 Participants n=100 Participants
Region of Enrollment United States	65 participants n=65 Participants	35 participants n=35 Participants	100 participants n=100 Participants
Cognitive Impairment Mild Cognitive Impairment	0 Participants Not applicable to this group	22 Participants n=35 Participants • Not applicable to this group	22 Participants n=35 Participants • Not applicable to this group
Cognitive Impairment Mild Dementia	0 Participants Not applicable to this group	13 Participants n=35 Participants • Not applicable to this group	13 Participants n=35 Participants • Not applicable to this group

PRIMARY outcome

Timeframe: Baseline

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=100 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume n=100 Participants Hippocampal volume across all participants
ROC AUCs (MCI/AD vs Cognitively Unimpaired (CU)) for Medial Temporal Lobe (MTL) UCB-J Distribution Volume Ratio (DVR) and Hippocampal Volume	0.79 probability Interval 0.68 to 0.89	0.81 probability Interval 0.71 to 0.91

PRIMARY outcome

Timeframe: Baseline

Population: Usable data on 79 participants (due to processing)

DeLong's method will test whether the MTL UCB-J ROC AUC has better MCI/AD prediction accuracy than the hippocampal cingulum neurite density index ROC AUC. ROC AUC is a measure of the correctness of group (where group is MCI/AD and cognitively unimpaired) classification using a continuous predictor, in this case, the medial temporal lobe UCB-J uptake (11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density). This ROC AUC was compared to that of the comparator continuous predictor, hippocampal cingulum neurite density index.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=79 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume n=79 Participants Hippocampal volume across all participants
ROC AUCs (MCI/AD vs CU) for MTL UCB-J and Hippocampal Cingulum Neurite Density Index	0.82 probability Interval 0.71 to 0.93	0.79 probability Interval 0.69 to 0.89

PRIMARY outcome

Timeframe: Baseline and 2 years

Population: N = 25 contributing to the time estimate

Linear mixed effects regression will model UCB-J distribution volume ratio (DVR) as a function of time since baseline. 11C-UCB-J is a PET tracer for imaging the synaptic vesicle glycoprotein 2A in the human brain. It is considered a measure of synaptic density. Participants' synaptic density was examined as a change per year. A positive number would mean an increase in synaptic density, a negative number means a decrease.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=100 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume Hippocampal volume across all participants
Annual Rate of Change in UCB-J DVR	-.01 distribution volume ratio per year Interval -0.02 to 0.0	—

PRIMARY outcome

Timeframe: baseline and 2 years

Population: While 100 participants were enrolled in the study and entered into the model, 25 participants were measured at follow up and contributed to the time estimate; among those 25, 7 cognitively impaired and 18 unimpaired.

Baseline diagnosis (CU vs MCI/probable AD dementia) group differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Participants' synaptic density was examined as a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that impaired participants decreased in synaptic density more quickly and a positive number would mean that the impaired participants decreased less quickly.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=65 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume n=35 Participants Hippocampal volume across all participants
Baseline Diagnosis Group Differences in Annual Rate of Change in UCB-J DVR	0 distribution volume ratio per year Interval -0.02 to 0.01	-.02 distribution volume ratio per year Interval -0.04 to 0.0

PRIMARY outcome

Timeframe: baseline and 2 years

Population: 90 people contributed to the overall model, 24 participants contributed to the time estimate; 3 Amyloid positive, 21 Amyloid negative, centiloid values for amyloid scans unavailable for 10 participants (unable to process)

Amyloid positivity status differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Amyloid positivity status will be determined from amyloid PET. Participants' synaptic density was examined in a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that amyloid positive participants decreased in synaptic density more quickly and a positive number would mean that the amyloid positive participants decreased less quickly.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=43 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume n=47 Participants Hippocampal volume across all participants
Amyloid Positivity Status Differences in Annual Rate of Change in UCB-J DVR	-.02 distribution volume ratio per year Interval -0.05 to 0.01	-.01 distribution volume ratio per year Interval -0.02 to 0.0

PRIMARY outcome

Timeframe: baseline and 2 years

Population: While 94 participants were included in the model, 24 participants contributed to the time estimate; 1 Tau positive, 23 Tau negative, tau status unavailable for 6 participants, no data available for Tau scan.

Tau positivity status differences in rate of UCB-J DVR change will be estimated via group x time interaction term in a linear mixed effects model. Tau positivity status will be determined from tau PET. Participants' synaptic density was examined as a change per year. The difference in the rate of change in the two groups was estimated. A negative number means that tau positive participants decreased in synaptic density more quickly and a positive number would mean that the tau positive participants decreased less quickly.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=38 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume n=56 Participants Hippocampal volume across all participants
Tau Positivity Status Differences in Annual Rate of Change in UCB-J DVR	-.02 distribution volume ratio per year Interval -0.08 to 0.04	-.01 distribution volume ratio per year Interval -0.02 to 0.0

PRIMARY outcome

Timeframe: baseline and 2 years

Linear mixed effects will be used to model cognitively unimpaired participants' memory performance as a function of their age and synaptic density. Specifically, investigators will test whether those with higher synaptic density had less deterioration over time. Memory performance will be assessed using Rey Auditory Verbal Learning Test Delayed Recall. An interaction was tested, and a negative number means that those with higher synaptic density decreased faster over time, and a positive number means that they decreased slower over time.

Outcome measures

Outcome measures
Measure	Medial Temporal Lobe UCB-J n=65 Participants Synaptic density in the Medial Temporal Lobe across all participants	Hippocampal Volume Hippocampal volume across all participants
MTL UCB-J DVR Baseline Differences in a Cognitive Performance Age Slope in Non-demented Participants	-.05 diff in rate of change AVLT per year Interval -0.17 to 0.07	—

Adverse Events

Cognitively Unimpaired

Serious events: 0 serious events

Other events: 21 other events

Deaths: 0 deaths

Cognitively Impaired

Serious events: 0 serious events

Other events: 5 other events

Deaths: 3 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Additional Information

Barbara Bendlin, PhD, MA

UW School of Medicine and Public Health

Phone: (608) 265-2483

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	Cognitively Unimpaired n=65 participants at risk Results of most recent testing with the source cohort indicate the participant is cognitively unimpaired as judged by consensus or expert review.	Cognitively Impaired n=35 participants at risk Abnormal cognitive status of MCI or dementia as judged by consensus or expert review using National Institute of Aging and Alzheimer's Association (NIA-AA) 2018 criteria.
Eye disorders Transient Visual Disturbance	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Musculoskeletal and connective tissue disorders Pain in Extremity	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Nervous system disorders Memory Impairment	0.00% 0/65 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Psychiatric disorders Brain Fog	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Renal and urinary disorders Urinary Urgency	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Respiratory, thoracic and mediastinal disorders Cough	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Skin and subcutaneous tissue disorders Scab on Back of Head	0.00% 0/65 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Vascular disorders Hypertension	4.6% 3/65 • Number of events 3 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Nervous system disorders Dysgeusia	3.1% 2/65 • Number of events 2 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Psychiatric disorders Anxiety	0.00% 0/65 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Nervous system disorders Headache	10.8% 7/65 • Number of events 10 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 2 • data collected during study contact, up to 2 years on study
General disorders Pain	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Nervous system disorders Paresthesia	4.6% 3/65 • Number of events 3 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Musculoskeletal and connective tissue disorders Back Pain	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
General disorders Malaise	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Musculoskeletal and connective tissue disorders Muscle Cramp	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Nervous system disorders "Fizzies" in both legs	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Nervous system disorders Presyncopy	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Musculoskeletal and connective tissue disorders Myalgia	1.5% 1/65 • Number of events 2 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Skin and subcutaneous tissue disorders Scalp Pain	0.00% 0/65 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
General disorders Chills	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	2.9% 1/35 • Number of events 1 • data collected during study contact, up to 2 years on study
Musculoskeletal and connective tissue disorders Arthritis	1.5% 1/65 • Number of events 2 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
General disorders Coolness	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Psychiatric disorders Confusion and Headache	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
General disorders Non-cardiac chest pain	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
Psychiatric disorders Insomnia	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study
General disorders Anosmia	1.5% 1/65 • Number of events 1 • data collected during study contact, up to 2 years on study	0.00% 0/35 • data collected during study contact, up to 2 years on study