Overview
Study overview
The study screens a general population to recruit a Trial Ready cohort with 600 participants with pre-symptomatic AD and an auxiliary control cohort with 200 matched controls without AD. The objective is to always have 600 participants in the Trial Ready Cohort (pre-symptomatic AD). Whenever a participant leaves the Trial Ready Cohort, recruitment of a new individuals with pre-symptomatic AD will occur. Reason for leaving the Trial Ready Cohort might be referral to a clinical treatment trial (one aim of the study), progression to symptomatic AD (either minor or major neurocognitive disorder; DSM-5 [see appendix]), and drop-out at follow-up due to death or other causes. With this, the option of continuous recruitment for the Trial Ready Cohort up until study closure can be applied if needed.
Abnormal accumulation of Aβ is defined as abnormal levels in both CSF and PET, and these two measures exhibit a very high agreement11, 12. CSF Aβ42/Aβ40 and Aβ42/P-tau ratios will be analyzed for this purpose using predefined cut offs11, 12. Aβ-PET abnormality will be determined using the standardized centiloid scale13 similar to the AHEAD 3-45 studies (NCT04468659). Based on PET data from our BioFINDER-2 study the current study population with abnormal CSF Aβ42/Aβ40 and Aβ42/P-tau ratios will consist of two subgroups depending on the level om amyloid pathology, where approximately 200 participants will have centiloids between 20-40 (i.e., slightly elevated Aβ levels) and 400 participants will have centiloids above 40 (clearly elevated Aβ levels). The 200 participants with normal CSF ratios will have centiloids < 20.
Trial ready cohort
ENROLLMENT
Participants are recruited by advertisement. A first screening is done using telephone-MoCA, and blood analysis of plasma p-tau and APOE to estimate probability of amyloid depositions in the brain (blood-based risk algorithm). Individuals with unimpaired cognition and elevated risk of being amyloid positive continue in the study. A sample of matched subjects with low risk also continue. Remaining individuals with low risk terminate the enrollment process after blood collection.
Next, participants who continue the enrollment process undergo extensive cognitive testing, and cognitive, psychiatric and neurologic evaluation, followed by lumbar puncture. Everyone with abnormal CSF biomarkers (Aβ42/Aβ40 and Aβ42/p-tau ratios) are finally included in the study until the Trial Ready Cohort reaches 600 participants. A subset of matched controls with normal CSF biomarkers will also be included in the study up to 200 participants. Remaining individuals with normal CSF biomarkers terminate their participation after lumbar puncture.
For enrollment process and selection overview please see below figures below.
INCLUSION & EXCLUSION CRITERIA
| Trail Ready cohort | Control cohort | |
| Number | 600 | 200 |
| Years of follow-up | 4 years | 4 years |
| Inclusion criteria | 1. Age 50-80 | |
| 2. Individuals aged 50-60 require at least one of the following risk factors for AD: | ||
| a. Known APOE-e4 carrier | ||
| b. Known 1st degree family history of dementia or severe memory loss with onset prior to 75 | ||
| c. Known amyloid brain pathology by either CSF or PET scan | ||
| 3. MMSE ≥26 (aged >65); MMSE ≥27 (aged 50-65) | ||
| 4. Speaks and understands Swedish to the extent that an interpreter is not necessary to fully understand the study information and cognitive tests. | ||
| 5. Amyloid pathology according to CSF AD biomarkers and Aβ-PET scans. | 5. No sign of preclinical AD using CSF AD biomarkers or Aβ-PET scans. | |
| Exclusion criteria | 1. Fulfill the criteria for minor or major neurocognitive disorder according to DSM-5. | |
| 2. History of significant brain injury or other known neurologic disease or insult, resulting in lasting cognitive sequelae that would confound the assessment and staging of potential neurodegenerative disease. | ||
| 3. Major depression, bipolar disorder, or recurrent psychotic disorders within the past year. | ||
| 4. History of alcohol and/or substance abuse or dependence within the past year. | ||
| 5. Significant unstable systemic illness or organ failure, such as terminal cancer, that makes it difficult to participate in the study. | ||
| 6. Refusing or unable to complete baseline cognitive and biomarker assessments (i.e., cognitive testing, blood draw, MRI and PET). | ||
FOLLOW-UP FOR 4 YEARS
Every 12 months new clinical, cognitive, neurological, and psychiatric assessments will be performed. CSF/blood sampling, Tau PET, Amyloid PET, and MRI are performed every 2 years.
Participants can decide if they want a Disclosure visit where their Aβ-status is shared (i.e., results from Aβ-PET and CSF Aβ42/Aβ40 and Aβ42/P-tau ratios). Disclosure can take place throughout the study after inclusion and is not limited to a certain time point of the study. Individualized counselling is offered before the participants make the decision regarding disclosure as well as after receiving the information.
Figure Enrollment process
Enrollment process and study follow-up
Figure Enrollment selection
Enrollment selection