Primary prevention in Alzheimer disease: prediction of conversion to amyloid positivity in cognitively unimpaired elderly cohorts
Description: Background. The report of the beneficial effect of lecanemab in cases with very mild Alzheimer disease (AD) published in January 2023 represents the first success of curative treatments against this debilitating disorder. However, the clinical improvement remains modest pointing to the need for early interventions in asymptomatic cases. Performing primary prevention trials needs, however, an accurate identification of the conversion to amyloid positivity in cognitively unimpaired cases. Specific aims and working hypotheses. We plan to perform a 4-year prospective study based on our access to community and memory clinic cohorts and prospective recruitment of cognitively preserved elderly individuals free or with subthreshold amyloid deposition. According to our power analysis, 200 cases at the end of the study would be sufficient to test the following working hypotheses: a. AD process early lesion-related biomarkers (baseline centiloid values and regional patterns of distribution and combination of plasma p-tau, NfL or GFAP values at baseline) are independent predictors of the transition to subthreshold status (SS) and amyloid positivity (AP); b. Functional hyperconnectivity in AD-signature areas predict amyloid accumulation; c. Subtle changes in cognitive performances as well as personality dimensions at baseline (higher levels of Agreeableness and Consciousness, lower Openness) favor the transition to SS and AP; d. Regression models integrating these predictors provide high accuracy in the detection of future transition to amyloid positivity. Experimental design. We have access to two cohorts including healthy elders with no or subthreshold amyloid deposition as documented by mean centiloid values lower than 6 or between 6 and 22. The first cohort (Geneva Healthy Aging Cohort, GHAC) includes 139 cases with a first amyloid PET and MRI documentation within a mean period of 2.7 years prior to inclusion (mean age: 78 years). The second cohort (Memory Clinic Cohort, MCC) includes 100 amyloid with a first amyloid PET and MRI/fMRI scans within a mean period of 2 years prior to inclusion (mean age: 72 years). All of the cases had a detailed cognitive assessment made within a maximum of 2 years prior to inclusion. New prospectively recruited cases (NR) of cognitively unimpaired individuals (with an expected 75% of amyloid negative cases, > 70 years) will be also considered. At inclusion (T0), the cognitive evolution of GHAC and MHC cases will be assessed with comparison to the last available evaluation. In addition, plasma AD-related early biomarkers (plasma Aß42/40, p-tau 181, 217 and 231, plasma NfL and GFAP) and NEO-PI personality assessment will be obtained (when non already available at a maximum of 1 year prior to inclusion). NR cases will be also assessed with the same neuropsychological battery and will undergo a 3T multimodal MRI scan, diffusion MRI connectometry and resting state functional connectivity data, plasma AD-related early biomarkers (Aß42/40, p-tau 181, 217 and 231, NfL and GFAP) and NEO-PI personality assessment. At 18 months post-inclusion (T1), subtle changes in their cognitive performances will be evaluated. A new18F-Flumetamol amyloid PET scan will be performed in all of the cases between 18 and 45 months post-inclusion. Mean centiloid values as well as transition to SS and AP status will be used as the dependent variable in mixed linear regression models. The main independent predictors will be AD process biomarkers (baseline centiloid and regional patterns of distribution, increased plasma p-tau 231, NfL or GFAP values at baseline), fMRI markers of functional compensation, NEO-PI patterns, and presence of subtle neuropsychological decrement. Significance of the project. This project has the potential to bring decisive pieces of evidences in the definition of the algorithm that will allow to define the best candidates for anti-amyloid primary prevention during the critical therapeutic window of conversion to amyloid positivity.
Amount: CHF 731,200
Funding type: research
Funder scheme: Project funding
Start date: 2024-02-01
End date: 2028-01-31
Investigator: Giannakopoulos, Panteleimon
Institution: University of Geneva – GE
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Funded outputs count: 0
Funder award ID: 219546
OpenAlex ID: G1105553017