The ADAPTED partners have recently compiled a report on the progress of the project in its first year. Highlights of progress include:
One full set of iPSC lines has been generated. The set consists of 5 lines each edited to express one of the APOE genotypes: APOE ε2/ε2, APOE ε3/ε3, APOE ε3/ε4, APOE ε4/ε4 or knock-out controls. Gene editing to generate another three independent sets of iPSC lines is far advanced.
The extensive QC of the iPSC lines has provided us with new insights into required standards for gene-editing of iPSCs. More genetic variations have been identified than would have been possible with state of the art technology at the start of the project.
An exploration of existing datasets has identified 12 metabolites circulating in the blood which are associated with improved cognitive function and 3 metabolites which are associated with cognitive impairment.
Metabolite analysis revealed that AD patients carrying at least one APOE-ε4 allele showed a dysregulation in fatty acid pathways. This dysregulation is not observed in healthy controls stratified similarly to AD patients.
Harmonisation of the definition of mild cognitive impairment (MCI) across different patient cohorts was investigated. ADAPTED validation studies will use the MCI definition given locally by each cohort as harmonising the definitions was not found to increase statistical power.
ADAPTED validation studies will also use Mini Mental State Examination (MMSE) to evaluate cognitive decline as an analysis of several heterogenous cohorts found this to be the most efficient method.
Data from many publicly available datasets have been curated and integrated into the ADAPTED TranSMART database and are available for APOE stratified questioning.
Initial analysis of these datasets point towards APOE genotype dependent roles of neuroinflammation (but not peripheral inflammation), endosomal and mitochondrial pathways in AD pathophysiology.
The ADAPTED partners are very pleased with the achievements of the project during the first year and are looking forward to building on this progress in the remaining two years.