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Abstract
Background and Objectives Identifying protein targets that provide cognitive reserve is a strategy to prevent and treat Alzheimer disease and Alzheimer disease related dementias (AD/ADRD). Previous studies using bulk human brain tissue reported 12 proteins associated with cognitive reserve. This study examined whether the same proteins from induced neurons (iNs) are associated with cognitive reserve of their human donors.
Methods Induced pluripotent stem cell (iPSC) lines were generated from cryopreserved peripheral blood mononuclear cells of older adults who were autopsied as part of the Religious Orders Study or Rush Memory and Aging Project. Neurons were induced from iPSCs using a standard neurogenin2 protocol. Tandem mass tag proteomics analyses were conducted on iNs day 21. Cognitive reserve of their human donors was measured as person-specific slopes of cognitive change not accounted for by common neuropathologies.
Results The 53 human donors died at a mean age of 91 years, all were non-Latino White, and 36 (67.9%) were female. Eighteen were diagnosed with Alzheimer dementia proximate to death, and 34 had pathologic AD diagnosis at autopsy. Approximately 60% of the donors had above-average cognitive reserve such that their cognition declined slower than an average person with comparable burdens of neuropathologies. Eight of the 12 candidate proteins were quantified in iNs proteomics analyses. Higher adenylate kinase 4 (AK4) expression in iNs was associated with lower cognitive reserve, consistent with the previous report for brain AK4 expression.
Discussion By replicating cortical protein associations with cognitive reserve in human iNs, these data provide a valuable molecular readout for studying complex clinical phenotypes such as cognitive reserve in a dish.
Glossary
- Aβ=
- β-amyloid;
- AD=
- Alzheimer disease;
- AD/ADRD=
- Alzheimer disease and Alzheimer disease related dementias;
- AK4=
- adenylate kinase 4;
- iN=
- induced neuron;
- iPSC=
- induced pluripotent stem cell;
- LATE=
- limbic predominant age-related TDP-43 encephalopathy;
- MCI=
- mild cognitive impairment;
- NCI=
- no cognitive impairment;
- PBMC=
- peripheral blood mononuclear cell;
- PHFtau=
- paired helical filament tau;
- PRS=
- polygenic risk score;
- ROSMAP=
- Religious Orders Study or Rush Memory and Aging Project;
- SH3GL1=
- endophilin-A2
Footnotes
Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Submitted and externally peer reviewed. The handling editor was Linda Hershey, MD, PhD, FAAN.
- Received March 1, 2022.
- Accepted in final form July 1, 2022.
- © 2022 American Academy of Neurology
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