Age-equivalent neurons from MCI patients to investigate early determinants of AD

SUMMARY Alzheimer's disease (AD) affects over 50 million people worldwide. In the vast majority of patients, AD develops sporadically in the absence of any known etiology other than advanced age and is further influenced by a plethora of etiological mechanisms. Old age stands out as the most important risk factor for the

development of AD in most cases. The first pathological events leading to mild cognitive impairment (MCI) start many years before the onset of symptoms. Identification of the mechanisms that cause MCI, and those that trigger the conversion of MCI to AD, are of major interest, as they promise strong therapeutic benefit via halting

or slowing disease progression. However, a much better understanding of how the multiple heterogenous risk factors for MCI/AD, which include polygenic risk variants and biological aging, converge on key molecular pathways that initiate and drive MCI are needed. The teams around Dr. Mertens have established that direct conversion of human patient fibroblasts into

induced neurons (iNs) preserves signatures of cell aging and sporadic AD, and allows for the detection of cellular pathologies and disease drivers. Patient-derived iNs reflect an adult-like neuronal identity, and they stand out as a unique and complementary model system to animal and iPSC-based models to study the age-

dependent pathogenesis of MCI/AD. Importantly, patient-specific iNs capture the strongest risk factors, the genetic makeup and the biological age, of a patient at a given stage, and we here harness MCI patient iNs as a disease stage-specific model system to investigate the early trajectory of MCI/AD in human neurons.

Preliminary evidence indicates marked MCI-related signatures in iNs that intersect with the transcriptomic, epigenetic, and metabolic signatures of accelerated aging, and partially overlap with signatures of AD iNs. This project will integrate polygenetic risk scores for AD with deep and unbiased multi-omic

phenotyping, and will assess effects of impaired MCI neurons on human astrocytes and microglia in 3D microcarrier-based co-cultures. The teams will further assess how the underlying epigenetic landscapes and DNA binding patterns of disease factors associate with age acceleration and MCI neuronal phenotypes, and will

provide a deep functional characterization of the cells. The goal is to better understand early MCI/AD disease ethology, and to exploit the comprehensive multi-layered information emerging from this project for new treatment strategies.