Identifying the earliest-occurring clinically targetable precursors of late-onset Alzheimer's disease

Abstract

Most cases of Alzheimer's disease (AD) are late-onset dementias (LOAD). However, research on AD is predominantly of early-onset disease (EOAD). The determinants of EOAD, gene variants of APP and presenilin proteins, are not the basic precursors of LOAD. Rather, multiple other genes and associated cellular processes underlie risk for LOAD. These determinants could be modified in individuals at risk for LOAD well before signs and symptoms appear. Studying brain cells produced from patient-derived induced-pluripotent-stem-cells (iPSC), in culture, will be instrumental in developing such interventions. This paper summarises evidence accrued from iPSC culture models identifying the earliest occurring clinically targetable determinants of LOAD. Results obtained and replicated, thus far, suggest that abnormalities of bioenergetics, lipid metabolism, digestive organelle function and inflammatory activity are primary processes underlying LOAD. The application of cell culture platforms will become increasingly important in research and also on LOAD detection, assessment, and treatment in the years ahead.

Keywords: Induced-pluripotent-stem cells; Inherent determinants; Late-onset Alzheimer's disease; Prevention.

Fig. 1

Interrelations of core factors underlying risk and development of LOAD. Schematic of very early appearing abnormalities associated with LOAD. These factors were all reported in studies of iPSC-derived cells from patients with LOAD. Genetic variants underlie these abnormalities, with multiple gene products likely determining each factor. Membranous organelles, mitochondria and autophagosomes, are placed centrally because of their connections with other cellular elements. Arrows indicate production or processes. Red indicates abnormalities observed in the LOAD-associated cells. The blue lightning-bolt arrow indicates that the APOE protein binds and transports lipids. (APOE has other interactions not shown here.) Toxic proteins, such as Aβ and hpTau, are not only produced by abnormal processes associated with LOAD, they also feedback and interact with these same processes, interfering in multiple ways with cell membranes and core functions. Ca⁺⁺ storage and release from mitochondria is shown, but Ca⁺⁺ is also stored and released from other sites. Abnormalities of cell signalling, cycle, growth, and morphology seen in cells derived from patients with LOAD, are higher level anomalies that may largely be a consequence of dysfunctions of the elements shown. External elements are also involved. For example, diet would feed into the model through glucose and lipids, in addition to providing other metabolic precursors. Exercise is known to alter gene expression and resulting cellular metabolism.