Early-Onset Alzheimer's Disease: What Is Missing in Research?

Early-onset Alzheimer's disease (EOAD), defined as Alzheimer's disease (AD) occurring before age 65, is significantly less well studied than the late-onset form (LOAD) despite EOAD often presenting with a more aggressive disease progression. The aim of this review is to summarize the current understanding of the etiology of EOAD, their translation into clinical practice, and to suggest steps to be taken to move our understanding forward. EOAD cases make up 5-10% of AD cases but only 10-15% of these cases show known mutations in the APP, PSEN1, and PSEN2, which are linked to EOAD. New data suggests that these unexplained cases following a non-Mendelian pattern of inheritance is potentially caused by a mix of common and newly discovered rare variants. However, only a fraction of this genetic variation has been identified to date leaving the molecular mechanisms underlying this type of AD and their association with clinical, biomarker, and neuropathological changes unclear. While great advancements have been made in characterizing EOAD, much work is needed to disentangle the molecular mechanisms underlying this type of AD and to identify putative targets for more precise disease screening, diagnosis, prevention, and treatment.