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

Abstract

Purpose of Review 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. Recent Findings 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. Summary 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.

Radiomic Features of the Hippocampus for Diagnosing Early-Onset and Late-Onset Alzheimer’s Disease

“…AD is clinically classified into early-onset AD (EOAD) and late-onset AD (LOAD) based on the age of symptom onset (Tellechea et al, 2018). A recent study has suggested considerable differences between EOAD and LOAD in etiological and clinical heterogeneity (Ayodele et al, 2021). Compared with LOAD patients, EOAD patients exhibit more aggressive disease progression and an atypical presentation of preserved memory function but focal cortical symptoms such as language, visuospatial, and executive dysfunction (Cacace et al, 2016).…”

Brain transcriptomes of zebrafish and mouse Alzheimer's disease knock-in models imply early disrupted energy metabolism

“…AD has a strong genetic basis (reviewed by Sims et al, 2020 ). In some rare cases, early-onset familial forms of AD (EOFAD, occurring before 65 years of age) arise due to dominant mutations in one of four genes: presenilin 1 ( PSEN1 ), presenilin 2 ( PSEN2 ), amyloid β precursor protein ( APP ) and sortilin-related receptor 1 ( SORL1 ) (reviewed by Barthelson et al, 2020a ; Bertram and Tanzi, 2012 ; Ayodele et al, 2021 ). However, most AD cases are sporadic, showing symptom onset after the arbitrarily defined threshold of 65 years (late-onset sporadic AD, LOAD).…”

Triggering Innate Immune Receptors as New Therapies in Alzheimer’s Disease and Multiple Sclerosis

“…The other AD form is (2) early onset AD (EOAD), which is rarer but more aggressive [39]. EOAD is triggered by the mutation of genes involved in amyloid protein precursor (APP) or enzymes responsible for the cleavage of APP, namely PSEN1 and 2 [25].…”