Alzheimer’s: a question of genetic timing?

#Alzheimer #Genetics #Neurology   Alzheimer’s disease is a progressive neurodegenerative disorder responsible for irreversible cognitive decline, linked to abnormal accumulation of amyloid and tau proteins in the brain. While early-onset familial forms are caused by rare genetic mutations, most cases are sporadic, shaped by a complex interplay of genes and environment. Among the key factors, the age at onset of first symptoms plays a central role, directly influencing clinical progression and functional prognosis.   Despite progress in genomics, the genetic determinants that modulate age at onset remain poorly understood, largely because of underrepresentation of non-European ancestries in genetic cohorts, limiting the applicability of findings to diverse populations. In this context, this study set out to identify genetic variants associated with Alzheimer’s age at onset, examining both known loci and novel genomic regions.   Which genes accelerate the clock?
A total of 51,043 patients with Alzheimer’s disease were compared with 660,168 controls, drawn from 13 populations including European, African, Asian, Hispanic, and other ancestries. Data were harmonized across multiple international cohorts using standardized protocols.   Among the 82 loci linked to age at onset, 33 were already known to be associated with Alzheimer’s disease, while 49 were new or specifically modified onset age. Genes such as APOE, BIN1, MS4A6A, and PICALM were confirmed, while novel loci were identified, including near PRPF19 and CTSB, involved in DNA repair, autophagy, and inflammation. Functional analyses suggest that some variants influence the length of the preclinical phase by modulating neuronal resilience or immune responses.   Significant ancestry-specific differences were observed, underscoring the importance of greater genetic diversity to refine risk signatures.   Genetics opens the way to targeted prevention
Alzheimer’s disease remains a multifactorial condition in which age at onset is a critical factor, influenced by complex genetic modifiers. A major challenge is to identify these variants precisely while accounting for ancestry differences, often neglected in past studies.   This study confirms the involvement of known loci while revealing novel regions associated with age at onset, paving the way for early detection and personalized prevention. However, limitations remain, calling for further research: longitudinal analyses, functional validation of identified loci, and integration of multi-omics data (epigenomics, transcriptomics, proteomics). Expanding research to underrepresented populations is also essential to ensure genomic equity. Ultimately, these advances could make it possible to predict age at onset in at-risk individuals and tailor neurocognitive prevention strategies to each genetic profile.