2025-03-13
Genes and Alzheimer’s: the key to the mystery?
Psychiatry
#Alzheimer #Genetics #Neurodegeneration #PrecisionMedicine #GWAS #MultiAncestral
Alzheimer’s disease (AD) is the most common form of dementia, affecting millions worldwide. It is characterized by a progressive decline in cognitive functions, impacting memory, language, and spatial orientation. While environmental factors and lifestyle contribute to its onset, genetics play a crucial role in disease predisposition. It is estimated that 70% to 80% of the risk of developing AD is hereditary, highlighting the importance of identifying the genes involved to better understand the pathology and develop targeted therapeutic approaches.
Genome-wide association studies (GWAS), which detect genetic variations linked to AD, have so far been predominantly conducted on populations of European ancestry. This limitation presents several challenges: some genetic markers are prioritized, while variants potentially specific to other ethnic groups remain overlooked. AD incidence and clinical manifestations can vary across populations, suggesting different genetic influences.
The underrepresentation of non-European populations prevents a comprehensive understanding of genetic risk factors and hinders the development of screening and treatment strategies tailored to all patients. An incomplete genetic picture of AD reduces researchers’ ability to develop reliable biomarkers and effective personalized treatments for diverse communities. Addressing these challenges requires integrating more diverse cohorts into genetic research to identify universal and population-specific therapeutic targets.
Four major international cohorts (NIAGADS, NIMH, UK Biobank, and All of Us), including a total of 49,149 cases of Alzheimer’s disease (AD), were selected. Among them, 12,074 patients were clinically diagnosed, and 37,075 were identified through family proxy reports. A total of 383,225 patients were selected as controls.
Through whole-genome sequencing (WGS), researchers studied the influence of genetic diversity on Alzheimer’s disease risk, incorporating underrepresented populations from previous studies.
In this study, 16 new loci were associated with AD. Fourteen were identified in clinically diagnosed patients (five common variants and nine rare variants), and two were detected only in proxy cases. These loci play a key role in essential biological functions such as neuroplasticity, neuronal communication, and inflammatory response. Their involvement suggests a direct link with the underlying mechanisms of Alzheimer’s disease.
A low overlap was observed between loci associated with clinically diagnosed cases and those identified in proxy cases. This discrepancy suggests that family history alone is not a reliable indicator of genetic mechanisms, especially in genetically diverse populations. These findings emphasize the need to refine genetic classification criteria and conduct further research on hereditary mechanisms in AD through more inclusive population-based analyses.
Alzheimer’s disease is a neurodegenerative disorder where genetics plays a critical role in individual risk. Identifying these genetic factors is essential for improving diagnosis, prevention, and treatment strategies. However, a major challenge remains—the lack of diversity in genetic studies, which overwhelmingly focus on European populations. This underrepresentation limits the understanding of risk factors and slows down the development of treatments for all individuals.
This study explores the impact of genetic diversity on AD risk, conducting a large-scale multi-ancestral genome-wide analysis. The findings identified 16 novel AD-associated loci, providing new insights into the disease’s underlying mechanisms. These discoveries reinforce the importance of a more inclusive genetic approach to refine prevention and treatment strategies.
Despite its strengths, the study presents some limitations, including data heterogeneity and the difficulty of validating certain loci across different cohorts. Additionally, the differences between clinically diagnosed cases and proxy cases highlight the need to refine AD’s genetic criteria. Moving forward, integrating whole-genome sequencing could enhance early diagnosis and pave the way for personalized treatments. Expanding cohorts and improving genetic models will be essential to translate these discoveries into clinical applications.
Alzheimer’s disease (AD) is the most common form of dementia, affecting millions worldwide. It is characterized by a progressive decline in cognitive functions, impacting memory, language, and spatial orientation. While environmental factors and lifestyle contribute to its onset, genetics play a crucial role in disease predisposition. It is estimated that 70% to 80% of the risk of developing AD is hereditary, highlighting the importance of identifying the genes involved to better understand the pathology and develop targeted therapeutic approaches.
Genome-wide association studies (GWAS), which detect genetic variations linked to AD, have so far been predominantly conducted on populations of European ancestry. This limitation presents several challenges: some genetic markers are prioritized, while variants potentially specific to other ethnic groups remain overlooked. AD incidence and clinical manifestations can vary across populations, suggesting different genetic influences.
The underrepresentation of non-European populations prevents a comprehensive understanding of genetic risk factors and hinders the development of screening and treatment strategies tailored to all patients. An incomplete genetic picture of AD reduces researchers’ ability to develop reliable biomarkers and effective personalized treatments for diverse communities. Addressing these challenges requires integrating more diverse cohorts into genetic research to identify universal and population-specific therapeutic targets.
Alzheimer’s disease: are new clues hidden in our genes?
Four major international cohorts (NIAGADS, NIMH, UK Biobank, and All of Us), including a total of 49,149 cases of Alzheimer’s disease (AD), were selected. Among them, 12,074 patients were clinically diagnosed, and 37,075 were identified through family proxy reports. A total of 383,225 patients were selected as controls.
Through whole-genome sequencing (WGS), researchers studied the influence of genetic diversity on Alzheimer’s disease risk, incorporating underrepresented populations from previous studies.
In this study, 16 new loci were associated with AD. Fourteen were identified in clinically diagnosed patients (five common variants and nine rare variants), and two were detected only in proxy cases. These loci play a key role in essential biological functions such as neuroplasticity, neuronal communication, and inflammatory response. Their involvement suggests a direct link with the underlying mechanisms of Alzheimer’s disease.
A low overlap was observed between loci associated with clinically diagnosed cases and those identified in proxy cases. This discrepancy suggests that family history alone is not a reliable indicator of genetic mechanisms, especially in genetically diverse populations. These findings emphasize the need to refine genetic classification criteria and conduct further research on hereditary mechanisms in AD through more inclusive population-based analyses.
Read next: Alzheimer’s Disease: The Amyloid Hypothesis Is Not the Only Factor
A future without Alzheimer’s thanks to genetics?
Alzheimer’s disease is a neurodegenerative disorder where genetics plays a critical role in individual risk. Identifying these genetic factors is essential for improving diagnosis, prevention, and treatment strategies. However, a major challenge remains—the lack of diversity in genetic studies, which overwhelmingly focus on European populations. This underrepresentation limits the understanding of risk factors and slows down the development of treatments for all individuals.
This study explores the impact of genetic diversity on AD risk, conducting a large-scale multi-ancestral genome-wide analysis. The findings identified 16 novel AD-associated loci, providing new insights into the disease’s underlying mechanisms. These discoveries reinforce the importance of a more inclusive genetic approach to refine prevention and treatment strategies.
Despite its strengths, the study presents some limitations, including data heterogeneity and the difficulty of validating certain loci across different cohorts. Additionally, the differences between clinically diagnosed cases and proxy cases highlight the need to refine AD’s genetic criteria. Moving forward, integrating whole-genome sequencing could enhance early diagnosis and pave the way for personalized treatments. Expanding cohorts and improving genetic models will be essential to translate these discoveries into clinical applications.
Read next: Predicting Amyloid: AI for Early Detection
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