Lessons from genetic studies in Alzheimer disease

Area of Science:

• Neurogenetics
• Alzheimer's Disease Pathophysiology
• Complex Trait Genetics

Background:

• Alzheimer disease (AD) genetics research has significantly advanced understanding of its complex pathophysiological mechanisms.
• AD etiology is categorized into monogenic (autosomal dominant) and complex (multifactorial) forms.
• Genetic factors in complex AD include APOE alleles, common variants from GWAS, and rare variants from sequencing studies.

Purpose of the Study:

• To review recent advances in Alzheimer disease genetics, encompassing both monogenic and complex forms.
• To highlight the impact of various genetic factors, including APOE, GWAS-identified loci, and rare variants, on AD risk.
• To discuss the implications of these genetic findings for AD risk prediction and prevention.

Main Methods:

• Review of current research on Alzheimer disease genetics.
• Analysis of genetic factors including mutations, common alleles (APOE), genome-wide association studies (GWAS), and rare variants.
• Examination of penetrance curves and oligogenic inheritance models.

Main Results:

• Novel genetic loci discovered through larger GWAS have doubled previously identified hits.
• Rare variants in genes such as TREM2, SORL1, ABCA7, ABCA1, and ATP8B4 contribute to AD risk, suggesting oligogenic inheritance in some cases.
• APOE alleles (ɛ4, ɛ2) have a strong impact on AD risk, with ongoing efforts to refine penetrance curves across diverse ethnicities.

Conclusions:

• Most genetic determinants of AD, across both monogenic and complex forms, implicate amyloid-beta (Aβ) aggregation as a pivotal factor.
• Targeting Aβ aggregation may offer an efficient preventive strategy for individuals at risk of AD.
• Further research into neuroinflammation, microglia, and Tau pathology is essential for disease modification.