Genetic Contributions to Alzheimer's Disease

Alzheimer’s disease (AD) arises from a complex interplay between genetic and environmental factors. Rare, highly penetrant mutations in amyloid precursor protein (APP) and presenilin genes (PSEN1, PSEN2) underlie autosomal dominant early-onset forms, accounting for a small proportion of familial cases. In contrast, late-onset AD is influenced by a combination of common alleles—most notably APOE ε4—and numerous low-frequency variants identified through genome-wide association studies. Recent evidence also points to somatic mutations and mosaicism in brain-resident cells, particularly microglia, contributing to neuroinflammatory cascades. Across populations, rare coding variants in genes linked to lipid metabolism, immune response and endosomal trafficking broaden the heritable architecture of AD. This expanding genetic landscape informs risk stratification, highlights convergent pathogenic pathways such as amyloidogenic processing and tau phosphorylation, and underpins the development of targeted diagnostics and precision therapies.

Research from Nature Portfolio

A foundational study employing targeted next-generation sequencing of over 50 neurodegeneration-associated genes in early-onset AD cohorts revealed both known pathogenic mutations in PSEN1 and PSEN2 and novel missense variants in susceptibility genes. By extending analysis beyond classic APP and presenilin loci to include genes implicated in frontotemporal dementia and prion disease, the work has underscored genetic pleiotropy and the necessity of comprehensive gene panels in clinical screening. These data also highlighted rare variants in inflammatory and cholesterol-transport pathways, suggesting overlapping mechanisms across neurodegenerative disorders and refining candidate genes for functional follow-up.

Genetic Contributions to Alzheimer's Disease publication trend

The graph below shows the total number of articles in genetic contributions to alzheimer's disease across all publications each year (not limited to Nature Index journals).

Technical terms

Rare variant: A genetic alteration occurring at low frequency in the population, often with higher effect size on disease risk.

Amyloid precursor protein (APP): A membrane protein whose aberrant cleavage generates amyloid-β peptides that accumulate in AD brains.

Presenilin (PSEN1/PSEN2): Catalytic subunits of the γ-secretase complex responsible for processing APP and other substrates.

Next-generation sequencing: High-throughput DNA sequencing technologies that enable rapid analysis of multiple genes or entire genomes.

Palmitoylation: A reversible lipid modification of proteins that regulates their membrane association and functional activity.

Cerebral amyloid angiopathy (CAA): Deposition of amyloid-β in cerebral blood vessel walls, leading to vessel fragility and haemorrhage.

References

1. Aberrant palmitoylation caused by a ZDHHC21 mutation contributes to pathophysiology of Alzheimer’s disease. BMC Medicine (2023).
2. Phenotype and imaging features associated with APP duplications. Alzheimer's Research & Therapy (2023).
3. A microglia clonal inflammatory disorder in Alzheimer’s disease. eLife (2025).
4. Genetic analyses of early-onset Alzheimer’s disease using next generation sequencing. Scientific Reports (2019).
5. The genetic architecture of Alzheimer's disease: beyond APP, PSENs and APOE. Neurobiology of Aging (2010).