Genetic Risk Factors in Alzheimer's Disease

Alzheimer’s disease is a complex neurodegenerative disorder with a substantial genetic component that contributes to individual susceptibility, age at onset and rate of progression. Early-onset cases often involve highly penetrant mutations in APP, PSEN1 or PSEN2, whereas late-onset Alzheimer’s disease is driven by a multifactorial architecture encompassing common and rare variants. The ε4 allele of APOE remains the strongest genetic risk factor for sporadic disease, yet genome-wide association studies have identified over 75 loci implicating diverse biological pathways including amyloid precursor protein processing, tau phosphorylation, lipid metabolism, innate immunity and synaptic function. Rare coding variants in genes such as ABCA7, TREM2 and SORL1 further highlight the contribution of microglial activation and endolysosomal trafficking to pathogenesis. Polygenic risk scores that aggregate the effects of multiple single-nucleotide polymorphisms can stratify individuals by lifetime risk and inform selection for clinical trials. Integrative analyses using endophenotypes—such as cerebrospinal fluid biomarkers, neuroimaging measures and cognitive trajectories—are refining our mechanistic understanding and opening avenues for precision medicine interventions around amyloid-β, tau and neuroinflammation.

Research from Nature Portfolio

Recent studies have developed cell-type-specific polygenic risk scores that localise genetic susceptibility to astrocytes and microglia. Analyses in post-mortem and neuroimaging cohorts demonstrate that astrocytic risk alleles predominantly associate with amyloid-β plaque burden, while microglial risk alleles drive tau pathology, neuritic plaques and microglial activation even during preclinical stages. This work provides direct genetic evidence that distinct glial populations contribute to separate facets of Alzheimer’s pathophysiology.

Large-scale genome-wide association efforts involving over 100,000 cases and several hundred thousand controls have expanded the catalogue of risk loci to more than 75, nearly half of which were newly discovered. Pathway enrichment confirms key roles for amyloid and tau cascades, and highlights microglial-mediated processes, including the tumour necrosis factor alpha pathway. An updated polygenic risk model demonstrates a near doubling of predictive power between lowest and highest risk deciles, emphasising the potential utility of genetic profiling to forecast disease onset and guide preventive strategies.

Genetic Risk Factors in Alzheimer's Disease publication trend

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

Technical terms

Genome-wide association study (GWAS): An analysis scanning the genome for single-nucleotide variants associated with disease traits.

Polygenic risk score (PRS): A composite measure of an individual’s genetic predisposition based on the weighted sum of risk alleles.

Endophenotype: A measurable biological or behavioural trait intermediate between genotype and clinical symptoms.

Pleiotropy: The phenomenon by which a single genetic variant influences multiple phenotypic traits.

Locus (plural loci): A specific position on a chromosome where a genetic variant is located.

Cerebrospinal fluid (CSF) biomarkers: Proteins measured in CSF that reflect Alzheimer’s pathology, including amyloid-β and tau species.

References

1. A genome-wide search for pleiotropy in more than 100,000 harmonized longitudinal cognitive domain scores. Molecular Neurodegeneration (2023).
2. Cell-type-specific Alzheimer’s disease polygenic risk scores are associated with distinct disease processes in Alzheimer’s disease. Nature Communications (2023).
3. Multivariate GWAS of Alzheimer’s disease CSF biomarker profiles implies GRIN2D in synaptic functioning. Genome Medicine (2023).
4. Step by step: towards a better understanding of the genetic architecture of Alzheimer’s disease. Molecular Psychiatry (2023).
5. New insights into the genetic etiology of Alzheimer’s disease and related dementias. Nature Genetics (2022).
6. Common variants in Alzheimer’s disease and risk stratification by polygenic risk scores. Nature Communications (2021).