Genetic Factors and Mechanisms in Alzheimer’s Disease Pathogenesis

Alzheimer’s disease pathogenesis is underpinned by a complex interplay of genetic factors that influence amyloid-β metabolism, tau aggregation, lipid homeostasis, endosomal trafficking and neuroinflammatory responses. Early-onset familial forms arise from autosomal mutations in APP, PSEN1 and PSEN2 that aberrantly process amyloid precursor protein, leading to toxic amyloid-β accumulation. Late-onset disease is driven by a constellation of risk alleles identified through genome-wide association studies, including APOE ε4, BIN1, CLU, PICALM, SORL1, TREM2 and others. These variants converge on cellular mechanisms such as clathrin-mediated endocytosis, autophagy-lysosomal clearance, cholesterol transport, membrane repair and microglial activation. Disruption of endosomal pathways impairs amyloid-β clearance across the blood–brain barrier, while genetic perturbations of tau-modifying kinases and scaffold proteins promote fibrillar deposition and synaptic dysfunction. Risk alleles in immune regulators shape microglial surveillance and cytokine release, exacerbating neuronal damage. Collectively, these insights reveal interdependent pathways linking genetic variation to hallmark neuropathology, offering avenues for biomarker development and targeted therapeutics.

Research from Nature Portfolio

Genome-wide studies have elucidated how endocytic adaptors modulate proteostatic mechanisms in Alzheimer’s pathology. In particular, research has demonstrated that variants in a clathrin assembly protein not only alter autophagic flux but also regulate the turnover of tau species. Functional experiments in cellular and zebrafish models reveal that reduced expression of this adaptor impairs autophagosome formation and degradation, thereby exacerbating tau toxicity. Conversely, restoration of adaptor levels enhances tau clearance, underscoring a critical genetic link between trafficking pathways and neurofibrillary pathology. These findings provide a mechanistic basis for targeting endosomal-autophagic processes in therapeutic strategies.

Genetic Factors and Mechanisms in Alzheimer’s Disease Pathogenesis publication trend

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

Technical terms

Autophagy: Cellular process for degrading and recycling cytoplasmic components via lysosomes.

Endocytosis: Mechanism by which cells internalise extracellular material through membrane invagination.

Genome-wide association study (GWAS): Unbiased screening of common genetic variants across the genome to identify disease risk loci.

Amyloid-β (Aβ): Peptide fragment derived from amyloid precursor protein that aggregates into extracellular plaques.

Tau: Microtubule-associated protein that forms intracellular neurofibrillary tangles when hyperphosphorylated.

Blood–brain barrier (BBB): Endothelial cell layer that regulates molecular exchange between blood and brain parenchyma.

Calcium homeostasis: Regulation of intracellular calcium levels critical for neuronal signalling and survival.

References

1. Anti-malaria drug artesunate prevents development of amyloid-β pathology in mice by upregulating PICALM at the blood-brain barrier. Molecular Neurodegeneration (2023).
2. Endo‐Lysosomal Network Disorder Reprograms Energy Metabolism in SorL1‐Null Rat Hippocampus. Advanced Science (2024).
3. The Alzheimer’s disease risk gene BIN1 regulates activity-dependent gene expression in human-induced glutamatergic neurons. Molecular Psychiatry (2024).
4. PICALM modulates autophagy activity and tau accumulation. Nature Communications (2014).