PSEN1/2
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PSEN1 and PSEN2 encode the presenilin proteins, core components of the gamma-secretase complex that helps process amyloid precursor protein. Pathogenic variants in these genes are major causes of early-onset familial Alzheimer’s disease (AD), especially PSEN1, which is the most known cause of monogenic AD.
Normal function
Presenilin-1 and presenilin-2 help form the working core of an enzyme called gamma-secretase, which cleaves amyloid precursor protein and many other proteins. In healthy biology, this process is tightly regulated. Presenilins are therefore crucial in determining which amyloid-beta species are produced.
Mutation and effect
Pathogenic PSEN1/PSEN2 variants alter gamma-secretase function and usually shift amyloid precursor protein processing toward a more pathogenic amyloid profile. This means gamma-secretase produces increased long and aggregation-prone types of amyloid-beta. PSEN1 variants are generally associated with earlier onset and often more severe familial disease than PSEN2 variants.
Key mechanisms involved
The main mechanisms involve altered protein processing which cause increased production of more toxic amyloid species that are likely to aggregate. The downstream effects of this on synaptic function, inflammation, and tau pathology further drive the symptoms of Alzheimer’s. There is also an ongoing discussion about whether presenilin dysfunction involves broader gamma-secretase loss-of-function features beyond amyloid precursor protein alone.
Implications for treatment
PSEN1-related disease often differs from typical sporadic late-onset Alzheimer’s by showing up much earlier, often in the 30s to 50s; it can include atypical features like seizures, myoclonus, or language deficits. PSEN2 disease is rarer and often has later and more variable onset. Both are central to prevention trials and research on early intervention.
Research focus
Research focuses on variant-specific effects on gamma-secretase function, predicting age at onset, and understanding why different presenilin variants cause different phenotypes. These genes remain among the strongest tools for studying how inherited amyloid dysregulation leads to full Alzheimer’s pathology over time.
Inheritance
PSEN1 and PSEN2 cause the same rare inherited form of early-onset Alzheimer's, but they're not equally common. PSEN1 is the more frequently mutated and tends to cause the earliest symptoms, typically starting in someone's 30s to 50s. PSEN1 mutations alone make up around 56% of the inherited-Alzheimer's cases. However, the whole inherited, dominant category of AD, combining APP, PSEN1, and PSEN2, only accounts for about 1-2% of all Alzheimer's cases. Both are dominant, so each child of a carrier faces 50/50 odds of inheriting the mutation, and inheriting it means developing the disease with near certainty.
Sources
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De Strooper, B., Iwatsubo, T., & Wolfe, M. S. (2012). Presenilins and γ-secretase: structure, function, and role in Alzheimer disease.
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Lanoiselée, H.-M., Nicolas, G., Wallon, D., et al. (2017). APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases.
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MedlinePlus Genetics. (2021). PSEN1 gene.