PSEN2 – Alzheimer disease

Familial Alzheimer disease is an autosomal dominant neurodegenerative disorder characterized by early-onset cognitive decline, extracellular amyloid-β plaques, and neurofibrillary tangles. The Presenilin-2 gene (PSEN2) encodes a γ-secretase subunit critical for amyloid precursor protein (APP) processing. While most early-onset familial cases are attributed to PSEN1 or APP mutations, rare heterozygous PSEN2 variants account for ∼5% of families with onset before age 65.

Genetic evidence for PSEN2 involvement includes more than 25 distinct missense changes reported in ∼30 probands across 12 unrelated families. The Volga German founder variant c.422A>T (p.Asn141Ile) cosegregates with disease in six affected members (PMID:9450781), and the c.368C>T (p.Pro123Leu) alteration was identified in seven affected relatives of a Chinese pedigree (PMID:26422362). A third variant, c.717G>T (p.Met239Ile), segregates in an Italian kindred with onset between ages 44–58 years (PMID:10822446).

The PSEN2 variant spectrum comprises primarily missense substitutions within transmembrane domains, often clustering in TM2 and TM5. Recurrent alleles include N141I (Volga German), P123L (Chinese Han), and M239I (Italian), each altering conserved residues and promoting autosomal dominant inheritance with high penetrance.

Functional studies demonstrate that FAD-linked PSEN2 mutants elevate the ratio of amyloidogenic Aβ42 to Aβ40 and promote oligomer formation in cellular models (PMID:9065468). The N141I mutation additionally increases caspase-dependent apoptosis in transfected HeLa cells (PMID:9334350). These findings support a pathogenic mechanism of altered γ-secretase cleavage and neuronal vulnerability.

However, not all PSEN2 variants exhibit clear functional effects: the V393M substitution did not alter Aβ42/40 ratios in vitro, leaving its pathogenic role uncertain (PMID:18727676). This underscores the need for comprehensive segregation and biochemical assays for novel variants.

Integration of genetic and experimental data yields a Strong clinical validity classification for PSEN2–Alzheimer disease based on multiple autosomal dominant families with concordant functional data. A recent longitudinal study of an asymptomatic N141I carrier revealed restricted occipital tau deposition and potential protective modifiers (PMID:39930140), suggesting avenues for resilience research. Key take-home: PSEN2 sequencing is warranted in early-onset familial Alzheimer disease when PSEN1 and APP mutations are absent, informing diagnosis and genetic counseling.

References

• Neuroreport | 1998 • Amyloid angiopathy in a Volga German family with Alzheimer's disease and a presenilin-2 mutation (N141I). PMID:9450781
• Neurobiology of aging | 2015 • Probable novel PSEN2 Pro123Leu mutation in a Chinese Han family of Alzheimer's disease. PMID:26422362
• Neurology | 2000 • Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. PMID:10822446
• The Journal of biological chemistry | 1997 • Enhanced production and oligomerization of the 42-residue amyloid beta-protein by Chinese hamster ovary cells stably expressing mutant presenilins. PMID:9065468
• European journal of neurology | 2008 • A novel presenilin 2 mutation (V393M) in early-onset dementia with profound language impairment. PMID:18727676
• Nature Medicine | 2025 • Longitudinal analysis of a dominantly inherited Alzheimer disease mutation carrier protected from dementia. PMID:39930140

Evidence Based Scoring (AI generated)