rs61761208 — PSEN2 N141Y

PSEN2 N141Y — A Rare Pathogenic Mutation at the Heart of the Gamma-Secretase Complex

The PSEN2 gene encodes presenilin-2, one of four subunits of the γ-secretase complex¹¹ one of four subunits of the γ-secretase complex
The others are nicastrin, APH-1, and PEN-2; together they form an intramembrane aspartyl protease, the enzyme responsible for cleaving amyloid precursor protein (APP) within its transmembrane domain. Presenilin-2 forms the catalytic core of this complex, contributing the two catalytic aspartate residues essential for proteolysis. When γ-secretase cleaves APP, it generates amyloid-beta (Aβ) peptides of varying lengths — primarily Aβ40 (the most abundant form) and Aβ42 (the more fibrillogenic, plaque-forming form). Mutations in PSEN2 that shift cleavage toward longer, stickier Aβ42 and Aβ43 peptides are a direct molecular cause of early-onset familial Alzheimer's disease.

PSEN2 is the rarest of the three major familial AD genes (APP, PSEN1, PSEN2), accounting for fewer than 5% of all familial early-onset cases²² fewer than 5% of all familial early-onset cases
MedlinePlus reports at least 11 PSEN2 mutations causing early-onset AD; PSEN1 mutations account for the majority of genetic cases. A distinguishing feature of PSEN2-associated AD is variable and incomplete penetrance — unlike PSEN1 mutations, which are nearly fully penetrant, PSEN2 mutation carriers occasionally remain unaffected into their 80s, with population-level penetrance estimated at approximately 95% by age 80³³ 95% by age 80
Some PSEN2 mutation carriers have been documented as cognitively intact at ages well above the family mean, suggesting modifier loci or protective genetic factors. Age of onset is also broader than PSEN1, spanning roughly 40–75 years.

The N141Y variant (c.421A>T, p.Asn141Tyr, rs61761208) was first reported by Niu et al. in 2014⁴⁴ Niu et al. in 2014
Novel mutation in the PSEN2 gene (N141Y) associated with early-onset autosomal dominant Alzheimer's disease in a Chinese Han family. Neurobiol Aging, 2014 in a three-generation Han Chinese family from northern China, making it the first pathogenic PSEN2 mutation documented in any Asian population. Six family members across three generations developed dementia in their fifth decade and died in their sixth decade. The proband developed progressive memory impairment with inability to manage finances at age 43, and died at age 55 with autopsy-confirmed Alzheimer's disease. Grandparents, mother, and aunts were similarly affected. Sanger sequencing of seven family members confirmed perfect segregation: the mutation was present in all affected individuals and absent in all five unaffected relatives and 188 ethnically matched controls.

The Mechanism

Asparagine-141 sits in the first transmembrane domain (TM1) of presenilin-2, a region critical for the structural integrity of the catalytic cleft and for positioning APP substrate relative to the catalytic aspartates⁵⁵ a region critical for the structural integrity of the catalytic cleft and for positioning APP substrate relative to the catalytic aspartates
Structural studies of the γ-secretase complex show TM1 participates in a conformational gate that controls substrate access. Substituting the polar asparagine with the bulkier, aromatic tyrosine likely alters TM1 packing and shifts the geometry of APP cleavage. Functional studies of N141Y demonstrate the molecular fingerprint of pathogenic presenilin mutations: an elevated Aβ42/Aβ40 ratio (0.32 vs. 0.15 in wild-type), accumulation of toxic Aβ43 peptide, and a reduced Aβ37/Aβ42 ratio (0.17 vs. 0.44 in wild-type). This pattern — more long-chain, aggregation-prone Aβ peptides relative to the short-chain Aβ40 — is a hallmark of presenilin gain-of-dysfunction mutations.

Codon 141 appears to be a mutational hotspot in PSEN2: in addition to N141Y (Chinese Han families), N141I is associated with Volga German families (the most extensively characterized PSEN2 mutation), N141D has been reported in additional Chinese pedigrees, and N141S was recently validated functionally. The recurrence of mutations at this position across unrelated populations and ancestries supports the inference that asparagine-141 performs an essential, conserved structural role⁶⁶ supports the inference that asparagine-141 performs an essential, conserved structural role
Convergent evolution of disease mutations at the same position in independent families is itself moderate evidence of pathogenicity under ACMG criteria (PM5).

The Evidence

The Alzforum mutation database classifies N141Y as pathogenic based on ACMG/AMP criteria PS3, PM2, PM5, PP1, and PP3⁷⁷ classifies N141Y as pathogenic based on ACMG/AMP criteria PS3, PM2, PM5, PP1, and PP3
PS3: functional data showing altered Aβ profiles; PM2: absent from population databases; PM5: novel missense at same codon as known pathogenic N141I; PP1: segregation with disease in the family; PP3: in silico predictions support pathogenicity. The variant is absent from gnomAD (v2.1.1), consistent with a rare highly penetrant disease allele.

Cai et al. 2015⁸⁸ Cai et al. 2015
Mutations in presenilin 2 and its implications in Alzheimer's disease and other dementia-associated disorders. Clin Interv Aging, 2015 catalogued N141Y among pathogenic PSEN2 mutations in a systematic review, noting that the asparagine-to-tyrosine change at codon 141 likely alters the Aβ42/Aβ40 ratio by the same mechanism as N141I. A comprehensive overview of early-onset familial AD mutations in China by Qin et al. 2020⁹⁹ Qin et al. 2020
Gene mutations associated with EOFAD in China. Mol Genet Genomic Med, 2020 confirmed N141Y in this Chinese Han family and described the clinical course in detail.

A broader context is provided by the largest screening study to date, Lanoiselée et al. 2017¹⁰¹⁰ Lanoiselée et al. 2017
APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease. PLoS Med, 2017, which showed that PSEN2 mutations are rare even among familial EOAD cases (only 4 distinct variants among 170 French families), and that PSEN2-associated AD has a mean onset around 53.9 years (range 45–69 years) — substantially later than PSEN1. Importantly, a systematic ACMG re-evaluation of all 63 reported PSEN2 variants by Holstege et al. 2021¹¹¹¹ Holstege et al. 2021
APP, PSEN1, and PSEN2 Variants in AD: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci, 2021 found that only about 20% of previously reported pathogenic PSEN2 variants actually meet current criteria — N141Y is among those that do.

Practical Actions

Carrying the N141Y variant is a high-stakes finding. The mutation is associated with very high (though not absolute) lifetime risk of early-onset Alzheimer's disease. The primary practical implications are:

1. Genetic counselling and family communication: Autosomal dominant inheritance means each first-degree relative has a 50% chance of carrying the mutation. Proactive genetic counselling allows at-risk relatives to make informed decisions about predictive testing and life planning.

2. DIAN-TU clinical trial eligibility: Carriers of documented pathogenic PSEN2 mutations are eligible for enrollment in the Dominantly Inherited Alzheimer Network Trials Unit (DIAN-TU), which runs prevention trials in pre-symptomatic carriers beginning 10–15 years before expected symptom onset. This is the most direct access to potential disease-modifying treatment.

3. Biomarker monitoring and early diagnosis: Amyloid PET, CSF Aβ42/Aβ40 ratio, and plasma Aβ42/Aβ40 tests can detect the Alzheimer's biological cascade 10–20 years before symptom onset. In carrier families, this window allows structured monitoring, early diagnosis, and entry into trials.

4. Cognitive reserve building: While no lifestyle intervention prevents or cures genetic AD, higher cognitive reserve — built through education, cognitive engagement, and social activity throughout life — is associated with later symptom onset and slower progression¹²¹² higher cognitive reserve — built through education, cognitive engagement, and social activity throughout life — is associated with later symptom onset and slower progression
   Meta-analyses consistently show a correlation between cognitive reserve and age at AD symptom presentation, even in genetic cases, likely by increasing the amount of pathology the brain can tolerate before clinical expression.

Interactions

The primary disease-relevant interaction is the APOE ε4 allele. In PSEN2 N141I families (the best-studied codon 141 mutation), APOE ε4 is a significant modifier of age at onset, accelerating symptom presentation by several years. Yu et al. 2010¹³¹³ Yu et al. 2010
The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol, 2010 identified APOE genotype as a significant covariate in nine N141I families. This interaction likely extends to N141Y given the structural similarity of the mutations. N141Y carriers who also carry APOE ε4 may have earlier onset than carriers without it.

In cells, presenilin-2 γ-secretase activity is partially compensated by presenilin-1 (PSEN1); the two presenilins are expressed at different levels and have partially overlapping substrates. However, because PSEN2 mutations appear to cause a partial loss-of-cleavage-function alongside a gain-of-Aβ42-production, this compensation is incomplete and disease results from heterozygous mutation alone.