Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PS4, PM1, PM2, PM5, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73664808 A>C
dbSNP ID: rs63750231
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GAA to GCA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 8

Findings

The E280A mutation is by far the most common cause of familial early onset Alzheimer’s disease, affecting hundreds of people. The majority of E280A carriers belong to a large kindred from the Colombian state of Antioquia. In fact, the mutation is often called the Paisa mutation in reference to the people of this region. The Colombian kindred is remarkable for a high level of participation in both longitudinal studies characterizing biomarker progression and pioneering prevention trials. Also, due to its large size, it has enabled the identification of genetic variants that confer protection against E280A, providing candidate therapeutic targets and insights into the mechanistic underpinnings of AD (see Genetic Modifiers below).

Currently, there are about 5,000 living members of the Colombian kindred spread among 25 families who live in a historically isolated region in the Andes Mountains. The pedigree spans five to seven generations, originating with a couple from the Basque region of Spain who settled in Colombia in the early 1700s (Lalli et al., 2014). Nearly half the living members of the kindred live in Medellín, the second-largest city in Colombia, with the majority of the others scattered in outlying villages. Of the 5,000 living members, it is estimated that nearly 1,000 carry the mutation, with about 400 confirmed carriers. Related carriers have been identified in other Colombian regions (Arango et al., 2001), and in other countries (Kwok et al., 1997). In addition, the mutation was identified in a Japanese family (FAD-Ok; Tanahashi et al., 1996). E280A was absent from the gnomAD variant database (gnomAD v2.1.1, July 2021).

Clinical Phenotype

Studies of the large Colombian kindred have revealed that mutation carriers typically develop memory deficits in the third decade of life, followed by progressive impairments in other cognitive domains, such as verbal fluency. Mild cognitive impairment sets in around age 45 and dementia by age 50. Although the vast majority of carriers develop dementia between age 45 and 50, a 30-year window has been documented, with rare cases experiencing onset as early as age 30 or as late as age 65. The mutation is, however, fully penetrant. The median duration from onset of dementia to death is approximately 10 years, ranging from nine to 12 years, with 59 being the median age at death (Acosta-Baena et al., 2011). There is no evidence of anticipation in subsequent generations. Homozygosity has been reported in this kindred. The age of onset for these individuals appears to be moderately accelerated relative to heterozygotes, although the sample is too small to reach statistical conclusions (Kosik et al., 2015).

The majority of E280A carriers present with symptoms fairly typical of AD, including progressive memory loss and changes in personality and behavior; however, there is phenotypic variability. For example, some patients also present with epilepsy, verbal impairment, and cerebellar ataxia. Specifically, mutation carriers present with memory impairment (100 percent), behavioral changes (94 percent), language impairment (e.g., aphasia, 81 percent), headache (73 percent), gait difficulties (65 percent), seizures and myoclonus (45 percent), and cerebellar signs and Parkinsonism (each 19 percent) (reviewed in Sepulveda-Falla et al., 2012).  Interestingly, gender appears to contribute to differences in cognition and neurodegeneration (Vila-Castelar et al., 2020; Fox-Fuller et al., 2021; Vila-Castelar et al., 2022; Martinez et al., 2022; Vila-Castelar et al., 2023). For example, neurodegeneration was reported to proceed faster in women than in men, but the rate did not predict cognitive performance (Vila-Castelar et al., 2023).

Several early signs of disease have been reported in carriers of this mutation. Cognitive decline, for example, has been detected 12 years before clinical onset of disease. Analysis of total CERAD scores, as well as individual scores for memory, language, and praxis, identified word-list recall as a particularly early indicator of decline (Aguirre-Acevedo et al., 2016). Even cognitively unimpaired E280A carriers score slightly lower on the Mini-Mental State Exam and memory tests than non-carriers (Rios-Romenets et al., 2020). Of note, awareness of memory function appears to decrease in the predementia stages, reaching anosognosia close to the age of mild cognitive impairment onset (Vannini et al., 2020).

Additional alterations foreshadow clinical disease. For example, severe headaches appear to be a common early symptom, typically occurring several years before dementia onset (Lopera et al., 1997). The risk of mental disorders in mutation carriers under the age of 30 was found to be similar to that of non-carriers (Villalba et al., 2019), but early depressive symptoms were associated with faster dementia progression (Acosta-Baena et al., 2023), and in cognitively unimpaired carriers, lower hippocampal volume was associated with greater depressive symptoms (Langella et al., 2023).

Given its extremely high penetrance and predictable age of onset, E280A has been instrumental in the identification of markers of AD as a function of carriers’ estimated years to clinical onset (for review see Fuller et al., 2019). In addition, carriers of this variant have been recruited in clinical trials. The Alzheimer Prevention Initiative, for example, relied on presymptomatic members of the Colombian E280A kindred to assess the effects of the therapeutic candidate crenezumab—a monoclonal antibody against oligomeric Aβ (Reiman et al., 2022).

Genetic Modifiers

Remarkably, two rare genetic variants—APOE R154S (R136S), a.k.a. as the Christchurch mutation, and RELN H3447R, a.k.a. Reelin-COLBOS—have been reported to confer what appears to be robust protection against the PSEN1 E280A mutation. The APOE Christchurch mutation was identified in homozygous form in a Colombian carrier of E280A who had only subtle short-term memory loss in her 70s (Nov 2019 news, Arboleda-Velasquez et al., 2019). PET imaging followed by postmortem analysis revealed an unusually high burden of amyloid-β plaque in her brain, with tau pathology restricted to medial temporal and occipital regions. Areas typically involved in AD, including the frontal cortex and hippocampus, were mostly spared, with neurons considered extremely vulnerable to tau-induced neurodegeneration—RORB+ excitatory neurons—remaining mostly intact (Sep 2022 conference news, Sepulveda-Falla et al., 2022, Henao-Restrepo et al., 2023).

In brain regions free of tau pathology, homeostatic astrocytes and microglia expressing genes involved in acute immune responses were observed. In contrast, the occipital cortex was laden with microglia expressing an inflammatory transcriptional profile. Also, cerebral amyloid angiopathy (CAA) was found in the amygdala and occipital cortex, which correlated with the extent of tau pathology and was in contrast to the widespread CAA seen in most E280A carriers. Glucose metabolism levels in areas associated with AD, such as the precuneus, were similar to those of age-matched, non-E280A carriers, as was the level of neurofilament light chain in plasma, an indicator of neuronal damage.

Christchurch heterozygosity may provide some degree of protection against Paisa-associated AD, although results have been mixed. In the original 2019 study, four Paisa carriers who carried one copy of Christchurch were reported to have developed cognitive impairment at ages similar to non-Christchurch carriers (Arboleda-Velazquez et al., 2019), and a subsequent study of 340 Paisa carriers, including 11 Christchurch heterozygotes, also failed to identify a protective effect (Cochran et al., 2023). However, an unpublished analysis of Paisa carriers that included 12 Christchurch heterozygotes (10 of whom were also in the group studied by Cochran and colleagues) found average delays of seven years for mild cognitive impairment and four years for dementia compared with Christchurch noncarriers, with some Christchurch heterozygotes living five years longer than those carrying only the Paisa variant (Aug 2023 conference news). Brain imaging of two of these individuals revealed less atrophy, less tau pathology, and preserved metabolism in brain regions typically affected by AD compared with Christchurch noncarriers. Differences in how the ages at onset were estimated have been proposed to underlie this discrepancy—in the most recent study, these ages were revised after a more detailed review of clinical records.

The H3447R Reelin-COLBOS variant was identified in an E280A carrier who remained dementia-free 20 years after expected symptom onset (May 2023 news, Lopera et al., 2023). Like the homozygous APOE Christchurch carrier, he too had a high load of brain amyloid, with relatively few neurofibrillary tangles, particularly in the entorhinal cortex. The carrier of the Reelin variant had more phospho-tau, and microglia that were less activated than the Christchurch carrier. Both Christchurch and Reelin carriers had less ApoE in their cortical and hippocampal neurons than did other E280A carriers who had died in their 50s or 60s. The  sister of the Reelin carrier, who also carried the E280A and Reelin variants, showed signs of protection but she had co-morbidities that complicated the interpretation of her case.

The Reelin COLBOS variant enhances Reelin-Dab1 signaling which reduces tau phosphorylation. When crossed with a COLBOS knockin mice, P301L tauopathy mice did not develop their characteristic paralysis and had less p-tau205 in their hippocampi (Lopera et al., 2023, May 2023 news). Interestingly, several components of this signaling pathway accumulate in AD-susceptible brain regions in the early stages of sporadic AD (Ramsden et al., 2023).

ApoE and Reelin both bind to the VLDL and APOEr2 receptors, the protective variants of both are near or in heparin-binding regions, and they may both modulate tau phosphorylation, possibly through GSK3β. However, their modes of protection could be very different, with Christchurch conferring resistance to AD pathology via widespread effects in the brain, and COLBOS conferring resilience via localized effects on specific brain regions and cell populations (Sepulveda-Falla, 2023). (For a more detailed description of potential mechanisms underlying Christchurch's protective effects see APOE R154S (R136S) Christchurch).

Additional loci that modify age of onset have been reported, including several dominant major genes (Vélez et al., 2013; Vélez et al., 2016a; Vélez et al., 2016b), as well as recessive variants that delay onset, up to 11 years, or accelerate onset, up to eight years (Vélez et al., 2019). The largest published study, including 340 mutation carriers, identified 13 variants, several in loci that included genes of known AD relevance such as CLU encoding the molecular chaperone clusterin, and genes involved in heparin sulfate biology and amyloid processing (Cochran et al., 2023).

Also of note, the APOE alleles—APOE2, APOE3 and APOE4—modify Paisa-associated AD. Although initial reports from small cohorts yielded conflicting results (Lendon et al., 1997; Pastor et al., 2003, Vélez et al., 2015), a study including 675 Paisa carriers showed that APOE genotype alters age-related cognitive decline, with APOE4 accelerating it and APOE2 delaying it (Langella et al., 2023).

Neuropathology

Those affected by the E280A mutation show neuropathology consistent with a diagnosis of AD, including severe brain atrophy, Aβ pathology, and hyperphosphorylated tau-related pathology. Aβ42 is often particularly abundant in the cerebral cortex, hippocampus, cerebellum, midbrain, and basal ganglia. A study of frontal cortical tissue from 10 E280A carriers revealed an increased load of Aβ42 peptide and decreased loads of Aβ38 and Aβ43 peptides compared with cortical tissues from 10 individuals with sporadic AD (Dinkel et al., 2020). Also of note, cerebellar damage appears to be common in Paisa carriers (Lemere et al., 1996), with Aβ plaque deposition surfacing about a decade before the clinical onset of AD (Ghisays et al., 2021).

Comorbid pathologies are common in E280A carriers. Indeed, post-mortem brain tissues from 17 carriers described in a preprint, revealed that only 29 percent had exclusively AD pathology (Sepulveda-Falla et al., 2023).  Carriers had higher cerebral amyloid angiopathy (CAA) severity scores than either carriers of other PSEN1 mutations or non-carriers with early onset sporadic AD. Other cerebrovascular pathologies included atherosclerosis in the circle of Willis (19%), small vessel disease (25%), microinfarcts (4%) and cerebral microhemorrhages (2%). (The high percentage of athersoclerosis may be at least partially explained by environmental cardiovascular risk factors). In another study, amyloid-independent small vessel disease in the cortex and basal ganglia was found to be comparable to that seen in CADASIL patients, although often undetected by MRI (Littau et al., 2022). At least in the frontal cortex, E280A pathology appears to involve alterations in the gliovascular unit associated with hyperreactive astrocytes whose phenotype differs from that observed in astrocytes of patients with sporadic AD (Henao-Restrepo et al., 2023). 

Other neuropathologies have also been associated with E280A. For example, post-mortem tissues from 12 of 17 carriers (70 percent) had Lewy body disease, most being amygdala predominant, and 4 of 15 (27 percent) had TDP-43 pathology in the amygdala (Sepulveda-Falla et al., 2023). Moreover, transcriptional signatures of viral infection and inflammation in the olfactory bulb and tract have been reported (Bubak et al., 2023), and a subset of carriers suffering from seizures developed greater neuronal loss and hippocampal sclerosis similar to that found in epilepsy patients than patients without epileptic seizures (Velez-Pardo et al., 2004).

Early Structural, Functional, and Pathological Changes

Signs of structural and functional changes are consistent with the early signs of cognitive impairment discussed above in "Clinical Phenotype" (see Fuller et al., 2020 for review; Jul 2015 news). For example, hyperactivation within medial temporal lobe regions during the encoding of novel associations has been seen in young carriers, suggesting that carriers push their memory-forming circuitry harder to achieve equivalent performance (Quiroz et al., 2010; Quiroz et al., 2015). Presymptomatic reduction of hippocampal volume has also been reported (Fleisher et al., 2015). In addition, functional alterations in the precuneus have been detected at presymptomatic stages of disease (Fleisher et al., 2015; Ochoa et al., 2017), with a decline in locus coeruleus integrity foreshadowing tau pathology in this region (Jacobs et al., 2023). Interestingly, although robust reduction in cortical thickness was seen in carriers starting a decade before expected cognitive impairment, cortical thickness was increased in child carriers (Fox-Fuller et al., 2021). In another study, white matter hyperintensities increased prior to symptom onset and were tied to cognitive performance (Schoemaker et al., 2022).

Studies of Aβ and tau pathology using PET have also revealed early presymptomatic changes. For example, Aβ, as assessed by PiB-PET, was elevated in unimpaired carriers approximately 15 years prior to expected onset of mild cognitive impairment (Feb 2018 news; Quiroz et al., 2018). A longitudinal study tracking both amyloid and tau pathology confirmed this early Aβ accumulation, and mapped out subsequent pathological changes, including tau accumulation in the entorhinal cortex nine years prior to expected symptom onset, neocortical tau build-up and hippocampal atrophy six years prior to onset, and cognitive decline four years prior to onset (Sanchez et al., 2021). Of note, rates of tau accumulation among carriers were most rapid in the parietal neocortex, and tau levels in the entorhinal cortex predicted subsequent neocortical tau accumulation and cognitive decline.

Studies have also shown correlations between cognitive performance and amyloid and tau pathologies. For example, age-related elevation of Aβ in the striatum, which had a larger Aβ burden than the neocortex, was associated with lower memory scores and entorhinal tau pathology (Hanseeuw et al., 2019). Moreover, subjective cognitive decline, difficulties in recall tests, and impaired visual memory showed a close relationship with both cortical amyloid and tau pathology in the inferior temporal and entorhinal cortices (Gatchel et al., 2019; Guzmán-Vélez et al., 2020; Norton et al., 2020; Bocanegra et al., 2020). Neuroticisim in cognitively unimpaired carriers, on the other hand, was tied to entorhinal tau pathology, but not amyloid burden (Baena et al., 2021).

One study correlated tau and amyloid pathologies with patterns of connectivity in brain regions involved in memory and information-processing in non-demented E280A carriers (Guzmán-Vélez et al., 2022). The findings provide clues on the distinct ties the two pathologies have—both hypothesized to spread through functional networks—with the disruption of neural communication that results in cognitive impairment.

Presymptomatic changes in CSF and plasma biomarkers have also been examined. A reduction in Aβ42 and increases in total tau and phosphorylated tau were observed in the CSF of unimpaired mutation carriers (Fleisher et al., 2015; Jan 2015 news). All three changes were age-associated. Plasma Aβ42 levels were also found elevated, but not correlated with age. Of particular interest, plasma neurofilament light (NfL), was reported to distinguish mutation carriers from noncarriers as early as 22 years before expected disease onset (Aug 2019 conference news, Quiroz et al., 2020, May 2020 news, Masters, 2020), and higher plasma NfL levels were correlated with greater regional tau burden and worse cognition (Guzmán-Vélez et al., 2021). Moreover, plasma levels of p-tau217, a phosphorylated tau species whose plasma levels accurately discriminate between AD and other neurodegenerative disorders, distinguished mutation carriers 20 years prior to estimated onset of mild cognitive impairment (July 2020 news; Palmqvist et al., 2020) and were associated with the subsequent appearance of PET-detectable Aβ and tau deposits and reduced performance in memory tests (Aguillon et al., 2022). 

Biomarker differences have been detected in children as young as nine years old (see Fuller et al., 2019 for review; Jul 2015 news). Young mutation carriers had elevated plasma levels of Aβ1-42 and higher Aβ42:Aβ40 ratios, as well as changes in resting-state connectivity, and regional gray matter volumes. It is unknown if these differences are primarily neurodegenerative or neurodevelopmental (Quiroz et al., 2015; Jul 2015). 

Of note, some early alterations, such as changes in retinal thickness (Armstrong et al., 2021) and electroencephalography (EEG) patterns (García-Pretelt et al., 2022), are being examined for their potential as low-cost screening tools.

Biological Effects

In a variety of cell types, expression of mutant presenilin resulted in an increased level of secreted Aβ42, and an increased Aβ42/Aβ40 ratio (Murayama et al., 1999; Kaneko et al., 2007; Li et al., 2016, Soto-Mercado et al., 2020). Two of these studies suggested the mutation altered the specificity of the carboxypeptidase-like γ-cleavage, but spared the endoproteolytic ε-cleavage of APP and PSEN1 (Kaneko et al., 2007; Li et al., 2016). A subsequent cell-based study confirmed the increase in the Aβ42/Aβ40 ratio, but indicated Aβ42 production was decreased in cells expressing the mutant protein, as was production of total Aβ, Aβ38, and Aβ40 (Kakuda et al., 2021). Of note, this study revealed an increase in the toxic peptide Aβ43. A switch in the stepwise γ-cleavage pathway leading to production of this peptide may underlie or contribute to this effect. 

Consistent with the above observations, in vitro experiments with isolated proteins revealed an increase in the Aβ42/Aβ40 ratio, with reductions in both Aβ40 and Aβ42 production (Sun et al., 2017). Moreover, in vitro experiments testing the mutant’s γ-secretase activity at different temperatures showed the mutation increases enzyme-Aβn complex dissociation rates, enhancing the release of longer Aβ peptides (Szaruga et al., 2017; Jul 2017 news). 

More recently, two in-depth studies of the Aβ peptides produced by cells transfected with this variant revealed a deleterious effect, decreasing both the Aβ (37 + 38 + 40) / (42 + 43) and Aβ37/Aβ42 ratios compared with cells expressing wildtype PSEN1 (Apr 2022 news; Petit et al., 2022; Liu et al., 2022). Both ratios were reported to outperform the Aβ42/Aβ40 ratio as indicators of AD pathogenicity, with the former correlating with AD age at onset. Moreover, a follow-up study reported in a preprint, combined the Aβ (37 + 38 + 40) / (42 + 43) ratio with the commonly used Aβ42/Aβ40 ratio (a measure of the relative production of aggregation-prone Aβ) to yield a composite measure which reflects γ-secretase function as a percentage of wildtype activity (Schulz et al., 2023). This composite score (33.28 for E280A) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

As revealed by a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment, E280 appears to play a key role in stabilizing the hybrid β-sheet that forms between PSEN1 and APP in preparation for γ-secretase cleavage (Zhou et al., 2019; Jan 2019 news). The carboxylate side chain of E280 makes a bifurcated H-bond to the hydroxyl groups of Y154 and Y159, both from transmembrane domain 2 of PSEN1. These interactions are buttressed by two additional H-bonds from R278 to E280 and Y159. Based on these data, subsequent computational simulations suggest E280A reduces the stability of the protein and favors an open conformational state in which the substrate is held more loosely, resulting in imprecise cleavage and earlier release of longer Aβ peptides (Dehury et al., 2020).

Effects on other cellular functions have also been reported for this mutation. A comparison of single-nuclei transcriptomes in postmortem frontal cortices of E280A carriers with those of sporadic AD patients and controls, for example, indicated activation of chaperones and autophagy in astrocytes and neurons as distinctive of mutation carriers (Feb 2024 news; Almeida et al., 2024). The authors hypothesized this may reflect a homeostatic corrective response to the mutation's disruption of Psen1 folding. In contrast, Paisa microglia were less activated than those from sporadic AD patients, while several genes involved in immune responses to infection were  upregulated.

Additional effects on cellular physiology include reduced proteolytic processing of the Nav voltage-gated sodium channel in rodent neuroblastoma cells (Kim et al., 2014), as well as dysregulated mitochondrial function, autophagy, and calcium homeostasis (Rojas-Charry et al., 2020). Moreover, in cholinergic-like neurons derived from carrier mesenchymal stromal stem cells, the mutant was reported to increase tau phosphorylation at residues Ser202 and Thr205 (May 2020 news, Soto-Mercado et al., 2020). In addition, apoptosis markers were elevated accompanied by a disruption of mitochondrial potential and DNA fragmentation. Also in these cells, calcium flux was abnormal and acetylcholinesterase activity reduced. In glioblastoma cells, E280A has been reported to increase formation of mitochondria-associated endoplasmic reticulum membranes (MAMs), elevate production of mitochondrial superoxide, and disrupt mitochondrial membrane potential (Han et al., 2021). Moreover, in astrocytes derived from human induced pluripotent stem cells (iPSCs),  it altered metabolism and neurotransmitter transport (e.g., Salcedo et al., 2021, Salcedo et al., 2023).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Research Models

Several cell models carrying this mutation have been created. Two isogenic iPSC lines, with either a homozygous or a heterozygous E280A mutation, have been generated using CRISPR-Cas9 technology to mutate PSEN1 in an iPSC line from a healthy individual (Frederiksen et al., 2019). Also, an iPSC line derived from a patient with early onset AD has been created (Vallejo-Diez et al., 2019). Using mesenchymal stromal stem cells from umbilical cords, researchers have also generated cholinergic-like neurons carrying the mutation (May 2020 news, Soto-Mercado et al., 2020). 

Of note, non-iPS cells derived from patients carrying the E280A mutation, including menstrual blood-derived menstrual stromal cells (MenSCs) and umbilical cord-derived Wharton Jelly's mesenchymal stromal cells (WJ-MSCs), have been examined as alternative cellular models (Mendivil-Perez et al., 2023). Cholinergic-like neurons and cerebroid spheroids derived from these alternative sources have been reported to reproduce AD neuropathology more efficiently and faster than neurosn derived from mutant iPSCs.  

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Comments

1. • Alexei Koudinov
     
   • Posted: 11 Jul 2002
   • Paper: The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology.

   Please see the following letter in Science related to this article: Alzheimer's disease and amyloid beta protein Koudinov AR et al Science online,> Published 25 June 2002 [ Full Text ]

   View all comments by Alexei Koudinov

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References

Mutations Citations

1. APOE R154S (Christchurch)
2. APOE C130R (ApoE4)
3. APOE R176C (ApoE2)

News Citations

1. Can an ApoE Mutation Halt Alzheimer’s Disease? 4 Nov 2019
2. Does One Copy of the Christchurch ApoE Variant Slow Alzheimer’s? 12 Aug 2023
3. Reelin Variant Wards Off Dementia in Colombian Kindred Siblings 16 May 2023
4. Familial Alzheimer’s Gene Alters Children’s Brains 2 Jul 2015
5. In Familial Alzheimer’s, Tau Creeps into Cortex as Symptoms Show 14 Feb 2018
6. API Biomarker Data Mirror DIAN’s, Support Progression Models 16 Jan 2015
7. Colombian Cohort Delivers Data on Blood NfL 8 Aug 2019
8. In Colombian Alzheimer’s Kindred, Blood NfL Climbs 22 Years Before Symptoms 26 May 2020
9. Plasma p-Tau217 Set to Transform Alzheimer’s Diagnostics 29 Jul 2020
10. sAPP Binds GABA Receptor, and More News on APP 21 Jul 2017
11. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
12. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019
13. Different Cellular Mechanisms in Familial and Sporadic Alzheimer’s? 29 Feb 2024
14. Umbilical Cord With Presenilin Mutation Births New Cell Model of Familial AD 27 May 2020

Paper Citations

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