Overview

Pathogenicity: Alzheimer's Disease : Likely Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PP1, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr14:73637653 C>T
dbSNP ID: rs63749824
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GCC to GTC
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 4

Findings

This variant is associated with a wide range of age at onset of Alzheimer’s disease (AD) and, in a few cases, other neurodegenerative disorders, and appears to have incomplete penetrance. It was first identified in three AD patients from the Netherlands. The patients (1005, 1061, and 1087) were not known to be related, but genetic markers flanking PSEN1 suggested a relatively recent common ancestor. All three patients met NINCDS-ADRDA criteria for probable AD and had a family history of dementia. The ages at onset were 53, 55, and 58, consistent with early onset AD. The variant was absent in the 118 control individuals screened (Cruts et al., 1998).

Two years later, A79V was reported in a German individual with AD, known as patient 1. Like the previously reported Dutch cases, her symptoms began at age 58. The disease course was initially mild, but ultimately culminated in severe dementia more than 10 years after symptom onset. A similar age at onset and a 10-year disease duration were reported for this patient's mother (Finckh et al., 2000). Additional carriers have been reported in multiple studies, including three AD cases (Rogaeva et al., 2001; Miravalle et al., 2002), two families with early onset AD (Mol et al., 2022), and an individual with mild cognitive impairment and a family history of AD (Wright et al., 2023).

Of note, several reports have described variable ages at onset associated with this variant. For example, a family was identified with a mean age at onset of 69 years and a range of 55 to 78 years (Kauwe et al., 2007). The mutation segregated with disease in this family, which included three demented individuals who carried the mutation, five nondemented elderly siblings who were non-carriers, and five additional non-carriers whose parents were cognitively healthy. Of note, one affected individual was identified who did not carry the mutation and was thought to have sporadic AD (age at onset: 78 years).

A79V was also detected in a screen of 439 families with a history of late-onset AD (onset at age 65 or later) (Cruchaga et al., 2012). The mutation was found in four of these families, including in one individual from a previously reported family (Kauwe et al., 2007). The sequenced individual from this family had autopsy-confirmed AD and an age of onset of 76 years. A79V was found also in a sporadic AD case (out of 1,806 screened), but not in 1,346 unrelated controls. In addition, the mutation was identified in 10 of 22 members of a family of European ancestry who developed AD symptoms in their 70s and 80s (Day et al., 2016). Overall, their phenotypes were similar to those of patients with late-onset AD (LOAD), including onset age, duration of dementia, rate of progression, and associated symptoms and comorbidities. However, the early emergence of hallucinations and delusions was more frequent in this family than in sporadic LOAD. Age at onset was not influenced by APOE allele carrier status.

Subsequent studies identified additional late-onset cases, as well as evidence of reduced penetrance. For example, a U.S.-based study described a large family with late-onset AD, including at least two affected non-carriers and two cognitively healthy carriers (Fernández et al., 2017). However, the latter—67 and 68 years old—could have been presymptomatic given that six of nine affected individuals in this family had later ages at onset.  Also, in this study, A79V was found in seven individuals with sporadic late-onset AD from a case-control cohort of the Alzheimer’s Disease Sequencing Project (ADSP), including whole-exome and whole-genome sequences from 5,844 cases and 4,767 controls, most of European-American ancestry. The average age at onset for these individuals was 68 years old. Moreover, a preprint describing analyses of a newer release from the ADSP, including data from 13,825 AD cases and 14,715 controls, identified 11 carriers, 10 with AD and one control (Wang et al., 2023).

Based on its frequency (0.000014) in the gnomAD variant database, Koriath and colleagues predicted A79V as most likely having reduced penetrance (Koriath et al., 2018). A more recent gnomAD release reports a global frequency of 0.0000093, including 15 carriers, most of European (non-Finnish) ancestry (gnomAD v4.0.0, Jan 2024).

Of note, the A79V mutation also has been linked to other neurodegenerative phenotypes and pathologies. In a cohort including 490 Parkinson's disease (PD) patients, three individuals carried the mutation: an early onset case (44 years old at onset) and two late-onset cases (75 and 64 years old at onset). None of these carriers reported PD or AD family history. Neurological evaluation at 46, 86, and 82 years of age revealed no evidence of dementia after two, 11, and 18 years of disease onset, respectively (Ibanez et al., 2018). In addition, a 72-year-old carrier of the mutation, who suffered primarily from progressive memory loss, was diagnosed with probable dementia with Lewy bodies (Meeus et al., 2012), and another carrier from a Belgian study had mixed AD and vascular pathology (Perrone et al., 2020).

Neuropathology

Autopsies from at least seven mutation carriers have revealed neuropathology consistent with AD (Cruchaga et al., 2012; Day et al., 2016; Del-Aguila et al., 2019). In the five cases reported by Day and colleagues, Aβ plaques and neurofibrillary tangles were prominent in cortical association areas including the medial temporal lobe, and less abundant in deep gray nuclei. Mild to moderate cerebral amyloid angiopathy was reported. Lewy bodies limited to the substantia nigra pars compacta were present in one case, and arteriolosclerosis with lacunar infarcts was present in two cases. At least in one case, diffuse plaques were the predominant type of Aβ deposit, and primitive plaques were abundant (Maarouf et al., 2008). In this same case, vascular amyloid was very mild and neurofibrillary tangles were sparse. 

Although CSF Aβ42 and Aβ42/Aβ40 concentrations were found to be very high in one nondemented mutation carrier (Kauwe et al., 2007), a subsequent study including two carriers with early onset AD, revealed decreased CSF levels of Aβ42 (Perrone et al,, 2020). Levels of Aβ40, sAPPα, and sAPPβ were also decreased. Interestingly, peptide levels, particularly those of Aβ43, varied between the two carriers, with lower levels seen in the carrier with an APOE3/4 genotype compared with the carrier with an APOE3/3 genotype. Tau and phospho-tau levels were available for one of the carriers and these were elevated compared with controls.

Biological Effect

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 (Petit et al., 2022; Liu et al., 2022; Apr 2022 news). 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 (62.45 for A79V) was strongly associated, not only with age at onset, but with biomarker and cognitive trajectories.

Moreover, data from other experimental systems have revealed increases in the Aβ42/Aβ40 ratio, although different alterations have been found to underlie this change. In HEK-293 cells expressing APP with the Swedish mutation, A79V increased the Aβ42/Aβ40 ratio by decreasing Aβ40. There was no change in Aβ42 compared to cells expressing wild-type PSEN1 (Kumar-Singh et al., 2006). In contrast, in mouse embryonic fibroblasts lacking PSEN1 and PSEN2, expression of PSEN1 with the A79V mutation resulted in increased Aβ42 levels in conditioned media compared with concentrations produced by cells expressing wild-type PSEN1. Aβ40 levels and total Aβ (combined Aβ40 and Aβ42) levels were not significantly different from wild-type controls (Kauwe et al., 2007).

Yet another cell-based study, in CHO cells, reported decreases in the production of both peptides, with a reduction of greater magnitude in Aβ40 (Kakuda et al., 2021). This study also revealed a decrease in Aβ38 and an increase in Aβ43. Analyses of the short peptides generated from the stepwise processing of Aβ suggested Aβ43 may be generated from Aβ48 in several AD-associated mutants, rather than from the canonical Aβ49 precusor. Increased Aβ43 levels and increased production via this alternate pathway correlated with younger ages at disease onset. 

In an in vitro assay using purified proteins to test this mutant's ability to cleave the APP-C99 substrate, Aβ42 levels were dramatically reduced compared with those produced by wildtype PSEN1, and Aβ40 was undetectable (Sun et al., 2017). However, this assay appears to be limited in its cleavage efficiency given that 68 of 138 mutant recombinant PSEN1 enzymes tested produced less than 10 percent of the Aβ40 and Aβ42 produced by the wildtype protein (Liu et al., 2021).

Studies of how this variant affects gene expression in the brain have also been conducted. Single-nuclei RNA sequencing data were collected from the parietal cortices of a woman of European-American ancestry carrying this mutation and two non-carrier family members (May 2019 news; Del-Aguila et al., 2019). All three women had AD pathology when they died in their 80s. The carrier and one sibling had severe dementia at death, while the other sibling had mild dementia. Sequencing analyses revealed a reduced proportion of excitatory neurons in the carrier compared with the non-carriers.

Moreover, a transcriptomics analysis of glutamatergic neurons derived from A79V human induced pluripotent stem cells revealed alterations in the expression of components of the extracellular matrix, the MAPK signaling pathway, and the endoplasmic reticulum, as well as in genes involved in calcium homeostasis and synaptic function compared with isogenic controls (Corsi et al., 2023). In addition, a shift towards upregulation of regulatory circRNAs was reported.

In silico algorithms to predict the effects of this variant on protein function (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Cruchaga et al., 2012, gnomAD v2.1.1, Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Likely Pathogenic*

*This variant appears to have reduced penetrance, a condition outside the scope of the ACMG-AMP guidelines.

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

Research Models

An iPSC cell line has been generated from skin fibroblasts of a 48-year-old presymptomatic woman carrying the mutation (Li et al., 2016). An isogenic control line, in which the mutation has been corrected, is also available (Pires et al., 2016). As noted above, alterations in the transcriptional profiles of glutamatergic neurons derived from these cells have been reported (Corsi et al., 2023).

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References

News Citations

1. Ratio of Short to Long Aβ Peptides: Better Handle on Alzheimer's than Aβ42/40? 20 Apr 2022
2. When It Comes to Alzheimer’s Disease, Do Human Microglia Even Give a DAM? 23 May 2019

Paper Citations

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External Citations

1. gnomAD v2.1.1

Further Reading