Pathogenicity: Alzheimer's Disease : Pathogenic
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37 (105)
Position: Chr21:27269931 C>T
dbSNP ID: NA
Genomic Region: Exon 16
Mutation Type: Point, Missense
Codon Change: GCA to GTA
The A673V mutation in APP is unusual in that it appears to be recessive rather than autosomal-dominant.
It was detected as a homozygous allele in two Italian siblings with symptoms of Alzheimer’s disease. Genetic testing of multiple relatives revealed many heterozygous carriers who were not affected by AD. The proband presented with behavioral changes and cognitive deficits at the age of 36, and he was diagnosed with early onset Alzheimer's disease. His symptoms evolved into severe dementia with spastic tetraparesis (spasticity affecting all four limbs), and he died at 46 years old. The proband’s younger sister had mild cognitive impairment at the time the report was published.
Genotyping of relatives from both the maternal and paternal branches of the family revealed six heterozygous carriers who were unaffected by AD. The siblings’ parents were deceased and therefore could not be genotyped, but they are presumed to be heterozygous carriers and did not have AD at the time of their deaths (both at 60-plus). In addition to screening the APP gene, PSEN1, PSEN2, MAPT, and progranulin (PGRN) were interrogated, but no additional mutations were found (Di Fede et al., 2009).
Autopsy of the proband confirmed a diagnosis of definite AD by CERAD criteria. Extensive Aβ and tau pathology were noted (stage VI of Braak and Braak). Aβ plaques and cerebral amyloid angiopathy were abundant throughout the cerebral cortex, but largely spared the neostriatum. Plaques were unusually perfuse in the cerebellum and brainstem, and were frequently perivascular. Plaques contained abundant Aβ40, and were noted to be unusually large, with few preamyloid deposits. A detailed neuropathological analysis of the proband’s brain is reported in Giaccone et al., 2010.
The A673 residue of APP lies very near the primary β-secretase site, and after cleavage the residue becomes part of the Aβ peptide. In vitro studies suggest that the A673V mutation contributes to AD pathology not only by increasing total Aβ production, but also by enhancing Aβ aggregation and toxicity.
The A673V mutation makes APP a more favorable substrate for β-secretase, shifting APP processing toward the amyloidogenic pathway. When overexpressed in CHO and COS-7 cells, mutant APP produced higher levels of Aβ40 and Aβ42 peptides than wild-type APP. Additional β-secretase cleavage products, e.g., sAPPβ and APP-C99, were likewise increased. The ratio of Aβ40 to Aβ42 was unchanged (Di Fede et al., 2009). Elevated Aβ production was subsequently confirmed in primary mouse neurons expressing human APP (isoform 695) with A673V (Benilova et al., 2014; Maloney et al., 2014), and in iPSC-derived human neurons (Maloney et al., 2014).
In addition to increasing Aβ production, the A673V mutation accelerates Aβ aggregation. The mutant Aβ, called A2V because the A673V mutation occurs at position 2 of Aβ, is more aggregation-prone than wild-type Aβ. It is currently unclear whether this increase in aggregation is primarily due to effects on Aβ40, Aβ42, or both (see Di Fede et al., 2009; Benilova et al., 2014; Maloney et al., 2014).
Notably, given that this mutation appears to be pathogenic only in the homozygous state, a mixture of wild-type and mutant Aβ peptides aggregated more slowly than either peptide alone. Furthermore, in cultured neuroblastoma cells, a mixture of mutant and wild-type Aβ42 was less toxic than either peptide alone, suggesting that in heterozygoous carriers, a single mutant allele may actually protect against AD by reducing Aβ aggregation and toxicity (Di Fede et al., 2009; Di Fede et al., 2012). However, even as a pure peptide, A2V Aβ may only be mildly toxic to neurons, requiring a high concentration (10 µM) to reduce viability (Maloney et al., 2014).