Alzheimer's Disease, Familial or Cerebral Amyloid Angiopathy via the APP Gene

Familial Alzheimer's disease (FAD) is a neurodegenerative disorder characterized by onset of dementia at a relatively young age. Dementia initially presents in FAD patients as short term memory problems or disorientation between 30 and 60 years of age. Cognitive decline is observed over the next 10-20 years with apraxia, progressive memory loss and impaired spatial skills being common presentations (Wallon et al. 2012). Motor disturbances such as cerebellar ataxia and spastic paraparesis are also observed in a subset of patients. The key neuropathology of FAD includes: amyloid plaques, neurofibrillary tangles, neuronal loss and brain atrophy (Wu et al. 2012). An important feature of the FAD diagnosis is that an individual has at least one affected family member.

Cerebral amyloid angiopathy APP-related (CAA): Select pathogenic variants in the APP gene can also cause severe cerebral amyloid angiopathy, where amyloid fibrils accumulate in blood vessels and can lead to cerebral hemorrhage, stroke and progressive dementia. Clinical and neuropathologic symptoms of cerebral amyloid angiopathy overlap with Alzheimer's disease. Several variants such as Dutch, Iowa, Italian, Flemish, Arctic, etc. have been reported (Revesz et al. 2009; Biffi and Greenberg 2011; Kumar-Singh et al 2002).

Familial Alzheimer's disease is inherited in an autosomal dominant manner and can be caused by pathogenic variants in the APP gene. Almost all reported APP pathogenic variants are missense, frameshift and small deletion variants contained within Exons 16 and 17 of the APP gene, except rare large duplications. These variants disrupt processing of APP into mature amyloid-beta protein (Janssen et al. 2003; Mullan et al. 1992; Tomiyama et al. 2008). Large duplications encompassing the entire APP gene have also been identified in FAD patients (McNaughton et al. 2012). A rare recessive pathogenic variant in the APP gene was reported to cause FAD (Di Fede et al. 2009).

Cerebral amyloid angiopathy APP-related is inherited in an autosomal dominant manner. The causative pathogenic variants in cerebral amyloid angiopathy are missense variants and large duplications in APP gene. Most pathogenic variants such as Dutch, Iowa, Italian, Flemish Arctic etc. are concentrated in exon 17 (Biffi and Greenberg 2011; Sleegers et al 2006; Kumar-Singh et al 2002). APP encodes amyloid-beta precursor protein (APP). Numerous studies suggest that APP has a trophic function and it may be involved in neuronal stem cell development, neuronal survival, neurite outgrowth, neurorepair and memory formation (Dawkins and Small 2014; Bourdet et al. 2015). APP protein is post-translationally processed into two amyloid-beta isoforms: AB40 and AB42. The gamma-secretase complex that processes APP contains the proteins PSEN1 and PSEN2, which also play a role in FAD pathogenesis (Sua'rez-Calvet et al. 2014). Pathogenic variants in the APP gene that disrupt the gamma-secretase cleavage site can result in increased levels of the AB42 isoform relative to the AB40 isoform. This imbalance promotes amyloid-beta aggregation (Kumar-Singh et al. 2000). Pathogenic variants in the APP gene also result in hyperphosphorylation of the microtubule associated protein, tau (Umeda et al. 2014). Hyperphosphorylation causes tau to form long filaments and neurofibrillary tangles. The presence of amyloid plaques and neurofibrillary tangles leads to neuroinflammation and neuronal cell death, which underlie the dementia phenotype.

Point variants in the APP gene are identified in ~ 15% of familial Alzheimer's disease cases (Wallon et al. 2012; Janssen et al. 2003). Detection rate of pathogenic variants in the APP gene in cerebral amyloid angiopathy is unknown as no large-scale molecular studies have been done. APP-related cerebral amyloid angiopathy is the most common form of cerebral amyloid angiopathy.

This test provides full coverage of all coding exons of the APP gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.