Alzheimer's Disease, Familial, Plus APOE Panel

Familial Alzheimer's disease is a neurodegenerative disorder characterized by onset of dementia at a relatively young age. Dementia initially presents in patients with familial Alzheimer's disease 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. PubMed ID: 22475797). Motor disturbances such as cerebellar ataxia and spastic paraparesis are also observed in a subset of patients. The key neuropathology of familial Alzheimer's disease includes amyloid plaques, neurofibrillary tangles, neuronal loss, and brain atrophy (Wu et al. 2012. PubMed ID: 22728850). An important feature of a familial Alzheimer's disease diagnosis is that an individual has at least one affected family member.

Patients with familial Alzheimer's disease caused by PSEN2 pathogenic variants typically show a later age of onset in the 50s or 60s as compared to onset in the 30s or 40s as seen in familial Alzheimer's disease caused by APP or PSEN1 variants (Jayadev et al. 2010. PubMed ID: 20375137). In addition, patients with PSEN2-related familial Alzheimer's disease have a higher frequency of behavioral and psychotic symptoms of dementia, such as hallucinations or delusions (Canevelli et al. 2014. PubMed ID: 24594196).

Familial Alzheimer's disease is inherited in an autosomal dominant manner and can be caused by pathogenic variants in the APP, PSEN1, and PSEN2 genes.

Reported APP pathogenic variants include missense, frameshift, and small deletion variants mainly located in exons 16 and 17 of the APP gene. These variants disrupt the processing of APP into mature amyloid-beta protein (Janssen et al. 2003. PubMed ID: 12552037; Mullan et al. 1992. PubMed ID: 1302033; Tomiyama et al. 2008. PubMed ID: 18300294). Large duplications and large deletions encompassing the entire APP gene have also been identified in patients with familial Alzheimer's disease (McNaughton et al. 2012. PubMed ID: 21193246). A rare recessive pathogenic variant in the APP gene has been reported to cause familial Alzheimer's disease (Di Fede et al. 2009. PubMed ID: 19286555). APP encodes amyloid-beta precursor protein (APP). APP is post-translationally processed into two amyloid-beta isoforms: AB40 and AB42. The gamma-secretase complex that processes APP contains the proteins PS1 and PS2, which play a role in pathogenesis of familial Alzheimer's disease (Suárez-Calvet et al. 2014. PubMed ID: 24117942).

Most causative PSEN1 variants are missense variants distributed throughout the gene, though frameshifts, splice site variants, and large deletions in PSEN1 have also been identified in patients with familial Alzheimer's disease (Rogaeva et al. 2001. PubMed ID: 11524469; Janssen et al. 2003. PubMed ID: 12552037). PSEN1 encodes the presenilin-1 (PS1) protein. PS1 is the catalytic subunit of the gamma-secretase complex which cleaves the Alzheimer's-associated alpha-beta precursor protein (APP). PSEN1 variants are believed to act in a dominant negative manner to interfere with wildtype PS1 activity and to cause familial Alzheimer's disease via impaired APP processing by gamma-secretase (Nornes et al. 2008. PubMed ID: 17981814; Heilig et al. 2013. PubMed ID: 23843529).

The major causative PSEN2 variants are missense variants. Two variants, p.N141I and p.M239V, account for 74% of all PSEN2-related familial Alzheimer's disease cases (Canevelli et al. 2014. PubMed ID: 24594196). No large deletions or duplications have been reported to date. PSEN2 encodes the presenilin-2 (PS2) protein. PS2 is a subunit of the gamma-secretase complex which cleaves the Alzheimer's-associated alpha-beta precursor protein (APP). Although PSEN2 knockout mice do not show amyloid-beta processing defects, pathogenic PSEN2 variants were shown to alter AB40:AB42 ratios in in vitro cell-based assays (Herreman et al. 1999. PubMed ID: 10518543; Walker et al. 2005. PubMed ID: 15663477). 

APOE is a susceptibility gene for late onset Alzheimer's disease. In particular, the E4 allele is a risk factor for late-onset Alzheimer's disease. Note, however, that APOE genotyping is not fully specific or sensitive. APOE is just one of many risk factors for Alzheimer's disease (Desikan et al. 2017. PubMed ID: 28323831). Many individuals with the APOE E4/E4 genotype do not develop Alzheimer's disease during their lifetimes (Goldman et al. 2011. PubMed ID: 21577118; Bird. 2018. PubMed ID:20301340). Of note, several recent notable studies investigated APOE E4 effect on pathophysiology and therapeutic strategies (for example Koutsodendris and Rao. 2022. PubMed ID: 34460318; Raulin et al. 2022. PubMed ID: 36348357). 

Pathogenic variants in PSEN1 account for 30%-70% of early-onset familial Alzheimer's disease while pathogenic variants in APP are identified in ~15% of familial Alzheimer's disease cases. Fewer pathogenic variants are found in PSEN2, which account for about 5% of all early-onset familial Alzheimer's disease (Marcon et al. 2009. PubMed ID: 19276543; Campion et al. 1999. PubMed ID: 10441572; Wallon et al. 2012. PubMed ID: 22475797; Janssen et al. 2003. PubMed ID: 12552037).

In cohorts of autosomal dominant early-onset Alzheimer's disease, the clinical sensitivity of APP locus duplications can be roughly estimated to be 8% (Rovelet-Lecrux et al. 2006. PubMed ID: 16369530). Large deletions in PSEN1 in a large cohort of patients with autosomal dominant early-onset Alzheimer's disease is unavailable in the literature because large deletions have only been reported in individual cases. No large deletions/duplications in PSEN2 have been reported.

This panel provides 100% coverage of all coding exons of the genes listed, plus ~10 bases of flanking noncoding DNA. We define coverage as ≥20X NGS reads or Sanger sequencing.

We only report the following APOE genotypes: E4/E4, E4/E2 and E4/E3.