Alzheimer Disease, Familial, Panel

Familial Alzheimer disease is a neurodegenerative disorder characterized by onset of dementia at a relatively young age. Dementia initially presents in familial Alzheimer disease 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 familial Alzheimer disease includes: amyloid plaques, neurofibrillary tangles, neuronal loss and brain atrophy (Wu et al. 2012). An important feature of the familial Alzheimer disease diagnosis is that an individual has at least one affected family member.

Patients with familial Alzheimer 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 disease caused by APP or PSEN1 variants (Jayadev et al. 2010). In addition, PSEN2-related familial Alzheimer disease patients have a higher frequency of behavioral and psychotic symptoms of dementia, such as hallucinations or delusions (Canevelli et al. 2014).

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

The reported APP pathogenic variants are missense, frameshift and small deletion variants mainly contained within exons 16 and 17 of the APP gene. 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 and large deletion encompassing the entire APP gene have also been identified in familial Alzheimer disease patients (McNaughton et al. 2012). A rare recessive pathogenic variant in the APP gene was reported to cause familial Alzheimer disease (Di Fede et al. 2009). 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 PSEN1 and PSEN2, which play a role in pathogenesis of familial Alzheimer disease (Sua'rez-Calvet et al. 2014).

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 familial Alzheimer disease patients (Rogaeva et al. 2001; Janssen et al. 2003). 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 disease via impaired APP processing by gamma-secretase (Nornes et al. 2007; Heilig et al. 2013).

The major causative PSEN2 variants are missense variants. Two variants, N141I and M239V, account for 74% of all PSEN2-related familial Alzheimer disease cases (Canevelli et al. 2014). 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; Walker et al. 2005).

Pathogenic variants in PSEN1 gene accounts for 30%-70% of early onset familial Alzheimer disease while pathogenic variants in the APP gene are identified in ~15% of familial Alzheimer disease cases. Fewer pathogenic variants are found in PSEN2 gene which account for about 5% of all early onset familial Alzheimer disease (Marcon et al. 2009; Campion et al 1999; Wallon et al. 2012; Janssen et al. 2003).

In cohorts of autosomal dominant early-onset Alzheimer disease, the clinical sensitivity of the APP locus duplications can be roughly estimated to be 8% (Rovelet-Lecrux A. et al. 2006). Large deletions in PSEN1 in a large cohort of patients with autosomal dominant early-onset Alzheimer 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.