Dementia, Plus APOE Panel

Dementia is characterized by cognitive and behavioral decline. It is caused by a progressive degeneration and atrophy of various regions of the brain. Progressive dementia is common in several neurodegenerative syndromes in adults. The most prevalent forms are Alzheimer’s disease (AD) and Frontotemporal dementia (FTD) (Wu et al. 2012. PubMed ID: 22728850; Onyike and Diehl-Schmid 2013. PubMed ID: 23611343). Although there is a considerable phenotypic overlap between AD and FTD, several distinguishing features exist.

AD may be distinguished by a later age of onset and slower progression compared to FTD. In addition, memory loss and visual and spatial abnormalities are the chief complaints in AD; while behavioral abnormalities are the main features in FTD. Patients with FTD often develop motor abnormalities, which are rare in patients with AD (Harciarek and Jodzia. 2005. PubMed ID: 16328732).

Based on the age of onset of symptoms, AD is conventionally classified in two types: early-onset AD when symptoms begin before the age of 65 years, and late-onset AD when symptoms begin after the age of 65 years. Age of onset may differ among affected relatives (Brickell et al. 2006. PubMed ID: 16966510). Gross cortical atrophy accompanied by aggregation of beta-amyloid protein in the form of plaques and tangles are hallmark features of the disease (Blennow et al. 2006. PubMed ID: 16876668). The dysfunction of the affected areas of the brain results in gradual deterioration of memory that affects language, personality, and cognitive control. Symptoms include irritability, aggression, confusion and mood changes. As the disease progresses, additional symptoms develop and include sleep disturbances, loss of language skills, depression, and withdrawal. Eventually, patients do not recognize the faces of close family members and lose the ability to perform routine tasks independently (Bäckman et al. 2004. PubMed ID: 15324363).

FTD, previously referred to as Pick’s disease, is a clinically heterogeneous syndrome due to the progressive degeneration and atrophy of various regions of the frontal and temporal lobes of the brain. Frontal temporal dementias account for about 10% of all dementias. Symptoms are insidious and begin usually during the fourth and sixth decades of life; although earlier and later onsets have been documented (Snowden et al. 2002. PubMed ID: 11823324; Bruni et al. 2007. PubMed ID: 17620546). The annual incidence of FTD is 3-4 per 100,000 (Onyike and Diehl-Schmid 2013. PubMed ID: 23611343).

Two major forms, the behavioral-variant (FTD-bv) and the primary progressive aphasia (PPA), are recognized based on the site of onset of degeneration and the associated symptoms. FTD-bv comprises about half of FTD cases with the degenerative process beginning in the frontal lobes and resulting in personality changes and deterioration of social conducts. Most common behavioral changes are: disinhibition, apathy, deterioration of executive function, obsessive thoughts, compulsive behavior, and neglect of personal hygiene (Rascovsky et al. 2011. PubMed ID: 21810890). PPA is a language disorder that is further divided into two sub-forms: progressive nonfluent PPA and semantic variant PPA. Nonfluent PPA is characterized by difficulty in verbal communications, word retrieval, and speech distortion. Reading, writing and spelling are also affected; while memory is relatively preserved. Semantic variant PPA is characterized by the progressive impairment of word comprehension, object and face recognition, and loss of semantic memory. Reading and writing skills are relatively preserved (Gustafson. 1993. PubMed ID: 8401782).

Early-onset AD accounts for less than 2% of AD cases and is inherited in an autosomal dominant manner. In late-onset AD, disease and genetic etiology is unclear. Highly penetrant pathogenic variants in the PSEN1, APP, and PSEN2 genes account for up to 70%, 15% and 5% of early-onset AD cases (Bird. 2018. PubMed ID: 20301340). The majority of pathogenic variants in the PSEN1 gene are missense changes; however loss of function variants, including gross deletions, have been reported in a few cases (Evin et al. 2002. PubMed ID: 11997713). The c.839A>C (p.Glu280Ala) and c.617G>C (p.Gly206Ala) changes have been previously described as founder variants in Columbian and Caribbean Hispanics, respectively (Lalli et al. 2014. PubMed ID: 24239249; Lee et al. 2014. PubMed ID: 25333068). Missense changes in exons 16 and 17 resulting in disruption of APP processing into mature amyloid-beta protein represent ~60% of pathogenic variants in the APP gene whereas gross duplications of the APP gene account for about ~30% cases (Wallon et al. 2012. PubMed ID: 22475797; Rovelet-Lecrux et al. 2006. PubMed ID: 16369530). Missense changes primarily in exons 6 and 8 are the account for over half of the pathogenic variants found in the PSEN2 gene. The c.422A>T (p.Asn141Ile) change has been reported as a founder variant in Germany (Yu et al. 2010. PubMed ID: 20457965).

FTDs are inherited in 30-50% of cases in an autosomal dominant manner with pathogenic variants in C9orf72, MAPT and GRN accounting for about 30%, 15% and 25% of these cases respectively. An expansion of a GGGGCC hexanucleotide repeat in an intron 1 non-coding region of the C9orf72 gene is the most common cause of FTD. Greater than 30 hexanucleotide repeats is considered pathogenic whereas less than 25 repeats is considered benign (Majounie et al. 2012. PubMed ID: 22406228; van der Zee et al. 2013. PubMed ID: 23111906). Missense changes in exons 2 and 9-13 are the most common pathogenic variants in the MAPT gene. However, spice site alterations, gross duplications and inframe deletions/insertions have also been reported (Goldman and Van Deerlin et al. 2018. PubMed ID: 29971646). Several different types of pathogenic variants including missense, nonsense, splicing and small insertions/deletions have been reported throughout the GRN gene. Gross deletions account for ~1.5% GRN-FTD cases (Hsiung and Feldman. 2020. PubMed ID: 20301545).

Pathogenic variants in the CHCHD10, CHMP2B, CSF1R, FUS, ITM2B, SQSTM1, TARDBP, TBK1, TREM2 and VCP genes have also been associated with autosomal dominant ALS but represent less than 5% of cases (Goldman and Van Deerlin et al. 2018. PubMed ID: 29971646). Pathogenic variants in the UBQLN2 gene are associated with X-linked disease (Siddique and Siddique. 2019. PubMed ID: 20301623). Pathogenic variants in the DCTN1 gene are associated with autosomal dominant Perry syndrome.

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). 

See individual gene summaries for more information about molecular biology of gene products and spectra of pathogenic variants. 

In ~95% of early onset AD cases, pathogenic variants in the PSEN1, PSEN2, and APP genes are detected (Bird. 2018. PubMed ID: 20301340). In familial FTD cases, pathogenic variants are identified in up to 65% of total cases with C9orf72, MAPT, and GRN accounting for about 75% of the positive cases (Goldman and Van Deerlin et al. 2018. PubMed ID: 29971646). The majority of genes in this panel have no or very few large deletions/duplications.

The C9orf72 hexanucleotide repeat expansion test will be performed first as this is the most common cause of ALS and FTD. If C9orf72 testing is negative then the sequencing panel will be performed. Results for the C9orf72 repeat expansion and sequencing panel will be reported separately. Concurrent testing is available upon request.

The C9orf72 repeat expansion tests each utilize four unique assays: (1) a repeat primed PCR assay with the locus specific primer 5’ (upstream) of the repeat region (2) a repeat primed PCR assay with the locus specific primer 3’ (downstream) of the repeat region and (3,4) two unique fluorescent fragment length assays.

The sequencing panel typically provides 98.2% coverage of all coding exons of the genes listed plus 10 bases of flanking noncoding DNA in all available transcripts along with other non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).