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Alzheimer’s Disease Type 4 (AD4)

January 28, 2018

Disease synonyms

Alzheimer’s disease type 4 (AD4); Dilated cardiomyopathy type 1V, CMD1V, Frontotemporal dementia, FTD

Inheritance pattern

Autosomal dominant

Clinical features

Alzheimer’s disease (AD) is the most common form of dementia. The term dementia describes a set of symptoms that can include memory loss and difficulties with thinking, problem-solving or language. In early stages, AD patients typically have memory loss, confusion, and inability to learn. In later stages their progressive dementia are associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating.

Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Occasionally, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism occur.

Alzheimer’s disease (AD) is diagnosed in individuals having memory problems with one of the followings:

  • other causes of dementia excluded
  • Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination 

Early-onset AD refers to persons affected with an onset consistently before ages 60 to 65 1. The three clinically indistinguishable subtypes of early onset AD based on the underlying genetic mechanism are as follows 1:

  • Alzheimer’s disease type 1 (AD1), caused by  pathogenic variants in APP (10-15% of EOFAD);
  • Alzheimer’s disease type 3 (AD3), caused by  pathogenic variants in PSEN1 (30-70% of EOFAD);
  • Alzheimer’s disease type 4 (AD4), caused by pathogenic variants in PSEN2 (<5%of EOFAD).

Alzheimer’s disease type 2 is late-onset, associated with APOE*4 allele.

The prevalence of AD increases with age: Approximately 10% of persons over age 70 years have significant memory loss and more than half of these individuals have AD. Furthermore, an estimated 25-45% of persons over age 85 years have dementia 1,2. The prevalence of early-onset AD is estimated at 41.2 per 100,000 for persons aged 40-59 years 2, and early onset familial AD (EOFAD) comprises less than 3% of all AD 1,3. Among families with EOFAD, 40-80% have a pathogenic variant in APP, PSEN1, or PSEN2 4, 5.

Alzheimer’s disease type 4 (AD4) is caused by variants in PSEN2 and accounts for <5% of EOFAD 1, 2. AD4 has been identified in a few families; most are of Volga German ancestry, living in the United States, in three Italian kindreds 6, in two Italian kindreds 7, and in two Spanish families 8.

Treatment of PSEN2-associated conditions and manifestations include supportive therapy, management of the symptoms of depression, aggression, sleep disturbance, seizures, and hallucinations. Affected individuals eventually require assisted living/nursing home care. Agents which increase cholinergic activity, such as Aricept® (donepezil), Exelon® (rivastigmine), and Reminy® (galatamine), show modest but variable benefit; memantine, an NMDA receptor antagonist, is approved for use in AD; physical and occupational therapy help manage activities of daily living.

CENTOGENE offers full PSEN2 gene sequencing and deletion/duplication testing. The PSEN2 gene is also part of the following panels:

Differential diagnosis

The differential diagnosis of PSEN2-related disorders – depending on the major symptoms in the initial case – includes the following diseases:

  • Frontotemporal dementia
  • Frontotemporal dementia with parkinsonism-17
  • Inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia
  • PGRN-related frontotemporal dementia
  • CHMP2B-related frontotemporal dementia
  • Amyotrophic lateral sclerosis with frontotemporal dementia
  • Huntington disease
  • Prion diseases

Diagnostic strategy

To confirm/establish the diagnosis, we offer hotspot testing, PSEN2 gene sequencing, and deletion/duplication gene testing. We also offer a broad selection of NGS panels which are designed for the molecular genetic diagnosis of related conditions/phenotypes.

Thus, CENTOGENE offers the following testing strategy for PSEN2 gene testing:

Step 1:   PSEN2 sequencing – covers the entire coding region, exon/intron boundaries and 200 bp of the gene promoter.

Step 2:   Deletion/duplication analysis/pathogenic variant scanning of PSEN2

Step 3:   If no pathogenic variant is identified after analysis of the PSEN2 gene, panel testing with related genes or further genetic testing of related genes can be done.

Step 4:   If no pathogenic variant is identified in any of the panel genes listed, we can offer whole exome sequencing, based on NGS technology.

Referral reasons

The following individuals are candidates for PSEN2 gene testing:

  • Individuals with a family history of early onset familial Alzheimer’s disease (EOFAD) and presentation of the most common symptoms
  • Individuals without a positive EOFAD family history, but with symptoms resembling this disease
  • Individuals with a negative but suspected family history of EOFAD, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of PSEN2 gene and related genes should be performed in all individuals suspected of having early onset Alzheimer’s disease. In parallel, other genes reported to be related to EOFAD should also be analyzed for the presence of pathogenic variants, due to the overlap in many clinical features caused by those particular genes.

Confirmation of a clinical diagnosis through genetic testing can allow for genetic counseling and may direct medical management.

Genetic counseling can provide a patient and/or family with the natural history of EOFAD, identify at-risk family members, provide information about reproductive risks as well as preconception/prenatal options, and allow for appropriate referral for patient support and/or resources.