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Alzheimer’s Disease Type 3 (AD3)

January 28, 2018

Disease synonyms

Alzheimer’s disease type 3 (AD3); Early onset Alzheimer’s disease type 3; Familial Alzheimer’s disease type 3; Dilated cardiomyopathy type 1U (CMD1U); Frontotemporal dementia (FTD); Frontotemporal lobar degeneration with Tau inclusions; FTLD with TAU inclusions; Frontotemporal lobe dementia (FLDEM); Multiple system aptrophy with presenile dementia (MSTD); Disinhibition dementia-Parkinsonism-amyotrophy complex (DDPAC); Welhemsen-Lynch disease (WLD); Ppallidopontonigral degeneration (PPND); Pick disease; Pick disease of brain; Lobar atrophy of brain; Dementia with lobar atrophy and neuronal cytoplasmic inclusions

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.

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 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.

Early-onset familial Alzheimer’s disease-3 (AD3) is caused by heterozygous pathogenic variants in the presenilin-1 gene (PSEN1) on chromosome 14q24, and these pathogenic variants account for 30-70% of all early onsets AD cases 1, 4, 5. The protein encoded by PSEN1 acts as part of the gamma secretase cleavage system for amyloid-β A4 protein. Clinical features of AD3 include relatively rapid progression of memory and cognitive function loss associated with seizures, myoclonus, and language deficits 6. Several families have had associated spastic paraplegia with "cotton wool" amyloid plaques 7.

More than 100 pathogenic variants which result in EOFAD have been described in almost a hundred families 4-7; the majority are missense variants. At least nine pathogenic variants occur in a cytosolic domain between transmembrane domains 6 and 7, and the rest of the variants are within the other hydrophobic domains or immediately at the hydrophilic/hydrophobic junctions, especially of transmembrane domain 2 4-7. The relative frequency of pathogenic variants in the cytosolic domain encoded by the alternatively spliced exon 8 suggests that this region of the protein is functionally important 6.

Abnormal PSEN1 results in increased production of the longer isoforms of amyloid-β peptide, which are neurotoxic and prone to self-aggregation 8. Some pathogenic variants may result in loss of the gamma secretase function of presenilin-1 9. Targeted analysis for pathogenic variants for a 4555-bp deletion spanning exon 9 is found in the Finnish population and is highly recommended for the relevant individuals. This variant is rarely observed in other populations 12.

Pathogenic variants in PSEN1 gene were also reported in association with other conditions, including frontotemporal type of dementia, psychiatric symptoms 1, early spastic paraparesis7, Lewy body pathology, Pick's disease 10, and dilated cardiomyopathy 11.

Treatment of PSEN1-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 PSEN1 gene sequencing and deletion/duplication testing. The PSEN1 gene is also part of the following panels:

Differential diagnosis

The differential diagnosis of PSEN1-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 PSEN1 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 PSEN1 gene testing:

Step 1:   PSEN1 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 PSEN1

Step 3:   If no pathogenic variant is identified after analysis of the PSEN1 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 PSEN1 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 PSEN1 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.