1. Dementia panel

Dementia panel

January 12, 2018

Disease synonyms

Dementia, Presenile and senile dementia, Senile dementia, Presenile dementia, Alzheimers disease, AD, Frontotemporal dementia, FTP, Multiple system tauopathy with presenile dementia  

Inheritance pattern

Autosomal dominant 

Clinical features

Dementia is a clinical syndrome of progressive deterioration of cognitive abilities and functional impairments. Approximately 25% of all people aged 55 years and older have a family history of dementia 1. Considering the huge variety of symptoms and individual variations in clinical presentations of dementia, the need for solid diagnostic criteria was imperative. Therefore, the American psychiatric association developed the diagnostic and statistical manual of mental disorders and today its fourth edition (DSM-IV) is in use for diagnostics of mental disorders worldwide 2.

According to clinical and research criteria there are four primary dementia subtypes:

1) Alzheimer’s disease

2) Vascular dementias

3) Frontotemporal dementias

4) Dementia with Lewy bodies 1, 2.

The most common type of dementia is Alzheimer’s disease (AD), which makes up 50-70% of cases 1, 2, or about two thirds of all dementia cases in the population older than 65 years 19. AD presents with an insidious onset and progresses gradually, resulting in cognitive impairment and memory decline 20. The memory changes associated with AD are characterized as storage deficits, with rapid forgetting and poor delayed memory recall. Deficits in declarative memory are prominent at disease outset, with more severe memory impairments emerging later over the course of the disease. Language impairment is also a prominent clinical feature, with the initial signs of reduced expressive language, word-finding difficulties, and limited vocabulary 20. Visuospatial dysfunctions are also common in advanced AD, manifesting as impaired driving ability, getting lost, and difficulty producing drawings of figures 20. Problems with mathematical calculations, executive dysfunction, decision making, and judgment are also commonly observed. In addition to cognitive impairments, behavioral and psychiatric symptoms are common in AD, with depression in up to 50% of AD individuals 20. Psychosis generally occurs later in the disease course, with delusions, hallucinations, and other symptoms. 

There are three known causative genes for early-onset Alzheimer’s disease: APP, PSEN1, and PSEN2 (see Table 1) and 86% of families with young-onset (<60 years) dementia in three or more generations have a pathogenic variant in one of these genes 5, 6, 8, 20. Pathogenic variants in PSEN1 are the most frequent cause, accounting for up to 70% (20-70%) of familial cases of AD 3, 6, 8. About 15% of families affected with AD have pathogenic variants in APP 5, 6. Pathogenic variants in PSEN2 are rare 3, 6, 8.

Although most people with Alzheimer's disease do not have pathogenic variants in the APP, PSEN1, or PSEN2 genes, there are other genetic variations which could increase the risk of AD, including allelic variants in APOE and TREM2. Typically, loss-of function variants in the TREM2 gene are associated with presenile dementia with bone cysts, also known as Nasu-Hakola disease. On the other side, several missense TREM2 variants are reported to be disease-causing or risk factor for AD (HGMD Professional Database). Furthermore, recent genome-wide association studies have revealed that methylation changes in TREM2 intron 1 might as well be associated with AD21

Vascular dementia is the second most common form of dementia, accounting for 25% of all dementia cases 1, 2, 20. However, its genetic component remains poorly understood, especially when compared to other causes of dementia such as Alzheimer’s disease (AD), Parkinson’s disease, and frontotemporal lobar degeneration.

The most common monogenic disorders associated with cerebral small vessel disease and resulting in vascular dementia include the following:

  • CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), caused by pathogenic variants in the NOTCH3 gene on chromosome 19q12 22. Common clinical manifestations include migraine headaches, recurrent subcortical ischemic events, cognitive impairment, mood disorders, and seizures.
  • Fabry disease, an X-linked lysosomal disease caused by a pathogenic variant of the GLA gene on chromosome Xq22. This results in an absent or reduced a-galactosidase activity which finally leads to accumulation of glycosphingolipid in different organs 23. Common clinical features and findings include stroke or transient ischemic attack, renal disease, and cardiomyopathy.
  • COL4A1/A2-related arteriopathy, and hereditary systemic angiopathy, due to TREX1 gene pathogenic variants. These cause small vessel arteriopathy and intracranial hemorrhages. The disease is characterized by cerebral leukodystrophy and retinal vasculopathy, cognitive impairment, migraine, psychiatric abnormalities, and seizures 24.
  • Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), due to pathogenic variants in the HTA1 gene. This has been described in Asians and recently in some European cases. Clinically, the disease is characterized by recurrent lacunar strokes associated with a rapidly progressive cognitive impairment, seizures, and psychiatrics disturbance including dementia 25.

Frontotemporal dementia is a heterogeneous group of syndromes characterized by progressive deterioration in behavior, speech and memory. Frontotemporal dementia can be subdivided into three clinical subtypes: behavioral-variant frontotemporal dementia, progressive non-fluent aphasia, and semantic dementia. Three causative genes explain over 80% of cases of frontotemporal dementia in families with a strong autosomal dominant family history: MAPT 13, GRN 12, and C9orf72 7

Pathogenic variants in MAPT account for up to 30% of frontotemporal dementia cases 13. The MAPT gene encodes Tau, a microtubule binding protein involved in the transport of organelles and other cellular components. Pathogenic variants in MAPT can either disrupt the tau protein structure or alter the proportion of different tau isoforms available, leading to impaired microtubule assembly, impaired axonal transport, and pathological tau filament aggregation.

Pathogenic variants in the GRN gene, encoding progranulin, account for 5% of FTD 7, 12 and 23% of frontotemporal lobar degeneration cases 7. The majority of pathogenic variants in GRN are null pathogenic variants which lead to a nonsense-mediated decay of mutant GRN mRNA and reduced expression of protein. 

Table 1. Overview of genes associated with dementia.

Locus Associated phenotypes (OMIM) Pathogenic variant frequency   
APP 104760 21q21.3 Alzheimer disease 1, familial (104300); Cerebral amyloid angiopathy, Dutch, Italian, Iowa, Flemish, Arctic variants (605714) 10-15% of early onset AD 5, 6
9q34.2 Frontotemporal dementia and/or ALS1 (105550) 74-100% for GGGGCC expansion 7, 8 ,9
3p11.2 Amyotrophic lateral sclerosis 17 (614696); Dementia, familial, nonspecific (600795) Missense pathogenic variants 7, 9
5q32 Leukoencephalopathy, diffuse hereditary, with spheroids (221820) 52/405 (13%) for ALSP 10
FUS 137070 16p11.2 ALS6 with or without frontotemporal dementia (608030); Tremor, hereditary essential, 4 (614782) ~4% of FALS 11
GRN 138945 17q21.31 Frontotemporal lobar degeneration with ubiquitin-positive inclusions (607485); Ceroid lipofuscinosis neuronal 11 (614706);

23% for frontotemporal lobar degeneration 7

5% of FTD 7, 12
MAPT 157140


Dementia, frontotemporal, with or without parkinsonism (600274); Pick disease (172700); Supranuclear palsy progressive (601104) and atypical (260540); Parkinson disease susceptibility (168600) 13-30% 13
PRNP 176640 20p13 Cerebral amyloid angiopathy (137440); Creutzfeldt-Jakob disease (123400);  Gerstmann-Straussler disease (137440); Huntington disease-like 1 (603218); Insomnia, fatal familial (600072); Prion disease with protracted course (606688); Kuru susceptibility (245300) 5-10% of inherited forms of prion diseases 14
PSEN1 104311 14q24.2 Alzheimer disease 3 (607822); Cardiomyopathy, dilated, 1U (613694), Dementia, frontotemporal (600274); Pick disease (172700) 20-70% 3, 6, 8
PSEN2 600759 1q42.13 Alzheimer disease 4 (606889); Cardiomyopathy, dilated, 1V (613697)  Rare  3, 6, 8
SORL1 602005 11q24.1 Alzheimer disease (104300) 5/14 early onset Ad negative for APP, PSEN1 and PSEN2 17
TARDBP 605078 1p36.22 Frontotemporal lobar degeneration, TARDBP-related (612069); ALS 10 (612069)  100% for TARDBP-related ALS 15
TREM2 605086 6p21.1 Nasu-Hakola disease (221770) Rare 3, 6, 8
UBE3A 601623 15q11.2 Angelman syndrome (105830) Rare 18
VCP 601023 9p13.3 ALS14 with or without FTD (613954); Charcot-Marie-Tooth disease type 2Y (616687); Inclusion body myopathy with Paget disease and FTD 1 (167320) 100% for Inclusion body myopathy 16 18

The expanded GGGGCC hexanucleotide repeats in the intronic region of the C9ORF72 gene have been linked to frontotemporal dementia with motor neuron disease 7, 8, 9. Less than 20 repeats in the C9ORF72 gene is regarded as normal, while more than 65 repeats is linked to a disease 26.

In addition to the three main frontotemporal dementia-causing genes, there are many genetic causes of frontotemporal dementia which are associated with rarer forms of disease, such as pathogenic variants in VPC, FUS, CHMP2B and TARDBP.

Dementia with Lewy bodies (DLB) is the second-largest neuropathological subgroup of dementia, preceded only by Alzheimer disease. This form of dementia is clinically characterized by cognitive decline, parkinsonian signs and symptoms, fluctuations in cognition and attention, and visual hallucinations 27. Pathologically, Lewy bodies are present in a pattern more widespread than usually observed in Parkinson disease. There is a substantial clinical overlap between DLB and AD, as well as Parkinson disease (PD). Patients with DLB generally exhibit hallucinations earlier in the course of illness than patients with AD, but their parkinsonian signs and symptoms are milder than in isolated PD. Genetic forms of dementia with Lewy bodies have been associated with pathogenic variants in synuclein genes (SCNA, SCNB) as well as with e4 allele variants in the APOE gene 19, 20.

There is no specific treatment for dementia. There are medications which can reduce agitation and other behavioral problems and/or depression. These treatments should be used to help improve quality of life. Researchers are looking for new treatments, seeking to change the course of the disease and to improve the quality of life for people with dementia.

CENTOGENE offers an analysis using our Dementia panel. Genes which are sequenced include: APP, CHMP2B, CSF1R, FUS, GRN, MAPT, PRNP, PSEN1, PSEN2, SORL1, TARDBP, TREM2, UBE3A, VCP. Genes which are analyzed by repeat expansion analysis: C9orf72 (only repeat expansion analysis, no sequencing) and PRNP.

Differential diagnosis

The differential diagnosis of dementia-related disorders includes the following diseases - depending on the major presenting symptoms:

  • Depression
  • Parkinson disease
  • Amyotrophic lateral sclerosis
  • Picks disease
  • Creutzfeldt-Jakob disease
  • Chronic drug intoxication
  • Chronic CNS infection
  • Thyroid disease
  • Vitamin B12 and thiamine deficiencies 

Diagnostic strategy

CENTOGENE offers an advanced, fast and cost-effective strategy to test large NGS panels and diagnose complex phenotypes based on PCR-free Whole Genome Sequencing and NGS technology. This approach offers an unparalleled advantage by reducing amplification/capture biases and provides sequencing of the entire gene with more uniform coverage. 

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for dementia using NGS Panel Genomic targeted towards this specific phenotype:

Step 1:       Repeat expansion analysis for the genes C9orf72 and PRNP

Step 2:       Whole genome sequencing from a single filter card. The sequencing covers the entire gene region (coding region, exon/intron boundaries, intronic and promoter) for all the genes included in the Dementia panel. Deletion/duplication analysis is performed separately.

Step 3:       If no pathogenic variant is identified after analysis of the Dementia panel, we further recommend continuing the bioinformatics analysis of the data obtained using whole genome sequencing to cover those genes which are either implicated in an overlapping phenotype or could be involved in a similar pathway but are not strongly clinically implicated based on the current information in literature.   

Referral reasons

The following individuals are candidates for dementia panel testing:

  • Individuals with a family history of dementia and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling dementia
  • Individuals with a negative but suspected family history, in order to perform proper genetic counseling (prenatal analyses are recommended in families with affected individuals).

Test utility

Sequencing, deletion/duplication of dementia related genes should be performed in all individuals suspected of having dementia. In parallel, other genes reported to be related with this clinical phenotype 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 dementia, 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.

More information on CENTOGENE´s genetic tests for Dementia panel can be found in our genetic test catalogue.