Dementia describes a set of clinical symptoms that include impairment of memory, communication, and ability to perform daily tasks. The lifetime risk of dementia in the general population is 10%. Approximately 25% of all people aged 55 years and older have a positive family history of dementia 1.
According to clinical and research criteria there are four primary dementia subtypes 1, 2:
1) Alzheimer’s disease (most common)
2) Vascular dementias
3) Frontotemporal dementias
4) Dementia with Lewy bodies.
5-10% of adults >60 years of age have dementia3
Major clinical symptoms 4:
- Memory failure and memory loss, subtle and poorly recognized, progressive.
- Language disturbance.
- Confusion and poor judgment.
- Progressive behavioral changes, agitation, withdrawal, and hallucinations.
Less common clinical symptoms 4:
- Seizures and myoclonus
- Parkinsonian features
- Increased muscle tone
- General malnutrition, pneumonia.
- Presence of the specific clinical features for progressive dementia.
- Neuropathologic findings of β-amyloid plaques and intraneuronal neurofibrillary tangles are the gold standard for diagnosis (however, performed only on the brain tissue).
- Positive family history of dementia.
- Identification of a heterozygous pathogenic variant in one of the following genes (Table 1): APOE, APP, CHMP2B, CSF1R, FUS, GRN, MAPT, PRNP, PSEN1, PSEN2, SORL1, TARDBP, TREM2, UBE3A, VCP.
- There are no specific treatments or cures to slow or stop the progression of dementia.
- There are medications that can reduce agitation and other behavioral problems and/or depression which can improve quality of life4.
- Parkinson disease
- Amyotrophic lateral sclerosis
- Picks disease
- Creutzfeldt-Jakob disease
- Chronic drug intoxication
- Chronic CNS infection
- Thyroid disease
- Vitamin B12 and thiamine deficiencies
To confirm/establish the diagnosis, CENTOGENE offers the following tests:
- Dementia NGS Panel Plus which includes sequencing of the genes APOE, APP, CHMP2B, CSF1R, FUS, GRN, MAPT, PRNP, PSEN1, PSEN2, SORL1, TARDBP, TREM2, UBE3A, VCP and repeat expansion analysis of the genes C9orf72 and PRNP
- Dementia NGS Panel Plus + CNV which includes sequencing and additionally detection of large deletions and duplications from the NGS data
- Individuals with a positive family history of dementia
- Individuals with most common symptoms of dementia (regardless of family history)
Confirmation of a clinical diagnosis through genetic testing of dementia can allow for genetic counseling and may direct medical management.
Table 1. Overview of the genes in CENTOGENE´s Dementia panel:
|Locus||Associated phenotypes (OMIM)||Pathogenic variant frequency|
|19q13.32||Alzheimer disease-2 (104310); Hyperlipoproteinemia, type III (617347); Lipoprotein glomerulopathy (611771); Sea-blue histiocyte disease (269600)||e4/e4 genotype in ~13% of all individuals with AD4|
|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 75% 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% 4, 6, 8|
|PSEN2 600759||1q42.13||Alzheimer disease 4 (606889); Cardiomyopathy, dilated, 1V (613697)||Rare 4, 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 4, 6, 8|
|UBE3A 601623||15q11.2||Angelman syndrome (105830)||Rare 17|
|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|