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Alzheimer Dementia and Dementia Panel

January 12, 2018

Disease synonyms

Alzheimer dementia, Alzheimer’s disease, AD, Presenile dementia

Inheritance pattern

Autosomal dominant 

Clinical features

Alzheimer’s disease (AD) is the most common form of dementia, affecting millions of people worldwide 1. Dementia is the loss of cognitive functioning, e.g. thinking, remembering, and reasoning, and behavioral abilities to such an extent that it interferes with a person’s daily life and activities

Alzheimer’s disease typically begins with subtle and poorly recognized failure of memory and slowly becomes more severe and, 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 speech impairments occur. Death usually results from general inanition, malnutrition, and pneumonia. The typical clinical duration of the disease is eight to ten years, with a range from one to 25 years.

Facts about AD age onset and incidence 1, 2:

  • Approximately 10% of persons over age 70 years have significant memory loss and more than half of these individuals have AD.
  • An estimated 25-45% of persons over age 85 years have dementia.
  • Approximately 1-6% of all cases are early onset (age <60-65 years) and approximately 60% of early-onset AD cases are familial, with 13% appearing to be inherited in an autosomal dominant manner.
  •  The incidence of AD increases from 2.8 per 1,000 person years in the 65-69 year age group to 56.1 per 1,000 person years in the older than 90 year age group 2.

Neuropathological findings in postmortem AD brains showed the presence of specific morphological features, hallmarks of AD: microscopic β-amyloid neuritic tangles and plaques 3. These structures contain tau protein and β-amyloid protein, respectively. The numbers of plaques and tangles is much higher than those found in age-matched controls without dementia 3. Aggregation of alpha-synuclein in the form of Lewy bodies may also be found in neurons in the amygdala 4

Early onset familial AD: Approximately 25% of AD is familial and approximately 1-6% of all Alzheimer’s disease cases are early onset (age <60-65 years). Furthermore, approximately 60% of early-onset AD is familial, with 13% appearing to be inherited in an autosomal dominant manner 5. However it is often speculated that late-onset AD is the result of unknown environmental factors acting on a predisposing genetic background 1, 10. Essentially all persons with Down syndrome (trisomy 21) develop the neuropathologic hallmarks of AD after age 40 years 1. If carefully observed or tested, more than half of individuals with DS also show clinical evidence of cognitive decline. The presumed reason for this association is the lifelong over-expression of APP on chromosome 21 encoding the amyloid precursor protein and the resultant overproduction of β-amyloid in the brains of persons who are trisomic for this gene.

Late-onset familial AD is a form of familial Alzheimer disease, which begins after age 65 and may involve multiple susceptibility genes 6, 7. The gene with the greatest known population contribution to the risk of developing late onset Alzheimer's disease – but with a very weak predictive value – is called apolipoprotein E (APOE). Recent scientific developments have allowed researchers to test many more genes to see whether these are additionally linked to Alzheimer's disease. This approach has revealed additional genes which are linked to significantly increased AD risk, including the genes APP, PRNP, PSEN1, PSEN2, SORL1, and TREM2 (Table 1).

  • Amyloid beta A4 protein The APP gene variant p.Ala673Thr has a frequency of about 0.13% in an AD population and  0.6-0.7% in the non-dementia control population in northern Europe 8, 9.
  • More than 150 pathogenic variants in the PSEN1 gene have been identified in patients with early-onset Alzheimer’s disease 10, 11. Pathogenic variants in the PSEN1 gene are the most common cause of early-onset Alzheimer’s disease, accounting for up to 70 percent of cases 10.
  • Pathogenic variants in the PSEN2 gene account for fewer than 5 percent of all early-onset cases of the disorder. Two of the most common PSEN2 pathogenic variants that cause early-onset Alzheimer’s disease are N141I and M239V 12. These pathogenic variants appear to disrupt the processing of amyloid precursor protein, leading to the overproduction of amyloid beta peptide.
  • Missense and nonsense inherited variants of the SORL1 gene encoding neuronal sorting receptor is associated with early-onset AD 13.
  • p. Arg47His allelic variant in TREM2 as a statistically significant risk factor of late-onset AD 14.

There is no cure for Alzheimer’s disease but many symptomatic treatments are available. In general, affected individuals eventually require assisted living arrangements or care in a nursing home. Clinical trials are currently in progress which are testing numerous potential drugs for AD treatment (e.g. Memantine, Gantenerumab, Adeno-Associated Virus Delivery of NGF, Resveratrol, and others). 

Differential diagnosis

The differential diagnosis of Alzheimer’s disease-related disorders includes the following diseases, depending on the major presenting symptoms:

Other causes of dementia, especially treatable forms of cognitive decline including:

  • Depression
  • Chronic drug intoxication
  • Chronic CNS infection
  • Thyroid disease
  • Vitamin B12 and thiamine deficiencies

Other degenerative disorders associated with dementia, such as:

  • Frontotemporal dementia
  • Picks disease
  • Parkinson disease
  • Diffuse Lewy body disease
  • Creutzfeldt-Jakob disease

Diagnostic strategy

To confirm/establish the diagnosis, CENTOGENE offers the following testing strategy for Alzheimer’s disease and dementia:

Step 1: NGS Panel (including repeat expansion testing)

Step 2: Whole genome sequencing

Referral reasons

The following individuals are candidates for Alzheimer dementia gene testing:

  • Individuals with a family history of Alzheimer dementia and presentation of the most common symptoms
  • Individuals without a positive family history, but with symptoms resembling Alzheimer 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 Alzheimer dementia related genes should be performed in all individuals suspected of having AD. 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 Alzheimer 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.