Hereditary Alzheimer’s Disease

The Hereditary Alzheimer’s Disease (AD) Panel analyzes three genes associated with early-onset hereditary Alzheimer’s disease
which is characterized by progressive memory loss, language disturbances, and psychiatric manifestations.
Individuals with a clinical diagnosis of early-onset AD, especially those with a strong family history of dementia, may benefit from diagnostic genetic testing. Identification of the molecular basis of disease in an affected individual may help to confirm the suspected diagnosis, provide anticipatory guidance, determine which relatives may be at risk, and/or promote enrollment in clinical trials.

Alzheimer’s disease is an irreversible, progressive brain disease. It is characterized by the development of amyloid plaques and neurofibrillary tangles; the loss of connections between nerve cells in the brain; and the death of these nerve cells.
There are two types of Alzheimer’s, which are early-onset and late-onset. Both types have a genetic component.

The Two Types of Alzheimer’s

  •  Early-onset Alzheimer’s disease (EOAD) is a form of dementia characterized by progressive loss of episodic memory,
    functioning skills, and language, which may be accompanied by other features including hallucinations, seizures, and
  • Early-onset Alzheimer’s disease occurs between a person’s 30s to mid-60s and represents less than 10 percent of all people
    with Alzheimer’s.
  •  EOAD presents with mild visuospatial deficits and memory loss. As the disorder progresses, dysfunction and language
    disturbances become more apparent, followed by features of motor stiffness, further impaired spatial skills, and psychiatric
    manifestations including apathy, depression, and agitation.
  •  In advanced stages of the disorder, individuals typically display severe cognitive, psychiatric/behavioral, and motor
  • The hallmark pathological findings of Alzheimer’s disease identified upon autopsy are beta-amyloid neuritic plaques and
    intraneuronal neurofibrillary tangles.
  • An estimated 25% of AD is familial, with two or more affected individuals in the same family.
  • 5% of individuals with familial AD have an early-onset form.
  • Early-Onset FAD is caused by any one of a number of different single-gene mutations on chromosomes 21, 14, and 1. Each
    of these mutations causes abnormal proteins to be formed. Mutations on chromosome 21 cause the formation of abnormal
    amyloid precursor protein (APP). A mutation on chromosome 14 causes abnormal presenilin 1 to be made, and a mutation
    on chromosome 1 leads to abnormal presenilin 2.
  • Each of these mutations plays a role in the breakdown of APP, and is part of a process that generates harmful forms of
    amyloid plaques, a hallmark of the disease
Gene AD Subtype Proportion Of Hereditary AD Cases
APP Alzheimer’s disease type 1 (AD1) 10-15%
PSEN1 Alzheimer’s disease type 3 (AD3) 55%
PSEN2 Alzheimer’s disease type 4 (AD4) <5%


  • Most people with Alzheimer’s have the late-onset form of the disease, in which symptoms become apparent in the mid-60s and later. The causes of late-onset Alzheimer’s are not yet completely understood, but they likely include a combination of genetic, environmental, and lifestyle factors that affect a person’s risk for developing the disease.
  • There is one genetic risk factor—having one form of the apolipoprotein E (APOE) gene on chromosome 19 increases a person’s risk. APOE comes in several different forms, or alleles:
    • APOE ε2 is relatively rare and may provide some protection against the disease. If Alzheimer’s disease occurs in a
      person with this allele, it usually develops later in life than it would in someone with the APOE ε4 gene.
    • APOE ε3, the most common allele, is believed to play a neutral role in the disease—neither decreasing nor increasing risk.
    • APOE ε4 increases risk for Alzheimer’s disease and is also associated with an earlier age of disease onset. A person has zero, one, or two APOE ε4 alleles. Having more APOE ε4 alleles increases the risk of developing Alzheimer’s.
    • APOE ε4 is called a risk-factor gene because it increases a person’s risk of developing the disease. However, inheriting an APOE ε4 allele does not mean that a person will definitely develop Alzheimer’s. Some people with an APOE ε4 allele never get the disease, and others who develop Alzheimer’s do not have any APOE ε4 alleles.


APP, PSEN1, and PSEN2 related forms of hereditary AD are all inherited in an autosomal dominant manner.


Pathogenic variants within the APP, PSEN1, and PSEN2 genes are associated with variable ages of onset, and penetrance is typically age-dependent. The penetrance of APP is thought to be approximately 100% by the early 60s, and the penetrance of PSEN1 is thought to reach approximately 100% by age 65. The PSEN2 gene has an estimated 95% penetrance, as unaffected individuals in their 80s have been reported.

Prevalence and Incidence

Alzheimer’s disease is the most common form of dementia, and affects an estimated 5% of individuals over age 70, with 25% of all cases being familial (two or more affected individuals within a family). Early-onset AD makes up approximately 1-5% of all cases of Alzheimer’s disease, with a prevalence of 41.2 per 100,000 individuals aged 40-59 years.

Approximately 1% of individuals with Alzheimer’s disease have a genetic form. However, an estimated 40-80% of individuals with EOAD and a family history of Alzheimer’s disease have a pathogenic variant in APP, PSEN1, or PSEN2.
While less common, approximately 6% of individuals with EOAD and no family history may have a pathogenic variant in one of those genes.

Considerations for Testing

A genetic cause for Alzheimer’s disease may be suspected in individuals who have:

  • A clinical diagnosis of early-onset Alzheimer’s disease (onset before 60 years of age), and a family history of dementia
    or related conditions
  • No personal history of AD but who are known to be at risk for a hereditary form of Alzheimer’s disease because of family

In addition to meeting one of the above criteria, individuals considering genetic testing for hereditary forms of Alzheimer’s
disease should first receive thorough pre-test genetic counseling from a professional qualified to fully understand the
implications of testing for neurodegenerative disorders that don’t have any well-known treatment or cure at this time.

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