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Invitae Hereditary Alzheimer's Disease Panel

Test code: 03504 •

Test description

The Invitae 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. These genes were curated based on the available evidence to date to provide a comprehensive test for the genetic causes of hereditary AD.

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.

Disorders tested

Ordering information

Turnaround time:

10–21 calendar days (14 days on average)

New York approved:

Yes

Preferred specimen:

3mL whole blood in a purple-top EDTA tube (K2EDTA or K3EDTA)

Alternate specimens:

Saliva, buccal swab, and gDNA are also accepted.Learn more about specimen requirementsRequest a specimen collection kit

Clinical description and sensitivity

Clinical description:

Early-onset Alzheimer’s disease (EOAD) is a form of dementia characterized by progressive loss of episodic memory, executive functioning skills, and language, which may be accompanied by other features including hallucinations, seizures, and parkinsonism. EOAD presents before 60-65 years of age (and often presents before 55 years of age) with mild visuospatial deficits and memory loss. As the disorder progresses, executive 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 dysfunction. 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, and 5% of individuals with familial AD have an early-onset form. Individuals with Alzheimer’s disease caused by pathogenic variants in PSEN2 typically show a later age of onset in the 50s or 60s, compared to onset in the 30s or 40s seen in individuals with Alzheimer’s disease caused by APP or PSEN1 variants. In addition, PSEN2-related Alzheimer’s disease has a higher frequency of behavioral and psychotic symptoms, such as hallucinations or delusions.

GeneAD subtypeProportion 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%

Clinical description and sensitivity

Clinical description:

Early-onset Alzheimer’s disease (EOAD) is a form of dementia characterized by progressive loss of episodic memory, executive functioning skills, and language, which may be accompanied by other features including hallucinations, seizures, and parkinsonism. EOAD presents before 60-65 years of age (and often presents before 55 years of age) with mild visuospatial deficits and memory loss. As the disorder progresses, executive 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 dysfunction. 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, and 5% of individuals with familial AD have an early-onset form. Individuals with Alzheimer’s disease caused by pathogenic variants in PSEN2 typically show a later age of onset in the 50s or 60s, compared to onset in the 30s or 40s seen in individuals with Alzheimer’s disease caused by APP or PSEN1 variants. In addition, PSEN2-related Alzheimer’s disease has a higher frequency of behavioral and psychotic symptoms, such as hallucinations or delusions.

GeneAD subtypeProportion 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%

Clinical sensitivity:


The clinical sensitivity of this panel is dependent on the patient’s true clinical diagnosis, which can often only be accurately determined upon autopsy. For each gene, the table in the Clinical description section above shows the percentage of clinical cases in which a pathogenic variant is expected. The sensitivity of this test also depends on age of onset and family history. For example, the probability of identifying a genetic mutation in APP, PSEN1, or PSEN2 is <1% for individuals with a clinical diagnosis of Alzheimer’s and an age of onset >65 years of age, even in those who have two or more affected first-degree relatives; however, the probability of identifying a pathogenic variant climbs to 86% in individuals with a clinical diagnosis of Alzheimer’s disease who have an age of onset <60 years of age who have affected family members in three generations.

Assay information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

Assay information

Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).

Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.

Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.

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Primary panel

3 genes selected
APP
PSEN1
PSEN2

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