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.
APP PSEN1 PSEN2
APP PSEN1 PSEN2
In some cases, Alzheimer’s disease may have nonspecific or overlapping features with different types of dementia and/or amyotrophic lateral sclerosis (ALS). In these cases, clinicians may consider the Invitae Frontotemporal Dementia Panel or the Invitae Combined Hereditary Dementia and ALS Panel.
Clinicians may consider the Invitae Hereditary Parkinson’s Disease and Parkinsonism panel for individuals with a personal or family history of Parkinson’s disease or parkinsonian features.
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.
|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%|
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.
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.
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.
A genetic cause for Alzheimer’s disease may be suspected in individuals who have:
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 provide such counseling regarding the implications of testing for neurodegenerative disorders that have no known treatment or cure at this time.
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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.
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.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|