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Synonym: EOFAD

, MD.

Author Information

Initial Posting: ; Last Revision: October 18, 2012.

Estimated reading time: 32 minutes



Clinical characteristics.

Alzheimer disease (AD) is characterized by adult-onset progressive dementia associated with cerebral cortical atrophy, beta-amyloid plaque formation, and intraneuronal neurofibrillary tangles. AD typically begins with subtle memory failure that becomes more severe and is eventually incapacitating. Other common findings include confusion, poor judgment, language disturbance, agitation, withdrawal, hallucinations, seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism. Familial AD (FAD) characterizes families that have more than one member with AD and usually implies multiple affected persons in more than one generation. Early-onset FAD (EOFAD) refers to families in which onset is consistently before age 60 to 65 years and often before age 55 years.


EOFAD is diagnosed in families with multiple affected individuals with mean age of onset before 65 years and/or with a documented pathogenic variant in one of the genes known to be associated with EOFAD. The three clinically indistinguishable subtypes of EOFAD based on the underlying genetic mechanism are: Alzheimer disease type 1 (AD1), caused by mutation of APP (10%-15% of EOFAD); Alzheimer disease type 3 (AD3), caused by mutation of PSEN1, (30%-70% of EOFAD); and Alzheimer disease type 4 (AD4), caused by mutation of PSEN2 (<5% of EOFAD). Kindreds with autosomal dominant EOFAD with no identifiable pathogenic variants in PSEN1, PSEN2, or APP have been described; thus, it is likely that variants in additional genes are causative.


Treatment of manifestations: Supportive; symptoms of depression, aggression, sleep disturbance, seizures, and hallucinations are managed on an individual basis; affected individuals eventually require assisted living/nursing home care; agents that increase cholinergic activity, such as Aricept® (donepezil), Exelon® (rivastigmine), and Reminy® (galatamine), show modest but variable benefit; memantine, an NMDA receptor antagonist, is approved for use in AD; physical and occupational therapy help manage activities of daily living.

Surveillance: Monthly monitoring to identify and manage secondary complications.

Agents/circumstances to avoid: Sudden changes in environment; over-sedation.

Genetic counseling.

EOFAD is inherited in an autosomal dominant manner. Most individuals with EOFAD had an affected parent; occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD. Each child of an individual with EOFAD has a 50% chance of inheriting the pathogenic variant and developing EOFAD. Prenatal testing for pregnancies at increased risk for is possible if the pathogenic variant in the family is known; however, prenatal testing for adult-onset disorders is uncommon.


Clinical Diagnosis

Alzheimer disease (AD) (see Alzheimer Disease Overview) is diagnosed in individuals with the following:

  • Adult-onset slowly progressive dementia
  • Absence of other causes of dementia
  • Cerebral cortical atrophy by neuroimaging studies
  • Beta-amyloid neuritic plaques and intraneuronal neurofibrillary tangles at post-mortem examination (see diagnostic criteria, National Institute on Aging Working Group [1998]).

Early-onset familial Alzheimer disease (EOFAD) is diagnosed in families that have more than one member with AD (usually multiple affected persons in more than one generation) in which the age of onset is consistently before age 60 to 65 years and often before age 55 years.

Molecular Genetic Testing

Genes. Pathogenic variants in three genes are known to be associated with early-onset familial Alzheimer disease:

Other loci. Kindreds with autosomal dominant EOFAD who have no identifiable pathogenic variants in PSEN1, PSEN2, or APP have been described; thus, it is likely that variants in additional genes are causative [Cruts et al 1998, Janssen et al 2003].



  • Sequence analysis/scanning for pathogenic variants. All pathogenic variants, except for rare duplications (see following bullet), are only known to occur in exons 16 and 17. Most variants are missense or nonsense; one indel is reported (Table 2). Sequence analysis is often limited to these exons because they encode the proteolytically cleaved A-beta peptide (see Molecular Genetics, APP). For this reason, laboratories sequencing only exons 16 and 17 may be listed as sequencing select exons or as sequencing the entire coding region; contacting the laboratory directly is advised.
  • Deletion/duplication analysis (including FISH analysis). Duplication of APP represents fewer than 1% of APP pathogenic variants [Rovelet-Lecrux et al 2006].


Table 1.

Genetic Testing Used in Early-Onset Familial Alzheimer Disease

Gene 1Proportion of EOFAD Attributed to Pathogenic Variants in GeneMethodPathogenic Variants Detected 2Variant Detection Frequency by Gene & Method 3
PSEN1 30%-70% 4Targeted analysis for pathogenic variants4555-bp deletion of exon 9 (Finnish founder variant5100% for the targeted variant
Sequence analysis 6Sequence variants~98%
Deletion/duplication analysis 7Partial- and whole-gene deletions, including exon 9 Finnish founder deletion100% for deletions, which are rare
APP 10%-15%Sequence analysis 6 / scanning 8 of exons 16 and 17 for pathogenic variantsSequence variants in exons 16 and 1799%
Deletion/duplication analysis 7Partial- and whole-gene duplications100% for the targeted duplication
PSEN2 <5%Sequence analysis 6Sequence variants~100%

See Molecular Genetics for information on allelic variants.


The ability of the test method used to detect a variant that is present in the indicated gene


The highest yield for identification of a pathogenic variant in PSEN1 is for persons with early-onset (age <60 years) AD who have another affected family member (especially a parent) with early-onset AD [Rogaeva et al 2001, Lleó et al 2002, Janssen et al 2003, Tedde et al 2003].


Finnish population; this variant is rarely observed in other populations.


Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.


Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.


Sequence analysis and scanning for pathogenic variants can have similar variant detection frequencies; however, variant detection frequencies for scanning may vary considerably among laboratories depending on the specific protocol used.

In one affected individual, a PSEN1 pathogenic variant was identified in peripheral lymphocyte DNA; however, her clinical presentation was distinct from that of her affected deceased mother whose diagnosis was based on post-mortem neuropathology. Follow up studies demonstrated that the mother had somatic mosaicism for the PSEN1 variant; using sequence analysis, the variant was detected in cerebral cortex DNA but not in peripheral lymphocyte DNA [Beck et al 2004].

Testing Strategy

Confirming/establishing the diagnosis in a proband requires molecular genetic testing to identify a pathogenic variant in one of the three genes known to be associated with EOFAD.

  • When the family history is positive for early-onset AD:
  • In simplex cases (i.e., a single occurrence in a family) the testing strategy is similar, but the likelihood of finding a pathogenic variant is relatively low (~6% in the study by Lleó et al [2002]). However, the likelihood of finding a pathogenic variant in a simplex case increases as age of onset decreases, especially in those with onset before age 50 years.

Note: Pathogenic variant detection frequency is low in persons with late-onset AD regardless of family history. Ninety percent of persons with PSEN1 pathogenic variants have onset before age 60 years.

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the pathogenic variant in the family.

Prenatal testing and preimplantation genetic testing for at-risk pregnancies require prior identification of the pathogenic variant in the family.

Clinical Characteristics

Clinical Description

Alzheimer disease (AD) typically begins with subtle and poorly recognized failure of memory [Godbolt et al 2004, Ringman et al 2005]. Slowly, over a period of years, the memory loss becomes more severe and is eventually incapacitating. Other common symptoms include confusion, poor judgment, language disturbance, agitation, withdrawal, and hallucinations. Some individuals may develop seizures, Parkinsonian features, increased muscle tone, myoclonus, incontinence, and mutism [Cummings et al 1998]. Death usually results from general inanition, malnutrition, and pneumonia.

AD3 (PSEN1 pathogenic variants). Age of onset is usually in the 40s or early 50s. Onset in the 30s and early 60s has been reported. Onset after age 65 years is thought to be rare. Relatively rapid progression over six to seven years is common and the disease is often associated with seizures, myoclonus, and language deficits [Fox et al 1997, Gustafson et al 1998, Menéndez 2004]. Several families have had associated spastic paraplegia with "cotton wool" amyloid plaques [Crook et al 1998, Brooks et al 2003, Ataka et al 2004, Hattori et al 2004, Raman et al 2007].

The APOE e4 allele may influence age of onset [Wijsman et al 2005] (see Alzheimer Disease Overview).

CSF Aβ42 levels have been reported to be low in presymptomatic persons with PSEN1 variants [Moonis et al 2005].

PET scans with Pittsburgh compound-B show early amyloid deposition in the striatum in persons with PSEN1 variants [Klunk et al 2007].

AD4 (PSEN2 pathogenic variants). AD4 has a wider range of onset age than either AD1 or AD3. The onset ranges from age 40 to 75 years with a few instances of non-penetrance after age 80 years [Bird et al 1996]. Mean duration of disease is 11 years. Jayadev et al [2010] have reviewed the clinical, pathologic, and genetic aspects of families with variants of PSEN2.

The APOE e4 allele influences age of onset (see Alzheimer Disease Overview) [Wijsman et al 2005].

AD1 (APP pathogenic variants). The dementia observed in families with APP variants is typical of AD. Age of onset is usually in the 40s and 50s (occasionally 60s). A few individuals have neuronal Lewy body inclusions in addition to plaques and tangles [Revesz et al 1997].

Homozygosity for the APOE e4 allele may be associated with younger age of onset (see Alzheimer Disease Overview).

Biomarkers. Bateman et al [2012] identified biomarker changes in individuals with a pathogenic variant in APP, PSEN1, or PSEN2 ten to 20 years prior to the onset of symptoms including amyloid deposition on PET imaging, decreased CSF beta-amyloid and increased CSF tau.

Neuropathology. Mutation of PSEN1 (AD1) or PSEN2 (AD4) results in excessive brain deposition of amyloid-β [Mann et al 1997] associated with neurofibrillary tangles and amyloid angiopathy. Lewy body pathology is also common [Leverenz et al 2006]. A wide range in severity of AD pathology may be seen [Maarouf et al 2008, Jayadev et al 2010].

Genotype-Phenotype Correlations




AD3 (PSEN1 pathogenic variants). Penetrance is complete by age 65 years, except for occasional later onset associated with the variants p.Ala79Val and p.Arg269His [Brickell et al 2007, Kauwe et al 2007, Larner et al 2007].

AD4 (PSEN2 pathogenic variants). Penetrance is approximately 95%. In rare instances, individuals with PSEN2 variants who are older than age 80 years have no manifestations of AD.


Anticipation has not been documented.


Campion et al [1999] found a prevalence of early-onset AD of 41.2 per 100,000 for the population at risk (i.e., persons aged 40-59 years).

Differential Diagnosis

Approximately 75% of individuals with Alzheimer disease (AD) have no family history of AD and approximately 25% of individuals with AD can be divided into several genetic subgroups. Familial cases appear to have the same phenotype as nonfamilial cases both clinically and pathologically and thus are distinguished only by a positive family history (see Alzheimer Disease Overview). Occasionally, cases of early-onset AD may occur in families with generally late-onset disease [Brickell et al 2006].

Other genetic causes of early-onset dementia include forms of frontotemporal dementia (e.g., frontotemporal dementia with parkinsonism-17 [FTDP-17], inclusion body myopathy with Paget disease of bone and/or frontotemporal dementia [IBMPFD], PGRN-related frontotemporal dementia, CHMP2B-related frontotemporal dementia, amyotrophic lateral sclerosis [ALS] with frontotemporal dementia [see ALS Overview]), Huntington disease, prion diseases, CADASIL, and other rare neurodegenerative disorders.


Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with early-onset familial Alzheimer disease (EOFAD), the following evaluations are recommended if they have not already been completed:

  • History (especially first symptoms, duration, progression). In particular, onset before age 45 years may indicate more rapid progression.
  • Examination (especially mental status)
  • MRI, PET. Severe cortical atrophy on MRI or marked metabolic deficits on PET imaging suggest more advanced disease.

Treatment of Manifestations

The mainstay of treatment is supportive and each symptom is managed on an individual basis [Clare 2002]. In general, affected individuals eventually require assisted living arrangements or nursing home care.

Although the exact biochemical basis of Alzheimer disease is not well understood, it is known that deficiencies of the brain cholinergic system and of other neurotransmitters are present. Agents that increase cholinergic activity, such as tacrine cholinesterase inhibitors, are approved for treatment and show modest but variable benefit. Aricept® (donepezil), Exelon® (rivastigmine), and Reminyl® (galatamine) are such drugs [Rogers et al 1998, Farlow et al 2000, Raskind et al 2000, Feldman et al 2001, Mohs et al 2001, Seltzer et al 2004].

Memantine, an NMDA receptor antagonist, has also been approved for use in AD [Reisberg et al 2003].

Medical and behavioral management of depression, aggression, sleep disturbance, seizures, and hallucinations is required. Depression and seizures should be treated with appropriate medications.

Physical and occupational therapy can be helpful to manage problems with gait and activities of daily living.


Monthly surveillance to identify and manage secondary complications is indicated.

Agents/Circumstances to Avoid

Sudden changes in environment and over-sedation should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Nonsteroidal anti-inflammatory drugs (NSAIDs), lipid-lowering agents, vitamin E, beta secretase inhibitors and β amyloid "vaccination" are being investigated as possible therapeutic agents for AD [Lahiri et al 2003]. None of these pharmacologic treatments has been systematically evaluated in individuals with EOFAD.

An amyloid vaccination immunization trial of Aβ42 in late-onset AD was stopped because encephalitis developed in 6% of the subjects [Holmes et al 2008].

A treatment trial of an anti-Aβ monoclonal antibody showed no significant differences when primary efficacy was analyzed [Salloway et al 2009].

A treatment trial with a gamma secretase inhibitor (tarenflurbil) showed no efficacy [Green et al 2009].

Retrospective studies of NSAIDs have been mixed, showing possible protective effects [Vlad et al 2008] and no protective effects [Breitner et al 2009].

Search Clinical in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members; it is not meant to address all personal, cultural, or ethical issues that may arise or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Early-onset familial Alzheimer disease (EOFAD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Most individuals diagnosed as having EOFAD have had an affected parent. Because the onset of EOFAD is typically in early adulthood and the progression is rapid, affected parents are not alive at the time of diagnosis of their children.
  • Occasionally, neither parent is identified as having had the disease, but a second-degree relative (e.g., an uncle, aunt, and/or grandparent) has or had EOFAD.
  • A proband with EOFAD may have the disorder as the result of a de novo pathogenic variant, although this has not been documented.

Note: Although most individuals diagnosed with EOFAD have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or reduced penetrance.

Sibs of a proband

  • The risk to sibs depends on the genetic status of the parents.
  • If a parent of the proband was affected or had a pathogenic variant, the risk to sibs of having inherited the variant is 50%.
  • When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.

Offspring of a proband. Offspring have a 50% chance of inheriting the altered gene.

Other family members of a proband. The risk to other family members depends on the genetic status of the proband's parents. If a parent was affected, his or her family members are at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition had the pathogenic variant, it is likely that the proband has a de novo variant. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of developing EOFAD.

Testing of at-risk asymptomatic adults. Testing of at-risk asymptomatic adults for EOFAD is possible for PSEN1 (presenilin-1), PSEN2 (presenilin-2), and APP pathogenic variants. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis in the family. The identification of a pathogenic variant in an at-risk individual with equivocal symptoms does not prove or even imply that the questionable symptoms are related to the presence of the variant.

Testing for the pathogenic variant in the absence of definite symptoms of the disease is considered predictive testing.

At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pre-test interviews in which the motives for requesting the test, the individual's knowledge of EOFAD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled regarding possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Other issues to consider are implications for the at-risk status of other family members. Informed consent for such testing is recommended and adequate procedures should be followed to safeguard confidentiality of test results and to ensure arrangements for long-term follow up and evaluations. In a study of 21 individuals at risk for EOFAD or MAPT-related disorders, Steinbart et al [2001] reported that most individuals undergoing presymptomatic testing demonstrated effective coping skills; long-term effects, however, are unknown.

Testing of at-risk individuals during childhood. Consensus holds that individuals at risk for adult-onset disorders should not have testing during childhood in the absence of symptoms. The principal arguments against testing asymptomatic individuals during childhood are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it may have serious educational and career implications. See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Testing

Once the pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic testing and embryo transfer have been successfully used to achieve a pregnancy in a 30-year-old asymptomatic woman with an APP pathogenic variant, resulting in the birth of a healthy child who does not have the APP pathogenic variant identified in the mother and her family [Verlinsky et al 2002]. Towner & Loewy [2002] and Spriggs [2002] identify some of the ethical issues arising from the decisions of parents and health care providers.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Alzheimer's Association
    225 North Michigan Avenue
    Fl 17
    Chicago IL 60601-7633
    Phone: 800-272-3900 (Toll-free 24/7 Helpline); 866-403-3073 (Toll-free 24/7 Helpline - TDD); 312-335-8700
    Fax: 866-335-5886 (toll-free)
  • Alzheimer's Disease Education and Referral Center (ADEAR)
    PO Box 8250
    Silver Spring MD 20907
    Phone: 800-438-4380 (toll-free)
    Fax: 301-495-3334
  • NCBI Genes and Disease
  • National Institute on Aging
    31 Center Drive
    Building 31, Room 5C27
    MSC 2292
    Bethesda MD 20892
    Phone: 301-496-1752; 800-222-2225 (toll-free); 800-222-4225 (toll-free TTY)
    Fax: 301-496-1072
  • National Library of Medicine Genetics Home Reference

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A.

Early-Onset Familial Alzheimer Disease : Genes and Databases

Data are compiled from the following standard references: gene from HGNC; chromosome locus from OMIM; protein from UniProt. For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click here.

Table B.

OMIM Entries for Early-Onset Familial Alzheimer Disease (View All in OMIM)



Gene structure. APP has 19 exons and encodes a large precursor protein of 695-770 amino acids that is proteolytically cleaved to form A-beta peptide. Alternative APP transcripts are often designated by the number of amino acids they encode, e.g., APP770 transcript or NM_000484.2. The A-beta peptide portion is encoded by parts of exons 16 and 17; these exons encode codons 655-737. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. The most common APP pathogenic variant is p.Val717Ile. Substitutions of phenylalanine and glycine may also occur at this codon. A two-nucleotide indel (insertion and deletion) in exon 16 (c.2010_2011delinsTC) produces the so-called Swedish variant (see Table 2).

APP duplication has been reported in a few families (see Genotype-Phenotype Correlations).

Table 2.

Selected APP Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.2149G>Ap.Val717Ile NM_000484​.2
c.2075C>Gp.Ala692Gly 1
c.2018C>Tp.Ala673Val 1
c.2078A>G 2p.Glu693Gly 1, 2

Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Pathogenic variant associated with cerebral hemorrhagic amyloidosis of the Dutch type

Normal gene product. The protein encoded for by APP, amyloid-β A4 protein, contains 695 to 770 amino acids and undergoes alternative splicing. A 57-amino-acid portion is homologous to Kunitz-type protease inhibitors. The major transcripts in peripheral tissues are the APP751 and APP770 variants. The A-beta peptide contains 38 to 42 amino acids and resides in the transmembrane domain of the protein. Amyloid-β A4 protein may be cleaved by an alpha secretase within the amyloid-β peptide sequence, thus eliminating the possibility of amyloid-β accumulation. However, amyloid-β A4 may also be cleaved by beta and gamma secretases that result in the accumulation of amyloid-β peptide.

Abnormal gene product. Imbalance in cleavage produces excess of longer amyloid beta peptide isoforms that are neurotoxic and prone to self-aggregation.


Gene structure. The coding region is composed of ten exons numbered 3 through 12. Exon 8 and part of exon 3 are alternatively spliced, so shorter isoforms of the protein are predicted to exist. Alternative splicing may also introduce a new exon between exons 10 and 11. PSEN1 and PSEN2 are highly homologous. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. More than 40 pathogenic variants that result in EOFAD have been described in more than 50 families [Cruts et al 1998, Cruts & Van Broeckhoven 1998, Poorkaj et al 1998, Larner & Doran 2006]. The majority are missense variants. One exception is a variant eliminating a splice site in which exon 9 is lost but the reading frame is unaltered and the protein is predicted to be 29 amino acids shorter. A genomic deletion spanning exon 9 is also found in the Finnish population. At least nine pathogenic variants occur in a cytosolic domain between transmembrane domains 6 and 7 and the rest of the variants are within the other hydrophobic domains or immediately at the hydrophilic/hydrophobic junctions, especially of transmembrane domain 2. The relative frequency of pathogenic variants in the cytosolic domain encoded by the alternatively spliced exon 8 suggests that this region of the protein is functionally important (see Table 3).

Table 3.

Selected PSEN1 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.236C>Tp.Ala79Val 1 NM_000021​.3
c.265G>Tp.Val89Leu 1
c.338T>Cp.Leu113Pro 1
c.415A>Gp.Met139Val 1
c.509C>Tp.Ser170Phe 1
c.697A>Gp.Met233Val 1
c.767A>Cp.Tyr256Ser 1
c.806G>Ap.Arg269His 1
c.839A>Cp.Glu280Ala 2
c.1175T>Cp.Leu392Pro 1
4,555-bp deletion of exon 9See footnotes 1 and 3

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Normal gene product. PSEN1 is predicted to encode a 467-amino acid protein with between seven and ten (probably eight) hydrophobic transmembrane domains. The presenilin-1 protein is highly homologous to the presenilin-2 protein; the regions of greatest divergence are between the two large hydrophilic loops, one at the amino terminal end and the other in the cytosolic domain between the sixth and seventh transmembrane domains [Tandon & Fraser 2002]. This cytosolic domain contains a proteolytic cleavage site [Podlisny et al 1997]. The protein is a functional homolog of SEL-12, a C elegans protein that facilitates signaling mediated by the Notch/LIN-12 receptor family [Wong et al 1997]. The protein acts as part of the gamma secretase cleavage system for amyloid-β A4 protein. PS1 knockout mice die in utero and have severe skeletal abnormalities [Shen et al 1997]. The presenilins cleave other proteins in addition to amyloid-β A4 protein [Thinakaran & Parent 2004].

Abnormal gene product. Abnormal PSEN1 results in increased production of the longer isoforms of amyloid-β peptide, which are neurotoxic and prone to self-aggregation [Jankowsky et al 2004]. Some pathogenic variants may result in loss of the gamma secretase function of presenilin-1 [De Strooper 2007, Shen & Kelleher 2007].


Gene structure. PSEN2 is highly homologous to PSEN1. It includes 12 exons with ten coding exons in a genomic region spanning 23,737 bp. The first two exons encode the 5' untranslated region. For a detailed summary of gene and protein information, see Table A, Gene.

Pathogenic variants. A single variant (p.Asn141Ile) has been found in several Volga German FAD pedigrees, confirming the founder effect in this population. Another pathogenic variant (p.Met239Val) has been reported in an Italian kindred with FAD [Rogaev et al 1995, Marcon et al 2004] (see Table 4). A few additional and possibly pathogenic variants have been reported [Beyer et al 1998, Cruts & Van Broeckhoven 1998, Tedde et al 2003, Zekanowski et al 2003].

Table 4.

Selected PSEN2 Pathogenic Variants

DNA Nucleotide ChangePredicted Protein ChangeReference Sequences
c.422A>Tp.Asn141Ile 1 NM_000447​.2

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen​ See Quick Reference for an explanation of nomenclature.


Normal gene product. PSEN2 is predicted to encode a 448-amino acid protein that is highly homologous to the presenilin-1 protein. The presenilin-2 protein is also thought to contain eight transmembrane domains. The regions of greatest divergence between the two proteins are at the amino terminal end and in the cytosolic domain between the sixth and seventh transmembrane domains [Uemura et al 2003, Thinakaran & Parent 2004].

Abnormal gene product. Presumably similar to that noted for PSEN1 pathogenic variants [Jankowsky et al 2004, Walker et al 2005, De Strooper 2007]


Published Guidelines / Consensus Statements

  • Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 9-5-2018.
  • National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available online. 2017. Accessed 9-5-2018.

Literature Cited

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Suggested Reading

  • George-Hyslop PH, Farrer LA, Goedert M. Alzheimer disease and the frontotemporal dementias: diseases with cerebral deposition of fibrillar proteins. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 234.
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  • Van Broeckhoven C. Alzheimer's disease: identification of genes and genetic risk factors. Prog Brain Res. 1998;117:315–25. [PubMed: 9932417]

Chapter Notes

Revision History

  • 13 September 2018 (ma) Chapter retired: covered in Alzheimer Disease Overview
  • 18 October 2012 (tb) Revision: changes in biomarkers identified in individuals with mutations associated with EOFAD
  • 2 August 2012 (tb) Revision: additional information about APP mutation p.Ala673Val
  • 23 December 2010 (me) Comprehensive update posted live
  • 28 April 2009 (tb) Revision: FISH testing available clinically for duplications in APP
  • 2 October 2007 (me) Comprehensive update posted live
  • 26 April 2007 (tb) Revision: sequence analysis for AD1 (APP mutations) clinically available
  • 12 February 2007 (tb) Revision: clinical testing for APP mutations no longer available
  • 19 September 2005 (me) Comprehensive update posted live
  • 15 September 2003 (tb) Revision: clinical testing for APP available
  • 7 August 2003 (me) Comprehensive update posted live
  • 20 June 2001 (ca) Comprehensive update posted live
  • 24 September 1999 (pb) Review posted live
  • Spring 1996 (tb) Original submission
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