Early-Onset Familial Alzheimer Disease – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY

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.

Diagnosis/testing.

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.

Management.

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:

• PSEN1. Pathogenic variants are associated with Alzheimer disease type 3 (AD3) [Larner & Doran 2006], which accounts for 30%-70% of EOFAD [Cruts & Van Broeckhoven 1998, Campion et al 1999, Rogaeva et al 2001, Lleó et al 2002, Janssen et al 2003].
• APP. Pathogenic variants are associated with Alzheimer disease type 1 (AD1) [Van Broeckhoven 1995], which accounts for no more than 10%-15% of EOFAD [Campion et al 1999].
• PSEN2. Pathogenic variants are associated with Alzheimer disease type 4 (AD4), which accounts for less than 5% of all EOFAD. AD4 has been identified in a few families (most are of Volga German ancestry) living in the United States, in three Italian kindreds [Bird et al 1988], in two Italian kindreds [Finckh et al 2000, Marcon et al 2004], and in two Spanish families [Beyer et al 1998, Lleó et al 2001].

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].

PSEN1

• Targeted analysis for pathogenic variants. A 4555-bp deletion spanning exon 9 is found in the Finnish population [Crook et al 1998, Prihar et al 1999, Verkkoniemi et al 2000]; this variant is rarely observed in other populations.
• Sequence analysis of the coding region and associated intronic regions detects pathogenic missense variants known to result in EOFAD. This method also detects pathogenic splice site variants that result in transcripts lacking exon 9 [Perez-Tur et al 1995].
• Deletion/duplication analysis for screening the entire gene to detect rare exon or whole-gene deletions [Smith et al 2001]. This testing can also detect the 4555-bp deletion in the Finnish population.

APP

• 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].

PSEN2

• Sequence analysis of the coding region detects pathogenic missense variants known to cause EOFAD.

Table 1.

Genetic Testing Used in Early-Onset Familial Alzheimer Disease

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:
  • First perform sequence analysis of PSEN1, the gene most commonly associated with EOFAD. If the affected individual is of Finnish ancestry, targeted analysis for pathogenic variants of PSEN1 can be performed first.
  • If no pathogenic variant is identified, perform sequence analysis of exons 16 and 17 of APP and all of PSEN2.
    Note: Duplication analysis of APP and of PSEN1 need only be done if the goal is to test for even the rarest pathogenic variants.
• 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 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

PSEN1

• Pathogenic variants in transmembrane loops 2, 4, and 6 of PSEN1 account for some differences in age of onset and duration between those with pathogenic variants of PSEN1 and of PSEN2 [Lippa et al 2000].
• A frontotemporal type of dementia with personality and behavioral changes has been associated with the pathogenic variants p.Leu113Pro [Raux et al 2000] and p.Val89Leu [Queralt et al 2002] PSEN1 proteins.
• Psychiatric symptoms at onset have been described in families with the pathogenic variants p.Leu392Pro and p.Met139Val PSEN1 proteins [Tedde et al 2000, Rippon et al 2003].
• Deletion of exon 9 in PSEN1 is associated with early spastic paraparesis [Crook et al 1998, Verkkoniemi et al 2000, Brooks et al 2003].
• Gómez-Isla et al [1999] have correlated the neuropathologic features of amyloid plaques and neurofibrillary tangle formation with various PSEN1 variants.
• Very early onset (mean age 30 years) with additional Lewy body pathology has been associated with the pathogenic variants p.Met233Val and p.Tyr256Ser PSEN1 proteins [Miklossy et al 2003].
• Two PSEN1 variants have been associated with pathologic changes of Pick's disease: c.548G>T and c.436A>C [Dermaut et al 2004, Halliday et al 2005].
• Later-onset FAD (50s-70s) has been associated with the pathogenic variants p.Ala79Val and p.Arg269His PSEN1 proteins [Brickell et al 2007, Kauwe et al 2007, Larner et al 2007].
• Purkinje cell loss in the cerebellum has been reported with the p.Ser170Phe variant in PSEN1 [Piccini et al 2007].

APP

• The combination of cerebral hemorrhage and presenile dementia is caused by the p.Ala692Gly variant in APP [Roks et al 2000].
• Di Fede et al [2009] reported that the p.Ala673Val variant in APP only causes disease in the homozygous state; therefore, inheritance is autosomal recessive. This variant is at the site where BACE1 cleaves the APP protein, part of the process that produces the β-amyloid peptide. Giaccone et al [2010] reported neuropathologic findings in a member of this family that included severe, typical plaque and tangle deposits of AD as well as β-amyloid deposition in the cerebellum.
• The p.Glu693Gly pathogenic variant (the "Arctic" variant) in APP, present in a Swedish family, is associated with enhanced β amyloid protofibril formation [Nilsberth et al 2001] and marked congophilic angiopathy [Basun et al 2008].
• EOFAD has been associated with APP locus duplication [Rovelet-Lecrux et al 2006]. Amyloid angiopathy [Sleegers et al 2006] and Lewy body pathology [Guyant-Marechal et al 2008] have been noted in single families with an APP duplication.

Penetrance

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

Anticipation has not been documented.

Prevalence

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).

• Sixty-one percent of individuals with early-onset AD had a positive family history and 13% had affected individuals in three generations [Campion et al 1999].
• EOFAD comprises less than 3% of all AD.
• Some families with Volga German ancestry have a founder variant in PSEN2 (c.422A>T) that has been reported in modern Germany [Nikisch et al 2008, Jayadev et al 2010, Yu et al 2010].
• Among families with EOFAD, 40%-80% have a pathogenic variant in APP, PSEN1, or PSEN2 (PSEN1 being the most common) [Janssen et al 2003, Kowalska et al 2003, Tedde et al 2003]. The frequency of such variants in simplex cases (i.e., a single occurrence in a family) of early-onset AD in the 50s is not well documented, but is apparently low (<5%); the frequency is higher in those with onset before age 50 years.
• APP duplication is quite rare, having been found in none of 141 persons with EOAD (75 familial) screened in Sweden and Finland [Blom et al 2008].
• PSEN1 pathogenic variants have been reported in Japanese [Furuya et al 2003, Hattori et al 2004], African American [Rippon et al 2003], and Black African [Heckmann et al 2004] families. The founder variant p.Ala431Glu has been reported in Mexican families [Yescas et al 2006], the founder variant p.Glu280Ala in Colombian families [Pastor et al 2003], and the founder variant c.839A>C in Caribbean Hispanics [Athan et al 2001].

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.

Surveillance

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 Trials.gov 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.

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.

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

• Ataka S, Tomiyama T, Takuma H, Yamashita T, Shimada H, Tsutada T, Kawabata K, Mori H, Miki T. A novel presenilin-1 mutation (Leu85Pro) in early-onset Alzheimer disease with spastic paraparesis. Arch Neurol. 2004;61:1773–6. [PubMed: 15534188]

• Athan ES, Williamson J, Ciappa A, Santana V, Romas SN, Lee JH, Rondon H, Lantigua RA, Medrano M, Torres M, Arawaka S, Rogaeva E, Song YQ, Sato C, Kawarai T, Fafel KC, Boss MA, Seltzer WK, Stern Y, St George-Hyslop P, Tycko B, Mayeux R. A founder mutation in presenilin 1 causing early-onset Alzheimer disease in unrelated Caribbean Hispanic families. JAMA. 2001;286:2257–63. [PubMed: 11710891]

• Basun H, Bogdanovic N, Ingelsson M, Almkvist O, Näslund J, Axelman K, Bird TD, Nochlin D, Schellenberg GD, Wahlund LO, Lannfelt L. Clinical and neuropathological features of the arctic APP gene mutation causing early-onset Alzheimer disease. Arch Neurol. 2008;65:499–505. [PMC free article: PMC2723757] [PubMed: 18413473]

• Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM, Holtzman DM, Santacruz A, Buckles V, Oliver A, Moulder K, Aisen PS, Ghetti B, Klunk WE, McDade E, Martins RN, Masters CL, Mayeux R, Ringman JM, Rossor MN, Schofield PR, Sperling RA, Salloway S, Morris JC., Dominantly Inherited Alzheimer Network. Clinical and biomarker changes in dominantly inherited Alzheimer's disease. N Engl J Med. 2012;367:795–804. [PMC free article: PMC3474597] [PubMed: 22784036]

• Beck JA, Poulter M, Campbell TA, Uphill JB, Adamson G, Geddes JF, Revesz T, Davis MB, Wood NW, Collinge J, Tabrizi SJ. Somatic and germline mosaicism in sporadic early-onset Alzheimer's disease. Hum Mol Genet. 2004;13:1219–24. [PubMed: 15115757]

• Beyer K, Lao JI, Fernandez-Novoa L, et al. Identification of a novel mutation (V148I) in the TM2 domain of the presenilin 2 gene in a patient with late-onset AD. Neurobiol Aging. 1998;19 Suppl 2:587. [PubMed: 10732806]

• Bird TD, Lampe TH, Nemens EJ, Miner GW, Sumi SM, Schellenberg GD. Familial Alzheimer's disease in American descendants of the Volga Germans: probable genetic founder effect. Ann Neurol. 1988;23:25–31. [PubMed: 3345066]

• Bird TD, Levy-Lahad E, Poorkaj P, Sharma V, Nemens E, Lahad A, Lampe TH, Schellenberg GD. Wide range in age of onset for chromosome 1--related familial Alzheimer's disease. Ann Neurol. 1996;40:932–6. [PubMed: 9007102]

• Blom ES, Viswanathan J, Kilander L, Helisalmi S, Soininen H, Lannfelt L, Ingelsson M, Glaser A, Hiltunen M. Low prevalence of APP duplications in Swedish and Finnish patients with early-onset Alzheimer's disease. Eur J Hum Genet. 2008;16:171–5. [PubMed: 18043715]

• Breitner JC, Haneuse SJ, Walker R, Dublin S, Crane PK, Gray SL, Larson EB. Risk of dementia and AD with prior exposure to NSAIDs in an elderly community-based cohort. Neurology. 2009;72:1899–905. [PMC free article: PMC2690966] [PubMed: 19386997]

• Brickell KL, Leverenz JB, Steinbart EJ, Rumbaugh M, Schellenberg GD, Nochlin D, Lampe TH, Holm IE, Van Deerlin V, Yuan W, Bird TD. Clinicopathological concordance and discordance in three monozygotic twin pairs with familial Alzheimer's disease. J Neurol Neurosurg Psychiatry. 2007;78:1050–5. [PMC free article: PMC2117553] [PubMed: 17615170]

• Brickell KL, Steinbart EJ, Rumbaugh M, Payami H, Schellenberg GD, Van Deerlin V, Yuan W, Bird TD. Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease. Arch Neurol. 2006;63:1307–11. [PubMed: 16966510]

• Brooks WS, Kwok JB, Kril JJ, Broe GA, Blumbergs PC, Tannenberg AE, Lamont PJ, Hedges P, Schofield PR. Alzheimer's disease with spastic paraparesis and 'cotton wool' plaques: two pedigrees with PS-1 exon 9 deletions. Brain. 2003;126:783–91. [PubMed: 12615638]

• Campion D, Dumanchin C, Hannequin D, Dubois B, Belliard S, Puel M, Thomas-Anterion C, Michon A, Martin C, Charbonnier F, Raux G, Camuzat A, Penet C, Mesnage V, Martinez M, Clerget-Darpoux F, Brice A, Frebourg T. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet. 1999;65:664–70. [PMC free article: PMC1377972] [PubMed: 10441572]

• Clare L. We'll fight it as long as we can: coping with the onset of Alzheimer's disease. Aging Ment Health. 2002;6:139–48. [PubMed: 12028882]

• Crook R, Verkkoniemi A, Perez-Tur J, Mehta N, Baker M, Houlden H, Farrer M, Hutton M, Lincoln S, Hardy J, Gwinn K, Somer M, Paetau A, Kalimo H, Ylikoski R, Pöyhönen M, Kucera S, Haltia M. A variant of Alzheimer's disease with spastic paraparesis and unusual plaques due to deletion of exon 9 of presenilin 1. Nat Med. 1998;4:452–5. [PubMed: 9546792]

• Cruts M, Van Broeckhoven C. Presenilin mutations in Alzheimer's disease. Hum Mutat. 1998;11:183–90. [PubMed: 9521418]

• Cruts M, van Duijn CM, Backhovens H, Van den Broeck M, Wehnert A, Serneels S, Sherrington R, Hutton M, Hardy J, St George-Hyslop PH, Hofman A, Van Broeckhoven C. Estimation of the genetic contribution of presenilin-1 and -2 mutations in a population-based study of presenile Alzheimer disease. Hum Mol Genet. 1998;7:43–51. [PubMed: 9384602]

• Cummings JL, Vinters HV, Cole GM, Khachaturian ZS. Alzheimer's disease: etiologies, pathophysiology, cognitive reserve, and treatment opportunities. Neurology. 1998;51:S2–17. [PubMed: 9674758]

• De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking point on the role of presenilin mutations in Alzheimer disease. EMBO Rep. 2007;8:141–6. [PMC free article: PMC1796779] [PubMed: 17268505]

• Dermaut B, Kumar-Singh S, Engelborghs S, Theuns J, Rademakers R, Saerens J, Pickut BA, Peeters K, van den Broeck M, Vennekens K, Claes S, Cruts M, Cras P, Martin JJ, Van Broeckhoven C, De Deyn PP. A novel presenilin 1 mutation associated with Pick's disease but not beta-amyloid plaques. Ann Neurol. 2004;55:617–26. [PubMed: 15122701]

• Di Fede G, Catania M, Morbin M, Rossi G, Suardi S, Mazzoleni G, Merlin M, Giovagnoli AR, Prioni S, Erbetta A, Falcone C, Gobbi M, Colombo L, Bastone A, Beeg M, Manzoni C, Francescucci B, Spagnoli A, Cantù L, Del Favero E, Levy E, Salmona M, Tagliavini F. A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis. Science. 2009;323:1473–7. [PMC free article: PMC2728497] [PubMed: 19286555]

• Farlow M, Anand R, Messina J Jr, Hartman R, Veach J. A 52-week study of the efficacy of rivastigmine in patients with mild to moderately severe Alzheimer's disease. Eur Neurol. 2000;44:236–41. [PubMed: 11096224]

• Feldman H, Gauthier S, Hecker J, Vellas B, Subbiah P, Whalen E., Donepezil MSAD Study Investigators Group. A 24-week, randomized, double-blind study of donepezil in moderate to severe Alzheimer's disease. Neurology. 2001;57:613–20. [PubMed: 11524468]

• Finckh U, Alberici A, Antoniazzi M, Benussi L, Fedi V, Giannini C, Gal A, Nitsch RM, Binetti G. Variable expression of familial Alzheimer disease associated with presenilin 2 mutation M239I. Neurology. 2000;54:2006–8. [PubMed: 10822446]

• Fox NC, Kennedy AM, Harvey RJ, Lantos PL, Roques PK, Collinge J, Hardy J, Hutton M, Stevens JM, Warrington EK, Rossor MN. Clinicopathological features of familial Alzheimer's disease associated with the M139V mutation in the presenilin 1 gene. Pedigree but not mutation specific age at onset provides evidence for a further genetic factor. Brain. 1997;120:491–501. [PubMed: 9126060]

• Furuya H, Yasuda M, Terasawa KJ, Tanaka K, Murai H, Kira J, Ohyagi Y. A novel mutation (L250V) in the presenilin 1 gene in a Japanese familial Alzheimer's disease with myoclonus and generalized convulsion. J Neurol Sci. 2003;209:75–7. [PubMed: 12686406]

• Giaccone G, Morbin M, Moda F, Botta M, Mazzoleni G, Uggetti A, Catania M, Moro ML, Redaelli V, Spagnoli A, Rossi RS, Salmona M, Di Fede G, Tagliavini F. Neuropathology of the recessive A673V APP mutation: Alzheimer disease with distinctive features. Acta Neuropathol. 2010;120:803–12. [PubMed: 20842367]

• Godbolt AK, Cipolotti L, Watt H, Fox NC, Janssen JC, Rossor MN. The natural history of Alzheimer disease: a longitudinal presymptomatic and symptomatic study of a familial cohort. Arch Neurol. 2004;61:1743–8. [PubMed: 15534185]

• Gómez-Isla T, Growdon WB, McNamara MJ, Nochlin D, Bird TD, Arango JC, Lopera F, Kosik KS, Lantos PL, Cairns NJ, Hyman BT. The impact of different presenilin 1 andpresenilin 2 mutations on amyloid deposition, neurofibrillary changes and neuronal loss in the familial Alzheimer's disease brain: evidence for other phenotype-modifying factors. Brain. 1999;122:1709–19. [PubMed: 10468510]

• Green RC, Schneider LS, Amato DA, Beelen AP, Wilcock G, Swabb EA, Zavitz KH, et al. Effect of tarenflurbil on cognitive decline and activities of daily living in patients with mild Alzheimer disease: a randomized controlled trial. JAMA. 2009;302:2557–64. [PMC free article: PMC2902875] [PubMed: 20009055]

• Gustafson L, Brun A, Englund E, Hagnell O, Nilsson K, Stensmyr M, Ohlin AK, Abrahamson M. A 50-year perspective of a family with chromosome-14-linked Alzheimer's disease. Hum Genet. 1998;102:253–7. [PubMed: 9544835]

• Guyant-Marechal I, Berger E, Laquerrière A, Rovelet-Lecrux A, Viennet G, Frebourg T, Rumbach L, Campion D, Hannequin D. Intrafamilial diversity of phenotype associated with app duplication. Neurology. 2008;71:1925–6. [PubMed: 19047566]

• Halliday GM, Song YJ, Lepar G, Brooks WS, Kwok JB, Kersaitis C, Gregory G, Shepherd CE, Rahimi F, Schofield PR, Kril JJ. Pick bodies in a family with presenilin-1 Alzheimer's disease. Ann Neurol. 2005;57:139–43. [PubMed: 15622541]

• Hattori S, Sakuma K, Wakutani Y, Wada K, Shimoda M, Urakami K, Kowa H, Nakashima K. A novel presenilin 1 mutation (Y154N) in a patient with early onset Alzheimer's disease with spastic paraparesis. Neurosci Lett. 2004;368:319–22. [PubMed: 15364419]

• Heckmann JM, Low WC, de Villiers C, Rutherfoord S, Vorster A, Rao H, Morris CM, Ramesar RS, Kalaria RN. Novel presenilin 1 mutation with profound neurofibrillary pathology in an indigenous Southern African family with early-onset Alzheimer's disease. Brain. 2004;127:133–42. [PubMed: 14570818]

• Holmes C, Boche D, Wilkinson D, Yadegarfar G, Hopkins V, Bayer A, Jones RW, Bullock R, Love S, Neal JW, Zotova E, Nicoll JA. Long-term effects of Abeta42 immunisation in Alzheimer's disease: follow-up of a randomised, placebo-controlled phase I trial. Lancet. 2008;372:216–23. [PubMed: 18640458]

• Jankowsky JL, Fadale DJ, Anderson J, Xu GM, Gonzales V, Jenkins NA, Copeland NG, Lee MK, Younkin LH, Wagner SL, Younkin SG, Borchelt DR. Mutant presenilins specifically elevate the levels of the 42 residue beta-amyloid peptide in vivo: evidence for augmentation of a 42-specific gamma secretase. Hum Mol Genet. 2004;13:159–70. [PubMed: 14645205]

• Janssen JC, Beck JA, Campbell TA, Dickinson A, Fox NC, Harvey RJ, Houlden H, Rossor MN, Collinge J. Early onset familial Alzheimer's disease: Mutation frequency in 31 families. Neurology. 2003;60:235–9. [PubMed: 12552037]

• Jayadev S, Leverenz JB, Steinbart E, Stahl J, Klunk W, Yu CE, Bird TD. Alzheimer's disease phenotypes and genotypes associated with mutations in presenilin 2. Brain. 2010;133:1143–54. [PMC free article: PMC2850581] [PubMed: 20375137]

• Kauwe JS, Jacquart S, Chakraverty S, Wang J, Mayo K, Fagan AM, Holtzman DM, Morris JC, Goate AM. Extreme cerebrospinal fluid amyloid beta levels identify family with late-onset Alzheimer's disease presenilin 1 mutation. Ann Neurol. 2007;61:446–53. [PubMed: 17366635]

• Klunk WE, Price JC, Mathis CA, Tsopelas ND, Lopresti BJ, Ziolko SK, Bi W, Hoge JA, Cohen AD, Ikonomovic MD, Saxton JA, Snitz BE, Pollen DA, Moonis M, Lippa CF, Swearer JM, Johnson KA, Rentz DM, Fischman AJ, Aizenstein HJ, DeKosky ST. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci. 2007;27:6174–84. [PMC free article: PMC3265970] [PubMed: 17553989]

• Kowalska A, Wender M, Florczak J, Pruchnik-Wolinska D, Modestowicz R, Szczech J, Rossa G, Kozubski W. Molecular genetics of Alzheimer's disease: presenilin 1 gene analysis in a cohort of patients from the Poznań region. J Appl Genet. 2003;44:231–4. [PubMed: 12817569]

• Lahiri DK, Farlow MR, Sambamurti K, Greig NH, Giacobini E, Schneider LS. A critical analysis of new molecular targets and strategies for drug developments in Alzheimer's disease. Curr Drug Targets. 2003;4:97–112. [PubMed: 12558063]

• Larner AJ, Doran M. Clinical phenotypic heterogeneity of Alzheimer's disease associated with mutations of the presenilin-1 gene. J Neurol. 2006;253:139–58. [PubMed: 16267640]

• Larner AJ, Ray PS, Doran M. The R269H mutation in presenilin-1 presenting as late-onset autosomal dominant Alzheimer's disease. J Neurol Sci. 2007;252:173–6. [PubMed: 17188713]

• Leverenz JB, Fishel MA, Peskind ER, Montine TJ, Nochlin D, Steinbart E, Raskind MA, Schellenberg GD, Bird TD, Tsuang D. Lewy body pathology in familial Alzheimer disease: evidence for disease- and mutation-specific pathologic phenotype. Arch Neurol. 2006;63:370–6. [PMC free article: PMC1892620] [PubMed: 16533963]

• Li D, Parks SB, Kushner JD, Nauman D, Burgess D, Ludwigsen S, Partain J, Nixon RR, Allen CN, Irwin RP, Jakobs PM, Litt M, Hershberger RE. Mutations of presenilin genes in dilated cardiomyopathy and heart failure. Am J Hum Genet. 2006;79:1030–9. [PMC free article: PMC1698711] [PubMed: 17186461]

• Lippa CF, Swearer JM, Kane KJ, Nochlin D, Bird TD, Ghetti B, Nee LE, St George-Hyslop P, Pollen DA, Drachman DA. Familial Alzheimer's disease: site of mutation influences clinical phenotype. Ann Neurol. 2000;48:376–9. [PubMed: 10976645]

• Lleó A, Blesa R, Gendre J, Castellví M, Pastor P, Queralt R, Oliva R. A novel presenilin 2 gene mutation (D439A) in a patient with early-onset Alzheimer's disease. Neurology. 2001;57:1926–8. [PubMed: 11723295]

• Lleó A, Blesa R, Queralt R, Ezquerra M, Molinuevo JL, Peña-Casanova J, Rojo A, Oliva R. Frequency of mutations in the presenilin and amyloid precursor protein genes in early-onset Alzheimer disease in Spain. Arch Neurol. 2002;59:1759–63. [PubMed: 12433263]

• Maarouf CL, Daugs ID, Spina S, Vidal R, Kokjohn TA, Patton RL, Kalback WM, Luehrs DC, Walker DG, Castaño EM, Beach TG, Ghetti B, Roher AE. Histopathological and molecular heterogeneity among individuals with dementia associated with Presenilin mutations. Mol Neurodegener. 2008;3:20. [PMC free article: PMC2600784] [PubMed: 19021905]

• Mann DM, Iwatsubo T, Nochlin D, Sumi SM, Levy-Lahad E, Bird TD. Amyloid (Abeta) deposition in chromosome 1-linked Alzheimer's disease: the Volga German families. Ann Neurol. 1997;41:52–7. [PubMed: 9005865]

• Marcon G, Giaccone G, Cupidi C, Balestrieri M, Beltrami CA, Finato N, Bergonzi P, Sorbi S, Bugiani O, Tagliavini F. Neuropathological and clinical phenotype of an Italian Alzheimer family with M239V mutation of presenilin 2 gene. J Neuropathol Exp Neurol. 2004;63:199–209. [PubMed: 15055444]

• Menéndez M. Pathological and clinical heterogeneity of presenilin 1 gene mutations. J Alzheimers Dis. 2004;6:475–82. [PubMed: 15505368]

• Miklossy J, Taddei K, Suva D, Verdile G, Fonte J, Fisher C, Gnjec A, Ghika J, Suard F, Mehta PD, McLean CA, Masters CL, Brooks WS, Martins RN. Two novel presenilin-1 mutations (Y256S and Q222H) are associated with early-onset Alzheimer's disease. Neurobiol Aging. 2003;24:655–62. [PubMed: 12885573]

• Mohs RC, Doody RS, Morris JC, Ieni JR, Rogers SL, Perdomo CA, Pratt RD, et al. A 1-year, placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology. 2001;57:481–8. [PubMed: 11502917]

• Moonis M, Swearer JM, Dayaw MP, St George-Hyslop P, Rogaeva E, Kawarai T, Pollen DA. Familial Alzheimer disease: decreases in CSF Abeta42 levels precede cognitive decline. Neurology. 2005;65:323–5. [PubMed: 16043812]

• National Institute on Aging Working Group. Consensus report of the Working Group on: "Molecular and Biochemical Markers of Alzheimer's Disease". The Ronald and Nancy Reagan Research Institute of the Alzheimer's Association and the National Institute on Aging Working Group. Neurobiol Aging. 1998;19:109–16. [PubMed: 9558143]

• Nikisch G, Hertel A, Kiessling B, Wagner T, Krasz D, Hofmann E, Wiedemann G. Three-year follow-up of a patient with early-onset Alzheimer's disease with presenilin-2 N141I mutation - case report and review of the literature. Eur J Med Res. 2008;13:579–84. [PubMed: 19073399]

• Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, Stenh C, Luthman J, Teplow DB, Younkin SG, Näslund J, Lannfelt L. The 'Arctic' APP mutation (E693G) causes Alzheimer's disease by enhanced Abeta protofibril formation. Nat Neurosci. 2001;4:887–93. [PubMed: 11528419]

• Pastor P, Roe CM, Villegas A, Bedoya G, Chakraverty S, García G, Tirado V, Norton J, Ríos S, Martínez M, Kosik KS, Lopera F, Goate AM. Apolipoprotein Eepsilon4 modifies Alzheimer's disease onset in an E280A PS1 kindred. Ann Neurol. 2003;54:163–9. [PubMed: 12891668]

• Perez-Tur J, Froelich S, Prihar G, Crook R, Baker M, Duff K, Wragg M, Busfield F, Lendon C, Clark RF, et al. A mutation in Alzheimer's disease destroying a splice acceptor site in the presenilin-1 gene. Neuroreport. 1995;7:297–301. [PubMed: 8742474]

• Piccini A, Zanusso G, Borghi R, Noviello C, Monaco S, Russo R, Damonte G, Armirotti A, Gelati M, Giordano R, Zambenedetti P, Russo C, Ghetti B, Tabaton M. Association of a presenilin 1 S170F mutation with a novel Alzheimer disease molecular phenotype. Arch Neurol. 2007;64:738–45. [PubMed: 17502474]

• Podlisny MB, Citron M, Amarante P, Sherrington R, Xia W, Zhang J, Diehl T, Levesque G, Fraser P, Haass C, Koo EH, Seubert P, St George-Hyslop P, Teplow DB, Selkoe DJ. Presenilin proteins undergo heterogeneous endoproteolysis between Thr291 and Ala299 and occur as stable N- and C-terminal fragments in normal and Alzheimer brain tissue. Neurobiol Dis. 1997;3:325–37. [PubMed: 9173929]

• Poorkaj P, Sharma V, Anderson L, Nemens E, Alonso ME, Orr H, White J, Heston L, Bird TD, Schellenberg GD. Missense mutations in the chromosome 14 familial Alzheimer's disease presenilin 1 gene. Hum Mutat. 1998;11:216–21. [PubMed: 9521423]

• Prihar G, Verkkoniem A, Perez-Tur J, Crook R, Lincoln S, Houlden H, Somer M, Paetau A, Kalimo H, Grover A, Myllykangas L, Hutton M, Hardy J, Haltia M. Alzheimer disease PS-1 exon 9 deletion defined. Nat Med. 1999;5:1090. [PubMed: 10502791]

• Queralt R, Ezquerra M, Lleó A, Castellví M, Gelpí J, Ferrer I, Acarín N, Pasarín L, Blesa R, Oliva R. A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances. J Neurol Neurosurg Psychiatry. 2002;72:266–9. [PMC free article: PMC1737723] [PubMed: 11796781]

• Raman A, Lin X, Suri M, Hewitt M, Constantinescu CS, Phillips MF. A presenilin 1 mutation (Arg278Ser) associated with early onset Alzheimer's disease and spastic paraparesis. J Neurol Sci. 2007;260:78–82. [PubMed: 17507029]

• Raskind MA, Peskind ER, Wessel T, Yuan W. Galantamine in AD: A 6-month randomized, placebo-controlled trial with a 6-month extension. The Galantamine USA-1 Study Group. Neurology. 2000;54:2261–8. [PubMed: 10881250]

• Raux G, Gantier R, Thomas-Anterion C, Boulliat J, Verpillat P, Hannequin D, Brice A, Frebourg T, Campion D. Dementia with prominent frontotemporal features associated with L113P presenilin 1 mutation. Neurology. 2000;55:1577–8. [PubMed: 11094121]

• Reisberg B, Doody R, Stöffler A, Schmitt F, Ferris S, Möbius HJ., Memantine Study Group. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348:1333–41. [PubMed: 12672860]

• Revesz T, McLaughlin JL, Rossor MN, Lantos PL. Pathology of familial Alzheimer's disease with Lewy bodies. J Neural Transm Suppl. 1997;51:121–35. [PubMed: 9470133]

• Ringman JM, Diaz-Olavarrieta C, Rodriguez Y, Chavez M, Fairbanks L, Paz F, Varpetian A, Maldonado HC, Macias-Islas MA, Murrell J, Ghetti B, Kawas C. Neuropsychological function in nondemented carriers of presenilin-1 mutations. Neurology. 2005;65:552–8. [PMC free article: PMC3373251] [PubMed: 16116115]

• Rippon GA, Crook R, Baker M, Halvorsen E, Chin S, Hutton M, Houlden H, Hardy J, Lynch T. Presenilin 1 mutation in an african american family presenting with atypical Alzheimer dementia. Arch Neurol. 2003;60:884–8. [PubMed: 12810495]

• Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, Chi H, Lin C, Holman K, Tsuda T, et al. Familial Alzheimer's disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer's disease type 3 gene. Nature. 1995;376:775–8. [PubMed: 7651536]

• Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001;57:621–5. [PubMed: 11524469]

• Rogers SL, Farlow MR, Doody RS, Mohs R, Friedhoff LT. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer's disease. Donepezil Study Group. Neurology. 1998;50:136–45. [PubMed: 9443470]

• Roks G, Van Harskamp F, De Koning I, Cruts M, De Jonghe C, Kumar-Singh S, Tibben A, Tanghe H, Niermeijer MF, Hofman A, Van Swieten JC, Van Broeckhoven C, Van Duijn CM. Presentation of amyloidosis in carriers of the codon 692 mutation in the amyloid precursor protein gene (APP692). Brain. 2000;123:2130–40. [PubMed: 11004129]

• Rovelet-Lecrux A, Hannequin D, Raux G, Le Meur N, Laquerrière A, Vital A, Dumanchin C, Feuillette S, Brice A, Vercelletto M, Dubas F, Frebourg T, Campion D. APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy. Nat Genet. 2006;38:24–6. [PubMed: 16369530]

• Salloway S, Sperling R, Gilman S, Fox NC, Blennow K, Raskind M, Sabbagh M, Honig LS, Doody R, van Dyck CH, Mulnard R, Barakos J, Gregg KM, Liu E, Lieberburg I, Schenk D, Black R, Grundman M., Bapineuzumab 201 Clinical Trial Investigators. A phase 2 multiple ascending dose trial of bapineuzumab in mild to moderate Alzheimer disease. Neurology. 2009;73:2061–70. [PMC free article: PMC2790221] [PubMed: 19923550]

• Seltzer B, Zolnouni P, Nunez M, Goldman R, Kumar D, Ieni J, Richardson S, et al. Efficacy of donepezil in early-stage Alzheimer disease: a randomized placebo-controlled trial. Arch Neurol. 2004;61:1852–6. [PubMed: 15596605]

• Shen J, Bronson RT, Chen DF, Xia W, Selkoe DJ, Tonegawa S. Skeletal and CNS defects in Presenilin-1-deficient mice. Cell. 1997;89:629–39. [PubMed: 9160754]

• Shen J, Kelleher RJ 3rd. The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007;104:403–9. [PMC free article: PMC1766397] [PubMed: 17197420]

• Sleegers K, Brouwers N, Gijselinck I, Theuns J, Goossens D, Wauters J, Del-Favero J, Cruts M, van Duijn CM, Van Broeckhoven C. APP duplication is sufficient to cause early onset Alzheimer's dementia with cerebral amyloid angiopathy. Brain. 2006;129:2977–83. [PubMed: 16921174]

• Smith MJ, Kwok JB, McLean CA, Kril JJ, Broe GA, Nicholson GA, Cappai R, Hallupp M, Cotton RG, Masters CL, Schofield PR, Brooks WS. Variable phenotype of Alzheimer's disease with spastic paraparesis. Ann Neurol. 2001;49:125–9. [PubMed: 11198283]

• Spriggs M. Genetically selected baby free of inherited predisposition to early-onset Alzheimer's disease. J Med Ethics. 2002;28:290. [PMC free article: PMC1733660] [PubMed: 12356954]

• Steinbart EJ, Smith CO, Poorkaj P, Bird TD. Impact of DNA testing for early-onset familial Alzheimer disease and frontotemporal dementia. Arch Neurol. 2001;58:1828–31. [PubMed: 11708991]

• Tandon A, Fraser P. The presenilins. Genome Biol. 2002; 3:reviews3014. [PMC free article: PMC244923] [PubMed: 12429067]

• Tedde A, Forleo P, Nacmias B, Piccini C, Bracco L, Piacentini S, Sorbi S. A presenilin-1 mutation (Leu392Pro) in a familial AD kindred with psychiatric symptoms at onset. Neurology. 2000;55:1590–1. [PubMed: 11094128]

• Tedde A, Nacmias B, Ciantelli M, Forleo P, Cellini E, Bagnoli S, Piccini C, Caffarra P, Ghidoni E, Paganini M, Bracco L, Sorbi S. Identification of new presenilin gene mutations in early-onset familial Alzheimer disease. Arch Neurol. 2003;60:1541–4. [PubMed: 14623725]

• Thinakaran G, Parent AT. Identification of the role of presenilins beyond Alzheimer's disease. Pharmacol Res. 2004;50:411–8. [PubMed: 15304238]

• Towner D, Loewy RS. Ethics of preimplantation diagnosis for a woman destined to develop early-onset Alzheimer disease. JAMA. 2002;287:1038–40. [PubMed: 11866654]

• Uemura K, Kitagawa N, Kohno R, Kuzuya A, Kageyama T, Chonabayashi K, Shibasaki H, Shimohama S. Presenilin 1 is involved in maturation and trafficking of N-cadherin to the plasma membrane. J Neurosci Res. 2003;74:184–91. [PubMed: 14515347]

• Van Broeckhoven CL. Molecular genetics of Alzheimer disease: identification of genes and gene mutations. Eur Neurol. 1995;35:8–19. [PubMed: 7737252]

• Verkkoniemi A, Somer M, Rinne JO, Myllykangas L, Crook R, Hardy J, Viitanen M, Kalimo H, Haltia M. Variant Alzheimer's disease with spastic paraparesis: clinical characterization. Neurology. 2000;54:1103–9. [PubMed: 10720282]

• Verlinsky Y, Rechitsky S, Verlinsky O, Masciangelo C, Lederer K, Kuliev A. Preimplantation diagnosis for early-onset Alzheimer disease caused by V717L mutation. JAMA. 2002;287:1018–21. [PubMed: 11866650]

• Vlad SC, Miller DR, Kowall NW, Felson DT. Protective effects of NSAIDs on the development of Alzheimer disease. Neurology. 2008;70:1672–7. [PMC free article: PMC2758242] [PubMed: 18458226]

• Walker ES, Martinez M, Brunkan AL, Goate A. Presenilin 2 familial Alzheimer's disease mutations result in partial loss of function and dramatic changes in Abeta 42/40 ratios. J Neurochem. 2005;92:294–301. [PubMed: 15663477]

• Wijsman EM, Daw EW, Yu X, Steinbart EJ, Nochlin D, Bird TD, Schellenberg GD. APOE and other loci affect age-at-onset in Alzheimer's disease families with PS2 mutation. Am J Med Genet B Neuropsychiatr Genet. 2005;132B:14–20. [PubMed: 15389756]

• Wong PC, Zheng H, Chen H, Becher MW, Sirinathsinghji DJ, Trumbauer ME, Chen HY, Price DL, Van der Ploeg LH, Sisodia SS. Presenilin 1 is required for Notch1 and DII1 expression in the paraxial mesoderm. Nature. 1997;387:288–92. [PubMed: 9153393]

• Yescas P, Huertas-Vazquez A, Villarreal-Molina MT, Rasmussen A, Tusié-Luna MT, López M, Canizales-Quinteros S, Alonso ME. Founder effect for the Ala431Glu mutation of the presenilin 1 gene causing early-onset Alzheimer's disease in Mexican families. Neurogenetics. 2006;7:195–200. [PubMed: 16628450]

• Yu CE, Marchani E, Nikisch G, Müller U, Nolte D, Hertel A, Wijsman EM, Bird TD. The N141I mutation in PSEN2: implications for the quintessential case of Alzheimer disease. Arch Neurol. 2010;67:631–3. [PMC free article: PMC3016011] [PubMed: 20457965]

• Zekanowski C, Styczyńska M, Pepłońska B, Gabryelewicz T, Religa D, Ilkowski J, Kijanowska-Haładyna B, Kotapka-Minc S, Mikkelsen S, Pfeffer A, Barczak A, Łuczywek E, Wasiak B, Chodakowska-Zebrowska M, Gustaw K, Łaczkowski J, Sobów T, Kuźnicki J, Barcikowska M. Mutations in presenilin 1, presenilin 2 and amyloid precursor protein genes in patients with early-onset Alzheimer's disease in Poland. Exp Neurol. 2003;184:991–6. [PubMed: 14769392]

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.

• Post SG, Whitehouse PJ, Binstock RH, Bird TD, Eckert SK, Farrer LA, Fleck LM, Gaines AD, Juengst ET, Karlinsky H, Miles S, Murray TH, Quaid KA, Relkin NR, Roses AD, St George-Hyslop PH, Sachs GA, Steinbock B, Truschke EF, Zinn AB. The clinical introduction of genetic testing for Alzheimer's disease: an ethical perspective. JAMA. 1997;277:832–6. [PubMed: 9052715]

• Van Broeckhoven C. Alzheimer's disease: identification of genes and genetic risk factors. Prog Brain Res. 1998;117:315–25. [PubMed: 9932417]

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