Genetic Heterogeneity

Familial cases appear to have the same phenotype as sporadic cases both clinically and pathologically  and, thus, are distinguished only by family history. AD can be divided into several subgroups on a genetic basis.

Subgroups of Alzheimer Disease
Type Proportion of All AD
Sporadic ~75%
Associated with Down Syndrome <1%
Early Onset Familial AD (AD1, AD3, AD4) <5%
Late Onset Familial AD (AD2) 10-25%

Sporadic AD: Includes most patients with AD who have a negative family history. Onset can be anytime in adulthood. The exact pathogenesis of the disease is unknown, but as in all forms of AD there are deficits of cholinergic neurotransmitter systems and accumulation of A Beta amyloid peptide (in neuritic plaques) and abnormally phosphorylated tau protein (in neurofibrillary tangles). A common hypothesis is that sporadic AD is multifactorial and results from a combination of aging, genetic predisposition, and exposure to one or more environmental agents such as head trauma, viruses and/or toxins. Such environmental agents have not yet been proven to be directly involved in the pathogenesis of AD.

AD associated with Down syndrome: Essentially all persons with trisomy 21 develop the neuropathological hallmarks of AD after 40 years. More than half such individuals also develop clinical evidence of cognitive decline if carefully observed or tested . The reason for this association is presumably the lifelong over-expression of the amyloid precursor protein (APP) gene on chromosome 21 and the resultant overproduction of A Beta amyloid in the brains of persons who are trisomic for this gene.

Early Onset Familial Alzheimer Disease
Disease Name Inheritance Proportion Gene/Locus  
Locus Normal Gene Product Testing  OMIM  
AD1 AD 10% APP 21q21.3-22 Amyloid Precursor Protein Research 104760
AD3 AD 40-70% Presenilin 1 (PS-1) 14q24.3 S182 Clinical 104311 
AD4 AD Rare Presenilin 2 (PS-2) 1q31-42 STM2 Research 600759

Early onset familial Alzheimer disease (EOFAD): This group comprises less than 5% of all AD . This category refers to families in which there are multiple cases of AD and the mean age of onset is  before 65 years (60 or 70 years in some studies).  There are at least three subtypes of early onset FAD .
AD1 refers to families with a point mutation in the APP (Amyloid Precursor Protein) gene on chromosome 21 . Such families represent no more than 10% of all early onset FAD (which is itself uncommon in the general population). The phenotype of dementia in families with APP mutations is that of typical AD. Age of onset is usually in the 40's and 50's (occasionally 60's).

AD3 is caused by mutations in presenilin 1 located on chromosome 14 . These families represent the majority of kindreds with early onset FAD (roughly 40-70% of that group). Age of onset is usually in the 40's or early 50's.  Onset in the 30's and early 60's has been reported.  Onset after age 65 is thought to be very rare with penetrance essentially complete by that age.  Relatively rapid progression over 6-7 years is common and the disease is often asssociated with seizures, myoclonus, and language deficits .

AD4 is caused by point mutations in the presenilin 2 gene on chromosome 1. Thus far, mutations in presenilin 2  have only been found in a few families, most of which are of  Volga German ancestry living in the United States and one Italian kindred (Rogaev et al, 1995). AD4 has a wider range of onset age than AD1 and AD3.  The onset age range extends from 40-75 years with a few instances of non-penetrance after age 80 (Bird, 1996). Mean duration of disease is 11 years.


          Late Onset Familial Alzheimer Disease
Disease Name Inheritance Proportion Gene/Locus Name  Locus Normal Gene Product Testing OMIM
AD2 ?AD 10-25% ApoE 19q13.2 Apolipoprotein E Clinical 107741 104310 

Late onset familial AD (AD2): Many families have multiple affected members all of whom have onset of dementia after the age of 65 or 70. This group probably represents at least 10-25% of all AD. No chromosomal assignment for a gene or genes directly responsible for this form of AD has yet been discovered. However, there is clear and well-documented association of late onset FAD with the e4 allele of Apolipoprotein E whose gene locus is on chromosome 19 . Apo E e4, by unknown mechanisms, appears to modify age of onset and shift the onset curve toward an earlier age. Disease duration is typically 8-10 years but the range varies from 2-25 years.

The place of Apo E testing is presently problematic. The association of Apo E e4 with AD is well-documented, but the usefulness of Apo E testing in clinical diagnosis and risk assessment remains unclear. There is general agreement that Apo E testing should not be used for prediction of AD in asymptomatic persons. A young asymptomatic person with the 4/4 genotype may have an approximately 30% lifetime risk of developing AD , but this estimate is not generally considered clinically useful.  On the other hand, ApoE may be useful as an adjunct diagnostic test [National Institute on Aging/Alzheimer's Association Working Group, Lancet, 1996]. Presence of an e4 allele in a demented individual increases the probability that AD is the cause of dementia, especially in an individual who is homozygous for the e4 allele. The clinical diagnosis of AD is correct 85-90% of the time and this accuracy is raised to about 97% in demented persons with the Apo E 4/4 genotype who have had prior clinical diagnostic testing . However, Apo E testing is not specific or definitive and the evaluation of the patient for other possible causes of dementia remains necessary . Lack of an e4 allele does not exclude the diagnosis of AD.

The following table shows the association between ApoE genotypes and AD. Note that a significant proportion of AD patients have an ApoE4 allele (i.e., genotypes 2/4, 3/4, 4/4).  The association between ApoE4 and AD is greatest when the patient has a positive family history of dementia.  The last column largely represents familial late onset AD.  Also note that the strongest association between ApoE4 and AD, relative to the normal control population,  is with the 4/4 genotype.  That genotype occurs in about 1% of the normal control population and in nearly 19% of the familial AD population.  Note that many persons with AD (about 65%) do not have an ApoE4 allele, emphasizing that the absence of an ApoE4 allele does not rule out the diagnosis of AD.


Percent of ApoE Genotypes in Control and AD Patients
Normal Controls  
(n = 304)
All AD Patients  
(n = 233)
AD Patients with  Positive   
Family History of Dementia  (n = 85)
2/2 1.3 0 0
2/3 12.5 3.4 3.5
2/4 4.9 4.3 8.2
3/3 59.9 38.2 23.5
3/4 20.7 41.2 45.9
4/4 0.7 12.9 18.8

Another way to look at this association between ApoE4 and AD is with allele frequencies as shown in the following table.

ApoE Allele Frequencies in Control and AD Patients
ApoE Allele Normal Controls  
All AD Patients  
AD Patients with Positive  
Family History of Dementia (n=85)
9.0 3.9 5.9
3 76.5 60.5 48.2
4 13.7 35.6 45.9