Thornhill Research Unit, University of Southampton, Moorgreen Hospital, Botley Road, West End, Southampton SO30 3JB, UK
See editorial, pp.
9798, this issue.
ABSTRACT
Background Patients with Alzheimer's disease show a wide variation in clinical phenotype. Genetic research has been largely concerned with the role of mutations or common variants as risk factors for the disease. Do genetic factors also influence clinical phenotype?
Aims To examine the evidence that genetic factors influence the clinical expression of the disease in addition to influencing risk.
Method A selective review was made of the key literature.
Results Mutations in three genes, coding for amyloid precursor
protein, presenilin-1 and presenilin-2, and a common variation (4) in
another gene, APOE, have been shown to lead to an earlier development
of the disease. More recently, genetic association and twin studies have
suggested a role for genetic factors in the development of other aspects of
clinical phenotype, notably the appearance of non-cognitive symptoms.
Conclusions In Alzheimer's disease genetic variation influences a number of aspects of clinical phenotype.
Early family and twin studies have indicated that a number of genes have an important part to play in the development of Alzheimer's disease. Variation in these genes, including both rare mutations and common polymorphisms, appears to confer increased risk for the development of the disease. However, apparent increased risk may be largely explained by the effects that genetic variation has on the clinical phenotype of Alzheimer's disease, particularly the age at which the disease presents. More recently, it has been proposed that genetic variation may also explain some of the other features of clinical phenotype, including the development of non-cognitive symptoms.
GENES AS RISK FACTORS
The clearest evidence for a genetic contribution to the aetiology of Alzheimer's disease is the existence of families in whom the disease is transmitted in a clear autosomal dominant pattern. Study of one of these large pedigrees revealed the transmission, from generation to generation, of a single point mutation in the gene for amyloid precursor protein (APP), found on chromosome 21 in family members developing early-onset Alzheimer's disease. Further studies of these families led to the discovery of other point mutations in the same gene and later the presence of mutations in two other genes, encoding presenilin-1 (PS-1) and presenilin-2 (PS-2), found on chromosomes 14 and 1, respectively. To date, 12 Alzheimer's disease-related mutations have been discovered in the APP gene, 69 mutations in the PS-1 gene and 5 mutations in the PS-2 gene. Significantly, research suggests that the different mutations in these three genes lead to a common result, an increase in ß-A4 peptide fragment of APP which forms the core of the neuritic plaques found in the brains of people with Alzheimer's disease.
While these findings are of immense importance in terms of elucidating the biological pathogenesis of Alzheimer's diease, it is important to recognise that these three causal genes may only account for 30-50% of all autosomal dominant early-onset cases, or around 10% of familial early-onset cases (Cruts et al, 1998). Thus, given that in the majority of cases (> 95%) Alzheimer's disease occurs after the age of 60 years, it is clear that these genetic mutations make only a small contribution to the risk of developing the disease in general.
The inheritance of late-onset Alzheimer's disease is more complex than that
of the early-onset form. In cross-sectional studies the presence of a positive
family history of late-onset Alzheimer's disease is a consistent risk factor
for subjects with the late-onset form, but a clear autosomal dominant pattern
of inheritance is rare. Both twin and family studies suggest a polygenic
multifactorial mode of inheritance and as a consequence the elucidation of
genetic risk factors for late-onset Alzheimer's disease requires different
methods from those used in the early-onset disease, with its simple Mendelian
patterns of inheritance. Association studies have so far dominated the
genetics of late-onset Alzheimer's disease. Such studies look for variation in
the frequency of an allele in samples of unrelated patients with late-onset
Alzheimer's disease compared with unrelated control subjects. These studies
have resulted in a number of candidate genes being proposed as having
importance as risk factors for late-onset Alzheimer's disease, and include
associations with variation in genes encoding the very low-density lipoprotein
(VLDL) receptor, PS-1 (an intronic mutation not associated with early-onset
Alzheimer's disease), butyrylcholinesterase, angiotensin-1 converting enzyme,
1-antichymotrypsin, the human leucocyte antigen (HLA)
complex,
2-macroglobulin, the low-density lipoprotein-like
receptor, the serotonin transporter and interleukin-1. Typically, interest in
these candidates has diminished as independent replication has not been
forthcoming, and little evidence now remains for an important role for genetic
variation in the VLDL receptor, PS-1 or
1-antichymotrypsin
genes in the development of late-onset Alzheimer's disease. The other
candidate genes still have their advocates and remain hotly disputed.
More recently, the results of a number of linkage studies have become available. The methods used for linkage studies in complex non-Mendelian diseases such as late-onset Alzheimer's disease are less powerful than those used for the early-onset form. However, such studies can reveal areas of interest in the genome that might later be explored by association studies. A complete genomic screen in a series of multiplex families affected with late-onset Alzheimer's disease has revealed five regions of interest on chromosomes 4, 6, 12, 19 and 20. Excluding the effects of the APOE4 locus, the maximum log likelihood ratio (lod) score in this study occurred in a region located on the short arm of chromosome 12 (Pericak-Vance et al, 1997). However, two subsequent studies following similar methods (Blacker et al, 1998; Wu et al, 1998) were unable to confirm linkage to this area. A large sibpair study (Kehoe et al, 1999) has revealed many possible loci showing linkage to late-onset Alzheimer's disease. These include loci on chromosomes 1, 5, 9, 10, 12, 14, 19 (close to APOE) and 21 (close to the APP gene). Currently, the main focus of attention is chromosome 10, with two independent studies showing evidence of a susceptibility locus in the same region (Ertekin-Taner et al, 2000; Myers et al, 2000). However, it is clear that a large number of loci are implicated and that there is some disagreement between studies in the predicted areas of interest. These findings demonstrate some of the limitations of this approach, but also serve to emphasise the polygenic nature of late-onset Alzheimer's disease. Further exploration of these areas by association studies the positional candidate approach is likely to dominate the genetics of Alzheimer's disease in the future.
Of the genetic risk factors that have been advocated as having a role in
the development of late-onset Alzheimer's disease, the least controversial
remains the increased risk associated with possession of one or more copies of
the APOE4 allele, coding for the apolipoprotein E (ApoE) variant
4. Significantly, the importance of APOE4 was determined using
a positional candidate gene approach. Since this finding, other studies
(Artiga et al, 1998;
Bullido et al, 1998;
Lambert et al, 1998)
have also suggested an association between a number of polymorphisms within
the transcriptional regulatory region of the APOE gene and late-onset
Alzheimer's disease that is independent of ApoE
4 status. Based on these
data, it was suggested that there are two independent mechanisms by which risk
of late-onset Alzheimer's disease can be modified by the APOE gene:
first, by variations in the coding regions, which alter the functional
properties of APOE; and second, by the presence of promoter variants
which result in quantitative differences in APOE expression
(Artiga et al, 1998).
However, this hypothesis is controversial, and more recent studies
(Helisalmi et al,
1999; Zurutuza et al,
2000) have failed to support the independence of APOE
promoter variants in the development of Alzheimer's disease.
GENETIC INFLUENCES ON CLINICAL PHENOTYPE
Age of onset
Families carrying mutations in the APP gene have ages of onset largely
within the range 40-65 years. To date, no APP mutation carrier has been
reported to be unaffected beyond the age of 67 years. Families carrying
mutations in the PS-1 gene have the earliest ages of onset, which fall largely
within the range 35-55 years, although one such family member has recently
been recorded with onset at 24 years
(Wisniewski et al,
1998). These mutations are largely associated with early-onset
familial Alzheimer's disease, but at least two of these mutations (Ala79Val
and His163Tyr) have been observed with late-onset Alzheimer's disease and may
be non-penetrant (Cruts et al,
1998). Families carrying mutations in the PS-2 gene have ages of
onset largely within the range 40-70 years and thus show some overlap with
late-onset Alzheimer's disease. Penetrance is high but may not be 100%, with
at least two reported cases of non-penetrance over the age of 80 years
(Bird et al,
1996).
The familial influence on age of onset in late-onset Alzheimer's disease may be substantial. Thus, one study of affected sib pairs suggests that shared familial effects may account for 40% of the variance (Tunstall et al, 2000). Indeed, studies have shown that in the late-onset disease the age of onset is approximately 6 years earlier in individuals who carry two copies of the APOE4 allele compared with non-carriers. This has led to the suggestion that the APOE4 allele is a risk factor for Alzheimer's disease mainly because in old age Alzheimer's disease and death are competing risks. Any factor leading to an earlier age of onset of Alzheimer's disease in the elderly (and hence the development of the disease prior to death) will be associated with Alzheimer's disease. Evidence confirming this hypothesis has come from a large study of approximately 5000 individuals (Meyer et al, 1998). This study showed a clear decline in relative risk of developing late-onset Alzheimer's disease in all subjects with increasing age but with a clear plateau beyond which no further new cases of the disease were reported. The age at which this plateau was reached was earlier in carriers of the APOE4 allele. Thus, it appears clear that the APOE4 allele has its predominant effect by determining when, but not if, an individual develops late-onset Alzheimer's disease (Meyer et al, 1998).
Non-cognitive features
If genetic risk factors for Alzheimer's disease are associated with
non-cognitive symptoms, then one might anticipate that subjects with a family
history of the disease have an increased frequency of these symptoms.
Likewise, one would expect an association between known genetic risk factors
for Alzheimer's disease, including the genes for APP, PS-1, PS-2 and the ApoE
4 allele, and these symptoms in Alzheimer's disease.
In fact, there appears to be little consistent evidence of an association between either a positive family history of Alzheimer's disease or variation in known candidate genes and an increase in the frequency of non-cognitive symptoms occurring for the first time within the disease. It thus seems unlikely that major genetic risk factors for the development of late-onset Alzheimer's disease have a substantial role to play in the development of non-cognitive symptoms within the late-onset disease. However, this does not mean that these symptoms have no genetic basis, since genes may influence the phenotypic expression of the disease without being involved directly in its aetiology. Indeed, early studies have shown evidence of an association between a positive family history of depressive illness and an increase in the frequency of depressive symptoms occurring for the first time within Alzheimer's disease (Pearlson et al, 1990). These early findings are supported by a sib-pair study (Tunstall et al, 2000) showing that familial factors have a role in the development of depressive illness in late-onset Alzheimer's disease. In addition, this small study also suggests a role for familial factors in a wide variety of non-cognitive symptoms, including agitation, aggression and psychosis.
A more direct approach has also been adopted whereby common genetic polymorphisms previously showing associations with other neuropsychiatric conditions have been found to be associated with non-cognitive symptoms in late-onset Alzheimer's disease. For example, one study (Holmes et al, 1998) of people with late-onset Alzheimer's disease found an association between common polymorphic variations in the 5-HT2A and 5-HT2C serotonin receptor genes (102-T/C and Cys23Ser polymorphisms, respectively), previously implicated in schizophrenia and bipolar affective disorder, with psychotic symptoms in Alzheimer's disease. Associations were found between the presence of the C102 allele and the presence of visual and auditory hallucinations and between the presence of the Ser23 allele and visual hallucinations. Another study (Sweet et al, 1998) has found evidence to suggest an association of psychosis and aggression in patients with Alzheimer's disease who carry common polymorphisms in the dopamine receptor genes DRD1 and DRD3. These studies need to be replicated but they suggest that common receptor polymorphisms may have a role in the genesis of psychotic or other non-cognitive symptoms that are not implicated as genetic risk factors for late-onset Alzheimer's disease.
Cognitive decline
No study to date has looked at rates of decline in carriers of APP, PS-1
and PS-2 mutations, but patients with late-onset Alzheimer's disease who have
a positive family history of Alzheimer's disease show no evidence of increased
rates of decline. The majority of studies have also failed to show any
relationships between possession of the APOE4 allele and increased
rates of decline. This lack of association is interesting since it implies
that genetic factors may determine only when the disease starts, not the rate
of degeneration. Clearly, caution is required when interpreting a negative
finding and it may be that associations will always be difficult to establish
because of the large number of confounding factors which may influence
cognitive deterioration as well as difficulties with the use of psychometric
scales over short periods. Indeed, a study by Craft et al
(1998) has suggested that there
is an increased rate of cognitive decline in APOE4 carriers, which
may be detectable by using a long follow-up period.
Duration
The mean duration of illness in families with PS-1 mutations is
significantly shorter (range 5.8-6.8 years) than in families with both PS-2
(range 4.4-10.8 years) and APP mutations (range 9.0-16 years), reflecting the
severity of PS-1-associated Alzheimer's disease. Studies of late-onset
Alzheimer's disease suggest that the duration of illness tends to be longer in
people who have a positive family history or in carriers of the APOE4
allele. However, it has since been shown that this relationship no longer
holds true once the confounding effects of age of onset have been taken into
account. Thus, in late-onset Alzheimer's disease, increased survival is more
directly related to an earlier age of onset, which is influenced by a number
of factors that are not exclusively genetic.
Clinical Implications and Limitations
CLINICAL IMPLICATIONS
LIMITATIONS
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Received for publication May 16, 2000. Revision received May 14, 2001. Accepted for publication May 23, 2001.
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