Like Mr. A, many patients ask about their baseline risk of dementia. Family physicians should appreciate that they are attempting to predict the onset of a heterogeneous group of diseases. As a consequence, it is possible that some risk factors may predispose to some types of dementia while having little influence on predicting the onset of other types. In this article we focus on Alzheimer disease, first considering genetic aspects, then vascular, lifestyle and finally sociodemographic risk factors ().
Genetic risk factors
To assess genetic risk in an individual or family, it is critical to obtain an accurate family history with as much information as possible about the diagnosis of dementia and age of onset in reportedly affected family members. Obtaining reliable answers to these questions is not a trivial task. If it is not possible to examine the affected family members, confirmation of diagnosis by review of clinical reports and neuropathologic findings, if available, adds to diagnostic certainty. In addition to confirming the diagnosis in relatives, attempting to establish the age of onset is also important. Often the medical history of a person's parents is unknown because of distance, life circumstance such as divorce, reticence of the previous generation to discuss personal issues, or death from other causes at a young age. Furthermore, the person may have no siblings, or have no information on siblings' health status. Incomplete family histories can be a major hurdle in assessing genetic risk.
Early-onset Alzheimer disease, which may have a significant genetic component, is generally defined as occurring before 60 years of age. It accounts for only 6%–7% of all cases of Alzheimer disease.19,20
From this small pool of patients, only 13% clearly exhibit autosomal dominant transmission over more than one generation, which means that a sibling, a parent and a grandparent also has Alzheimer disease.20,21
To date, all 3 known causative gene mutations (changes that almost always result in Alzheimer disease if the patient lives long enough) lead to the early-onset form.3
The first of these genes to be identified was the amyloid precursor protein gene, located on chromosome 21. Mutations in this gene cause excessive cleavage by the β- and γ-secretase enzymes, instead of normal cleavage by the α-secretase enzyme. The result is increased production of toxic β-amyloid fragments, which are converted into insoluble aggregates that form senile plaques in brain tissue ( and ). Two other genes that cause familial early-onset Alzheimer's disease are presenilin-1, located on chromosome 14, and presenilin-2, located on chromosome 1. Both of these genes are involved in the γ-secretase complex, and mutations lead to excessive cleavage by the γ-secretase enzyme, which results in increased production and accumulation of β-amyloid fragments (). These mechanisms are not known to be associated with late-onset or sporadic Alzheimer disease.
Figure 1: The amyloid precursor protein (APP) is a transmembrane protein that can undergo a series of proteolytic cleavage by secretase enzymes. When it is cleaved by α-secretase in the middle of the β-amyloid domain (Aβ), it is (more ...)
Figure 2: Images of normal hippocampus (A) and hippocampus of a patient with Alzheimer disease (B) [Bielschowsky stain]. The numerous dark brown spots seen in the abnormal hippocampus are the neuritic plaques typical of Alzheimer disease. (more ...)
Among families in which causal genetic mutations for early-onset Alzheimer disease have been identified, 30%–70% of mutations are in the presenilin-1 gene, 10%–15% are in the amyloid precursor protein gene, and less than 5% are in the presenilin-2 gene.23
Many cases of early-onset Alzheimer disease do not have an identified genetic mutation, possibly because the specific genes have not yet been identified or because some cases may have different causes.
To date, no single causal genetic mutation has been identified for late-onset Alzheimer disease. Most cases are believed to be complex and likely influenced by a mixture of genetic risk factors (e.g., the apolipoprotein E gene [APOE] and the sortilin-related receptor 1 gene [SORL1]) and by acquired risk factors such as hypertension and diabetes, and probably many other factors yet to be defined. The risk to a person who has a first-degree relative (parent or sibling) with late-onset Alzheimer disease is slightly higher than the risk in the general population but much lower than the risk to someone with a familial pedigree of early-onset disease (see “Risk estimation” on page 554).
For late-onset Alzheimer disease, several genes have been implicated as risk factors. These genes increase the probability of, but do not guarantee the development of, Alzheimer disease. However, their absence does not guarantee that Alzheimer disease will not develop. Currently only APOE
has been confirmed as a genetic risk factor in multiple large, population-based studies.3
gene has 3 common allele forms: ε2 (which occurs in 8% of white populations), ε4 (in 15%) and ε3 (in about 75%). The association of the ε4 allele with late-onset Alzheimer disease is well established (). APOE
is involved in cholesterol transport and β-amyloid formation, but its exact mechanism in promoting Alzheimer disease is unclear.24
The strength of the association between the APOE ε4 allele and Alzheimer disease is stronger among women than among men. It also diminishes with age, being stronger among people between 55 and 65 years old and less so among older people. This is likely because the risk of Alzheimer disease rises sharply in older age, whether or not the ε4 allele is present. Given the uncertainties surrounding potential increased risk for Alzheimer disease in an individual rather than in a population, screening for the APOE genotype is not recommended for clinically asymptomatic people as part of routine clinical practice.
Recently, the sortilin-related receptor gene (SORL1
) has been associated with late-onset Alzheimer's disease in several populations of different ethnic backgrounds in the United States.25,26 SORL1
is involved in amyloid precursor protein processing, which adds further support to the role of the amyloid cascade in the pathogenesis of Alzheimer disease. The utility of SORL1
in clinical risk assessment has yet to be determined, and testing for this gene is not yet available.
Although it is relatively straightforward to distinguish early-onset from late-onset Alzheimer disease when the age of onset is well below 60 or well above 65 years, there is ambiguity when the illness begins between 60 and 65 years, and a clear distinction between the 2 conditions is not always possible. There are well-documented cases of Alzheimer disease with proven pathogenic mutations in which symptoms first appeared after 65 years of age in some familial pedigrees of early-onset disease.27–30
Early-onset Alzheimer disease and familial Alzheimer disease are not synonymous. Sporadic cases of early-onset Alzheimer disease can occur with no family history and no genetic mutations, and familial late-onset pedigrees can occur with no responsible genes identified.31–33
A strong family history of dementia should trigger further investigation and referral to a specialist for consultation (). All patients suspected of having familial early-onset Alzheimer disease should be referred to a specialty memory clinic or genetic clinic for further evaluation (a list of Canadian centres offering clinical genetic services is available at http://ccmg.medical.org/clinical.html
Before any testing is performed, genetic counselling is considered essential. The discovery of an inherited causative gene for Alzheimer disease is likely to be extremely distressing. Thus, genetic testing should not take place unless all of the potential risks and benefits have been clearly explained and considered.
To help determine whether there is a causative gene in Mr. A's family, we must consider 2 important questions. First, at what age did Mr. A's mother first experience symptoms of Alzheimer disease? Second, do any of his other family members have dementia and, if so, at what age was the onset and how are they related to Mr. A? In this instance, Mr. A appears to be a reliable informant about his mother's health history. There is nothing in Mr. A's reported family history to suggest autosomal dominant multi-generational transmission. Therefore, Mr. A needs no further work-up or assessment for the genetic aspect of his risk assessment.