Thompson & Thompson Genetics in Medicine, 8th Edition

Case 4. Alzheimer Disease (Cerebral Neuronal Dysfunction and Death, MIM 104300)

Multifactorial or Autosomal Dominant


• Variable expressivity

• Genetic heterogeneity

• Gene dosage

• Toxic gain of function

• Risk modifier

Major Phenotypic Features

• Age at onset: Middle to late adulthood

• Dementia

• β-Amyloid plaques

• Neurofibrillary tangles

• Amyloid angiopathy

History and Physical Findings

L.W. was an older woman with dementia. Eight years before her death, she and her family noticed a deficit in her short-term memory. Initially they ascribed this to the forgetfulness of “old age”; her cognitive decline continued, however, and progressively interfered with her ability to drive, shop, and look after herself. L.W. did not have findings suggestive of thyroid disease, vitamin deficiency, brain tumor, drug intoxication, chronic infection, depression, or strokes; magnetic resonance imaging of her brain showed diffuse cortical atrophy. L.W.'s brother, father, and two other paternal relatives had died of dementia in their 70s. A neurologist explained to L.W. and her family that normal aging is not associated with dramatic declines in memory or judgment and that declining cognition with behavioral disturbance and impaired daily functioning suggested a clinical diagnosis of familial dementia, possibly Alzheimer disease. The suspicion of Alzheimer disease was supported by her apolipoprotein E genotype: APOE ε4/ε4. L.W.'s condition deteriorated rapidly during the next year, and she died in hospice at 82 years of age. Her autopsy confirmed the diagnosis of Alzheimer disease.


Disease Etiology and Incidence

Approximately 10% of persons older than 70 years have dementia, and approximately half of them have Alzheimer disease (AD, MIM 104300). AD is a panethnic, genetically heterogeneous disease; less than 5% of patients have early-onset familial disease, 15% to 25% have late-onset familial disease, and 75% have sporadic disease. Approximately 10% of familial AD exhibits autosomal dominant inheritance; the remainder exhibits multifactorial inheritance.

Current evidence suggests that defects of β-amyloid precursor protein metabolism cause the neuronal dysfunction and death observed with AD. Consistent with this hypothesis, mutations associated with early-onset autosomal dominant AD have been identified in the β-amyloid precursor protein gene (APP), the presenilin 1 gene (PSEN1), and the presenilin 2 gene (PSEN2) (see Chapters 8 and 12). The prevalence of mutations in these genes varies widely, depending on the inclusion criteria of the study; 20% to 70% of patients with early-onset autosomal dominant AD have mutations in PSEN1, 1% to 2% have mutations in APP, and less than 5% have mutations in PSEN2.

No mendelian causes of late-onset AD have been identified; however, both familial AD and sporadic late-onset AD are strongly associated with allele ε4 at the apolipoprotein E gene (APOE; see Chapter 8). The frequency of ε4 is 12% to 15% in normal controls compared with 35% in all patients with AD and 45% in patients with a family history of dementia.

There is evidence for at least a dozen additional AD loci in the genome. Evidence also suggests that mitochondrial DNA polymorphisms may be risk factors in Alzheimer disease. Finally, there have been associations between AD and various polymorphisms in many other genes.


As discussed in Chapter 12, β-amyloid precursor protein (βAPP) undergoes endoproteolytic cleavage to produce peptides with neurotrophic and neuroprotective activities. Cleavage of βAPP within the endosomal-lysosomal compartment produces a carboxyl-terminal peptide of 40 amino acids (Aβ40); the function of Aβ40 is unknown. In contrast, cleavage of APP within the endoplasmic reticulum or cis-Golgi produces a carboxyl-terminal peptide of 42 or 43 amino acids (Aβ42/43). Aβ42/43 readily aggregates and is neurotoxic in vitro and possibly in vivo. Patients with AD have a significant increase in Aβ42/43 aggregates within their brains. Mutations in APP, PSEN1, and PSEN2 increase the relative or absolute production of Aβ42/43. Approximately 1% of all cases of AD occur in patients with Down syndrome, who overexpress βAPP (because the gene for βAPP is on chromosome 21) and thus Aβ42/43. The role of APOE ε4 is clear, but the mechanism is uncertain.

AD is a central neurodegenerative disorder, especially of cholinergic neurons of the hippocampus, neocortical association area, and other limbic structures. Neuropathological changes include cortical atrophy, extracellular neuritic plaques, intraneuronal neurofibrillary tangles (Fig. C-4), and amyloid deposits in the walls of cerebral arteries. The neuritic plaques (see Fig. C-4) contain many different proteins, including Aβ42/43 and apolipoprotein E. The neurofibrillary tangles are composed predominantly of hyperphosphorylated tau protein; tau helps maintain neuronal integrity, axonal transport, and axonal polarity by promoting the assembly and stability of microtubules.


FIGURE C-4 A neurofibrillary tangle (left) and a neuritic plaque (right) observed on histopathological examination of the brain of an individual with Alzheimer disease. See Sources & Acknowledgments.

Phenotype and Natural History

AD is characterized by a progressive loss of cognitive function, including recent memory, abstract reasoning, concentration, language, visual perception, and visual-spatial function. Beginning with a subtle failure of memory, AD is often attributed initially to benign “forgetfulness.” Some patients perceive their cognitive decline and become frustrated and anxious, whereas others are unaware. Eventually patients are unable to work, and they require supervision. Social etiquette and superficial conversation are often retained surprisingly well. Ultimately, most patients develop rigidity, mutism, and incontinence and are bedridden. Other symptoms associated with AD include agitation, social withdrawal, hallucinations, seizures, myoclonus, and parkinsonian features. Death usually results from malnutrition, infection, or heart disease.

Aside from the age at onset, early-onset AD and late-onset AD are clinically indistinguishable. Mutations in PSEN1 are fully penetrant and usually cause rapidly progressive disease, with a mean onset at 45 years. Mutations in APP are fully penetrant and cause a rate of AD progression similar to that of late-onset AD; the age at onset ranges from the 40s to early 60s. Mutations in PSEN2 may not be fully penetrant and usually cause slowly progressive disease with onset ranging from 40 to 75 years. In contrast to early-onset AD, late-onset AD develops after 60 to 65 years of age; the duration of disease is usually 8 to 10 years, although the range is 2 to 25 years. For both late-onset AD and AD secondary to APP mutations, the APOE allele ε4 is a dose-dependent modifier of onset; that is, the age at onset varies inversely with the number of copies of the ε4 allele (see Chapter 8).


Except for patients in families segregating an AD-associated mutation, patients with dementia can be definitively diagnosed with AD only by autopsy; however, with rigorous adherence to diagnostic criteria, a clinical suspicion of AD is confirmed by neuropathological examination 80% to 90% of the time. The accuracy of the clinical suspicion increases to 97% if the patient is homozygous for the APOE ε4 allele.

Because no curative therapies are available for AD, treatment is focused on the amelioration of associated behavioral and neurological problems. Approximately 10% to 20% of patients have a modest decrease in the rate of cognitive decline if they are treated early in the disease course with agents that increase cholinergic activity.

Inheritance Risk

Old age, family history, female sex, and Down syndrome are the most important risk factors for AD. In Western populations, the empirical lifetime risk for AD is 5%. If patients have a first-degree relative in whom AD developed after 65 years, they have a threefold to sixfold increase in their risk for AD. If patients have a sibling in whom AD developed before 70 years and an affected parent, their risk is increased sevenfold to ninefold. APOE testing may be used as an adjunct diagnostic test in individuals seeking evaluation for signs and symptoms suggestive of dementia but is generally not used for predictive testing for AD in asymptomatic patients (see Chapter 18).

Patients with Down syndrome have an increased risk for AD. After the age of 40 years, nearly all patients with Down syndrome have neuropathological findings of AD, and approximately 50% manifest cognitive decline.

For families segregating autosomal dominant AD, each person has a 50% risk for inheriting an AD-causing mutation. With the exception of some PSEN2 mutations, full penetrance and relatively consistent age at onset within a family facilitate genetic counseling. Currently, clinical DNA testing is available for APP, PSEN1, and PSEN2, as well as several other genes; DNA testing should be offered only in the context of genetic counseling.

Questions for Small Group Discussion

1. Why is the APOE genotype not useful for predicting AD in asymptomatic individuals?

2. Why is AD usually a neuropathological diagnosis? What is the differential diagnosis for AD?

3. Mutation of MAPT, the gene encoding tau protein, causes frontotemporal dementia; however, MAPT mutations have not been detected in AD. Compare and contrast the proposed mechanisms by which abnormalities of tau cause dementia in AD and frontotemporal dementia.

4. Approximately 30% to 50% of the population risk for AD is attributed to genetic factors. What environmental factors are proposed for the remaining risk? What are the difficulties with conclusively identifying environmental factors as risks?


Bird TD. Alzheimer disease overview. [Available from]

Karch CM, Cruchaga C, Goate AM. Alzheimer's disease genetics: from the bench to the clinic. Neuron. 2014;83:11–26.