- Familial aggregation of a disease is suggested when the
recurrence risk among relatives of affected persons exceeds that
among relatives of unaffected persons.
In studies of twins, greater concordance for disease among
monozygotic twins as compared with dizygotic twins suggests genetically
If subjects with a high degree of inbreeding have an elevated
risk of disease, an autosomal recessive pattern of inheritance may
Co-segregation refers to the tendency of alleles that are
situated closely together on the chromosomes to be inherited together.
Linkage of a marker gene (with a known location in the genome)
and a disease susceptibility gene can suggest the particular chromosome
involved and where on the chromosome the susceptibility gene is
likely to be located.
- Segregation analysis of pedigrees is a complex statistical
technique used to determine whether a disease has, at least in part,
a genetic origin, and if so, the likely pattern of inheritance.
A 70-year-old retired car salesman is brought by his spouse of
50 years to their family physician for evaluation of “forgetfulness.” Over
the previous several years, the patient has had increasing difficulty
remembering recent events and has become lost when driving, even
near his home. More recently, he has often forgotten names and has
asked the same questions several times in succession. He is not
taking any medications, nor is there any history of alcoholism,
use of recreational drugs, exposure to toxins, high blood pressure,
or stroke. The patient’s family history is unremarkable,
except for a similar course of progressive memory loss and cognitive
disability in his mother and in the oldest of his three siblings.
The patient appears well nourished, without evidence of systemic
illness. On mental status examination, the patient does not know
the year, cannot remember any of three objects 5 minutes after learning
them, and cannot count backward from 100 by 7. Neurologic examination
is otherwise normal. After magnetic resonance imaging and further
tests to rule out specific, treatable causes of dementia, a diagnosis
of Alzheimer’s disease is made.
Dementia is characterized by impaired short- and long-term memory,
along with disturbances of other cognitive functions (eg, language
or visuospatial function). For a diagnosis of dementia to be made,
the patient’s loss of cognitive abilities must be of sufficient
magnitude to interfere with the individual’s performance
of social or occupational activities. More than 60 different clinical disorders
are associated with dementia, and Alzheimer’s disease is
the most common cause of dementia in many populations. This disease
was first reported in 1907 by Alois Alzheimer, who described morphological
changes in the brain of a patient who died with progressive dementia. The
clinical diagnosis of Alzheimer’s disease is made by excluding
other possible causes of dementia, among which vascular disorders
The “gold standard” for arriving at a diagnosis
of Alzheimer’s disease is a histologic examination of brain
tissue. Patients with pathologic confirmation of disease are characterized