Genetics of Alzheimer's disease

Abstract

Waning intellectual power may be accepted as part of old age, but dementia in the prime of life causes appalling social and personal problems. For patients with Alzheimer's disease the misery may be worse, since they are often aware of their plight: insight is often retained while memory and intelligence are destroyed. With little sound data based on biopsy evidence, the prevalence of Alzheimer's disease is not known with certainty; perhaps one in every 20 in the British population suffers from dementia by the age of 70. When no treatable underlying cause is found for dementia, the clinician may easily succumb to diagnosic nihilism, discouraged by the need for a brain biopsy to delineate the precise form of presenile dementia. Certainly the immediate need is to cope with the distress of the patient and family, but accurate diagnosis is essential both to determine the prognosis and to advise close relatives who are worried about their risk of becoming demented in the future. Henschke et al. (1978) and others have studied HLA antigens and some, but not all, have found that HLA-B7 and HLA-CW3 occur more frequently in patients with Alzheimer's disease than in normal controls. A separate unresolved problem is the part played by chromosome abnormalities in Alzheimer's disease. Most perhaps all, people aged over 40 with Down's syndrome develop an Alzheimer-like disease, and Heston et al. (1981) found a fivefold increase in the prevalence of people with Down's syndrome in families of patients with early-onset Alzheimer's disease. These findings are disturbing and suggest that amniocentesis should be offered to women in families with early-onset or familial Alzheimer's disease. Ward et al. (1979) believe that chromosome abnormalities are so typical of Alzheimer's disease that aneuploidy might be diagnostic even before the development of symptoms. What information can be given to anxious relatives of patients with dementia about the genetic risk to themselves and to their children? The first step must be to establish the precise diagnosis, excluding secondary and potentially treatable dementia. The distinction between the various forms of 'idiopathic' presenile dementia is based both on clinical findings and on neuropathological examination. A rapid course with pyramidal and extrapyramidal signs and death within a year suggests Creutzfeldt-Jakob disease, which can be confirmed neuropathologically. Pick's disease, while also distinguishable neuropathologically, may be confused clinically with Alzheimer's disease. Finding neurofibrillary tangles and senile plaques in a brain biopsy-specimen or at necropsy is characteristic both of Alzheimer's disease and of senile dementia, with which Alzheimer's disease overlaps clinically. Dramatic pedigrees with multiple cases of presenile dementia do occur and should alert the counsellor to the higher risk in these families than in those with an isolated case. The genetic risk is also much higher when the index patient's symptoms begin below the age of 65. Heston et al. studied 125 patients with histologically proved Alzheimer's disease in the United States. In 60% of cases the index patients were isolated with no other cases in the family. Patients were younger and the disease had a more rapid course in families in which secondary cases did occur. The findings of Heston et al. seem to clinch the argument that symptoms of dementia first occurring after the age of 70 carry little genetic risk for close relatives. In contrast, when the disease occurs in patients below the age of 65 and when another relative has had the disease, the risk is considerable. When the proband and a parent are affected, nearly half the siblings eventually become demented, the pattern closely resembling autosomal dominant inheritance in these unusual families.