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  • Updated 09.13.2023
  • Released 02.16.2006
  • Expires For CME 09.13.2026

Familial Alzheimer disease



Familial Alzheimer disease is a type of Alzheimer disease that is inherited in an autosomal dominant pattern (14). This means that if someone receives a mutated gene from one parent, they will develop the disease. Familial Alzheimer disease accounts for only slightly more than 5% of all cases of Alzheimer disease (32). Although the symptoms of familial Alzheimer disease are similar to those of Alzheimer disease, they usually tend to appear in life in a person’s 30s, 40s, or 50s (126). In this article, the author provides an overview of the genetics and clinical characteristics of familial Alzheimer disease and explores variations in how it presents among different ethnic groups. The author also discusses the role of variations in causing Alzheimer disease and touches on the factors in and available genetic testing options for diagnosing Alzheimer disease. Finally, the author discusses the genetic aspects of familial Alzheimer disease and addresses new evidence of clinical heterogeneity in the disease and new loci of genetic risk factors for Alzheimer disease: TOMM40, the clusterin (CLU) or APOJ gene, and the PICALM gene.

Historical note and terminology

The term “familial Alzheimer disease” means that two or more persons in the same family are affected by Alzheimer disease. The first case of familial Alzheimer disease with neuropathological studies was reported in 1932 (123). Since then, more than 500 families have been described with a multigenerational autosomal dominant pattern of Alzheimer disease transmission. In 1979 Cook and colleagues reported three new families completing with them 50 described in the medical literature and suggested a link between familial Alzheimer disease and transmissible dementia. Among those families, there was a patient with histologically confirmed Alzheimer disease whose sister had proved spongiform encephalopathy (26). Ten years later, Bird and colleagues suggested genetic heterogeneity by describing the variation of clinical and neuropathological characteristics in 180 demented individuals from 24 kindreds with familial Alzheimer disease, with at least two affected generations and neuropathological confirmation in one case (17).

Masters and colleagues have purified and characterized the cerebral amyloid protein that forms the plaque core in Alzheimer disease and in aged individuals with Down syndrome. This protein consists of multimeric aggregates of a polypeptide of about 40 residues (4 kDa) but there are no similarities between its amino acid sequence and those of scrapie polypeptides (85). Two years later, amyloid fibrils were purified from the leptomeningeal vessels of a patient who had no clinical signs of dementia, whose family had hereditary cerebral hemorrhage, with amyloidosis restricted to the leptomeninges and cerebral cortex. This protein showed homology to the beta-protein of Alzheimer disease and Down syndrome, which suggested that hereditary cerebral hemorrhage with amyloidosis of Dutch origin was pathogenetically related to Alzheimer disease (140).

As in sporadic forms of Alzheimer disease, there are two kinds of familial Alzheimer disease, namely: The early and late-onset varieties. Men and women in early-onset families had equivalent risk of dementia. Lifetime risk of dementia in early-onset familial Alzheimer disease kindreds is consistent with an autosomal dominant inheritance model. Late-onset familial Alzheimer disease has at least two etiologies: Alzheimer disease in some families may be transmitted as a dominant trait, whereas in others, it may be caused by other genetic or shared environmental factors (39).

In familial Alzheimer disease, the inheritance pattern follows Mendelian genetics, specifically autosomal dominant inheritance (11; 87; 136). This means that if a parent has a mutation in one of the genes associated with familial Alzheimer disease, each child has a 50% chance of inheriting the same mutation (136). There are three genes that have been associated with early-onset familial Alzheimer disease: presenilin 1 (PS1) on chromosome 14, presenilin 2 (PS2) on chromosome 1, and amyloid precursor protein (APP) on chromosome 21. Mutations in any of these three genes can lead to the development of familial Alzheimer disease (136).

It is important to note that familial Alzheimer disease accounts for less than 5% of all cases of Alzheimer disease (131). In contrast, the majority of Alzheimer cases are sporadic and not directly caused by genetic mutations (04). However, having a family history of Alzheimer disease does increase the risk of developing the disease (13). Individuals who have a parent or sibling with Alzheimer disease are more likely to develop the disease compared to those without a first-degree relative with Alzheimer disease (58). The risk is even higher for individuals who have more than one first-degree relative with Alzheimer disease (58).

Genetic testing is available to detect mutations in the genes associated with familial Alzheimer disease (131). However, the Alzheimer's Association cautions against routine genetic testing for Alzheimer disease risk without proper counseling and an understanding of the implications (58). Genetic testing can help identify individuals who are at a higher risk of developing familial Alzheimer disease, but it is not a definitive predictor of whether or not someone will develop the disease (37).

Familial Alzheimer disease follows Mendelian inheritance with an autosomal dominant pattern. Mutations in genes, such as PS1, PS2, and APP, can lead to the development of familial Alzheimer disease. Although having a family history of Alzheimer disease increases the risk of developing the disease, it is important to approach genetic testing with caution and to seek proper counseling.

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