Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.
While the majority of dementias are sporadic, many diseases causing dementia can also occur on a familial basis. Some of these show an autosomal or sex linked inheritance. In others, certain genes are not directly causative, but are major risk factors. Some dementias may be definitively diagnosed in vivo or prenatally using genetic testing. The discovery of causative genes has also led to the development of cellular and animal models of many of these diseases. Table 1 lists the hereditary dementias discussed in this article.
Familial Alzheimer’s disease
Alzheimer’s disease (AD), the most common cause of dementia, is characterised by the accumulation of neurofibrillary tangles and neuritic amyloid plaques. These histopathological changes lead to progressive cerebral atrophy and cognitive decline. While increasing age is the single greatest risk factor for the development of AD, AD in a first degree relative confers a doubling of the relative risk for an individual. In less than 5% of cases AD is inherited in an autosomal dominant manner with almost complete penetrance. Such autosomal dominant familial AD (FAD) is associated with mutations in three genes: β-amyloid precursor protein (APP) gene, presenilin 1, and presenilin 2. (An up to date list of all known mutations in these three genes is found at http://molgen-www.uia.ac.be/Admutations.) In some patients with FAD a definite mutation may not be found.
β-Amyloid precursor protein
The APP gene, located on the long arm of chromosome 21, encodes an alternatively spliced transcript that, in its longest isoform, expresses a single transmembrane polypeptide of 770 amino acids. APP is processed by two major pathways. The first, controlled by α-secretase, produces a non-amyloidogenic protein product. The second, combining the sequential action of β- and γ-secretases, generates Aβ peptides of 40–43 amino acids; the accumulation of Aβ-42, a highly amyloidogenic protein and the most abundant species within neuritic plaques, …