Genetics and biology of Alzheimer's disease and frontotemporal lobar degeneration

Alzheimer's disease (AD) is the most common cause of dementia in the elderly, whereas frontotemporal lobar degeneration (FTLD) is the most frequent neurodegenerative disorder with a presenile onset. The two major neuropathologic hallmarks of AD are extracellular Amyloid beta (A\u3b2) plaques and intracellular neurofibrillary tangles (NFTs). Conversely, in FTLD the deposition of tau has been observed in a number of cases, but in several brains there is no deposition of tau but instead a positivity for ubiquitin. In some families these diseases are inherited in an autosomal dominant fashion. Genes responsible for familial AD include the Amyloid Precursor Protein (APP), Presenilin 1 (PS1) and Presenilin 2 (PS2). The majority of mutations in these genes are often associated with a very early onset (40-50 years of age). Regarding FTLD, the first mutations described are located in the Microtubule Associated Protein Tau gene (MAPT). Tau is a component of microtubules, which represent the internal support structures for the transport of nutrients, vesicles, mitochondria and chromosomes within the cell. Mutations in MAPT are associated with an early onset of the disease (40-50 years), and the clinical phenotype is consistent with frontotemporal lobar degeneration (FTD). Recently, mutations in a second gene, named progranulin (GRN), have been identified in some families with FTLD. Progranulin is expressed in neurons and microglia and displays anti-inflammatory properties. Nevertheless, it can be cleaved into granulins which, conversely, show inflammatory properties. The pathology associated with these mutations is most frequently characterized by the immunostaining of TAR DNA Binding Protein 43 (TDP-43), which is a transcription factor. The clinical phenotype associated with GRN mutations is highly heterogeneous, including FTD, Progressive Aphasia, Corticobasal Syndrome, and AD. Age at disease onset is variable, ranging from 45 to 85 years of age. The majority of cases of AD and FTLD are however sporadic, and likely several genetic and environmental factors contribute to their development. Concerning AD, it is known that the presence of the e4 allele of the Apolipoprotein E gene is a susceptibility factor, increasing the risk of about 4 fold. A number of additional genetic factors, including cytokines, chemokines, Nitric Oxide Synthases, contribute to the susceptibility for the disease. Some of them also influence the risk to develop FTLD. In this review, current knowledge on molecular mechanisms at the basis of AD and FTLD, as well as the role of genetics, will be presented and discussed