inherited presenile dementias
Saturday 29 March 2008
In contrast to the common and genetically complex senile form of Alzheimer disease (AD), the molecular genetic dissection of inherited presenile dementias has given important mechanistic insights into the pathogenesis of degenerative brain disease.
Alzheimer disease (AD) and frontotemporal dementia (FTD) are linked in a genetic spectrum of presenile degenerative brain disorders in which tau (TAU) appears to be the central player.
When placed in the context of previous genotype–phenotype correlation studies, recent findings show that FTD and AD not only share important clinical and neuropathological features but are also etiologically linked at the molecular genetic level, implying that these disorders are part of a genetically interconnected spectrum of presenile degenerative brain disorders.
The tau protein (MAPT) is the major player throughout the AD–FTD spectrum:
(i) genetic alterations at the level of MAPT are strongly associated with different types of tau-mediated neurodegeneration
(ii) AD-causing PS mutations are intrinsically loss-of-function alleles;
(iii) PS loss-of-function can lead to tau pathology.
Within this framework, the etiologic and mechanistic establishment of PSENs loss-of-function in amyloid-independent and tau-mediated neurodegeneration as well as the identification of the molecular defect leading to tau-negative FTD (caused by MAPT or another gene nearby) are important future research topics.