CELL-TYPE-SPECIFIC ENHANCEMENT OF AMYLOID-BETA DEPOSITION IN A NOVEL PRESENILIN-1 MUTATION (P117L)

The presenilin-1 (PS1) gene mutation (Pro117Leu), recently identified in a Polish family is characterized by the earliest reported onset (fr om 24-31 years) of Alzheimer disease (AD) and a very short duration of disease (4-6 years). The neuropathology of 2 subjects with this PS1 m utation (ages at death: 35 and 37 years) was compared to four Down syn drome (DS) patients (mean age at death: 62 years) and 4 sporadic AD pa tients (mean age at death: 79 years with a mean duration of disease of 18 years). The Polish familial AD (FAD) patients showed a marked incr ease in the amyloid burden of 2-6-fold in most areas of the brain. The entorhinal cortex was an exception where the amyloid burden was simil ar in each category of patient. Some brain regions of the Polish FAD p atients showed a massive increase of amyloid, such as the molecular la yer of the cerebellum where a 7- and 25-fold increase was noted, compa red with DS and sporadic AD patients respectively. The cerebellar vess el amyloid burden was also greatly increased in the FAD patients, refl ecting a vascular compartment specific increase of amyloid beta deposi tion. The presence of this PS1 mutation has an even greater effect on both vascular and parenchymal amyloid deposition, than the overexpress ion of the amyloid beta precursor protein present in DS patients, sugg esting that PS mutations can be a critical factor determining amyloid deposition.