A MITOCHONDRIAL BOTTLENECK HYPOTHESIS OF ALZHEIMERS-DISEASE

Alzheimer's disease, in its early onset familial form, is known to be a heterogeneous disorder. This suggests that the different degenerativ e mechanisms, initiated by different genetic causes and ending in the shared phenotype of the disease, should intersect at some point in the degenerative cascade to form a 'bottleneck' from which the pathologic al features that are common to each of the genetic forms emerge. A gro wing body of evidence suggests that disturbances of energy metabolism may play a fundamental role in the onset and progression of Alzheimer' s disease. In light of this, we propose a 'mitochondrial bottleneck hy pothesis', which unifies the various forms of the disease in which dif ferent causes lead to the disorder via disturbances of mitochondrial f unction. The characterization of such a bottleneck would present a uni que target for therapeutic intervention because it would be the earlie st point in a neurodegenerative cascade shared by all forms of Alzheim er's disease, independent of cause.