Trying To Untangle Alzheimer’s

“Alzheimer’s Next Chapter” by Lisa Jarvis highlights the lack of consensus regarding the primary mechanism of neurodegeneration in Alzheimer’s disease (C&EN, June 1, page 11). This is a significant problem because understanding the causal mechanism of a disease process provides a rational platform for drug development.

Unfortunately, the Alzheimer’s field is dominated by two exclusive ideological factions—tauists and βaptists. In our opinion, this situation has impaired the search for effective pharmacotherapies. The myopic focus on the amyloid-β plaques and neurofibrillary tangles is dangerous and frankly unwarranted, since the presence of protein anomalies does not necessarily indicate pathogenic significance.

In this regard, it is noteworthy that some evidence suggests that the tangles and plaques are of secondary pathophysiological importance. Regardless, the failure to adequately consider alternative mechanisms can prematurely narrow the field of hypothesis testing.

Initial studies in the field of Alzheimer’s disease neuropathogenesis identified nerve terminal dysfunction and defective mitochondrial bioenergetics coupled to oxidative stress as early consequences of Alzheimer’s. Whereas some might consider these to be outdated parameters, the resulting changes in central nervous system neurotransmission represent a plausible basis for the cognitive deficits that characterize the disease.

Based on the probable complexity of Alzheimer’s neuropathogenesis, it is clear that the molecular process of Alzheimer’s disease neurodegeneration is highly complex and, as Genentech’s Carole Ho points out, the most effective approach will likely involve combination therapy.

Richard M. LoPachin
Bronx, N.Y.

Terrence Gavin
New Rochelle, N.Y.