The grim Catch-22 in Alzheimer's disease is that it can only bedefinitively diagnosed post-mortem. It takes a brain autopsy to find theb-amyloid neurite plaques and neurofibrillary tangles that distinguishAlzheimer's from other senile dementias.The latter disorders are treatable; Alzheimer's is not _ yet. Veryrecent trials of tacrine, Parke-Davis's Cognex, showed limited efficacyand severe side-effects (see BioWorld Today, April 6, p. 1).Alzheimer's affects more than 2.5 million people in the U.S. alone.Now for the paradox: "Soluble b-amyloid protein," says neurobiologistDaniel Alkon, "may cause a dysfunction that leads to memory loss inAlzheimer's even before the insoluble form congeals into plaques."Alkon heads the Laboratory of Adaptive Systems at the NationalInstitute of Neurological Disorders and Stroke (NINDS). Memory lossis among the earliest and most common symptoms of Alzheimer's.Alkon's report in today's Science (April 8) is titled: "Soluble b-Amyloid Induction of Alzheimer's Phenotype for Human FIbroblastK+ Channels."Goal One: A Simple Diagnostic TestThis Science paper extends his earlier finding that Alzheimer'smolecular manifestations are not limited to the brain, but occursystemically throughout the body, long before formation of the plaquesfound only at autopsy. To test this hypothesis with a view toward asimple diagnostic test, he and his team examined skin cells from a largecohort of Alzheimer's patients, compared to age-matched controls withother dementias. More recent research examined markers in olfactoryneurons."We looked at the first locus on our map of memory function, which isa particular potassium channel through the cell membrane. Thischannel is uniformly missing in Alzheimer's patients," Alkon toldBioWorld Today.His prediction that a missing signal would reveal the missing K channelin Alzheimer's, Alkon said, "is sufficiently specific and reliable thatthe NIH eight months ago filed for a major patent on it."One of Alzheimer's many puzzles is that the number and size ofplaques in the brains of deceased patients don't clearly correlate withthe degree of memory loss suffered. Alkon surmised that the b-amyloidwas doing in the brain what it did in the skin cells.So he took skin fibroblasts from normal individuals and incubatedthem for 48 hours with very low levels of soluble b-amyloid. "To oursurprise and satisfaction," Alkon said, "it eliminated the samepotassium channel that was missing with the Alzheimer's patients." Butthe functioning K channel remained intact in 94 percent of untreatedcontrol cells.Goal Two: Therapeutic Strategies"This," Alkon infers, "may reflect a systemic derangement of b-amyloid protein metabolism, disrupting membrane channels in thebrain, and thereby memory formation and storage, independent ofplaques." What the protein does in a normal brain, "nobody knows."Besides supporting Alkon's concept of a simple skin test to diagnoseAlzheimer's, "it suggests therapeutic strategies. Maybe we can dosomething about the way b-amyloid is working on potassium channelsin Alzheimer's patients," he said.His team is now examining cells of people who don't yet have thedisease, but are at risk because of affected family members. Efforts topredict which individuals may get Alzheimer's, Alkon says laconically,"are showing promising results." n
-- David N. Leff Science Editor
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