ALZHEIMER'S ADVANCES FIRM DIAGNOSIS IN LIVINGPATIENTS

By David N. LeffScience Editor

"There are three kinds of lies," someone once said; "plain lies, damnlies and statistics." Whoever coined that truism was lying.

Statistical probability is the fourth dimension of molecular geneticresearch, as witnessed by a paper in the latest Lancet, dated July 13,1996. Its title: "Specificity, sensitivity and predictive value ofapolipoprotein-E genotyping for sporadic Alzheimer's disease."

The article's authors, at Duke University in Durham, N.C., describehow they used simple statistical tests to sharpen the diagnoses ofsenile-dementia patients thought to be suffering from Alzheimer'sdisease (AD).

It's a grim irony that to date autopsying the brain after death is theonly way to verify that an elderly individual with failing memory andcognition was truly a victim of AD. So far, a neurologist's finding ofAlzheimer's is a judgment call, an educated guess, not a biologicallyfounded finding.

That occurs only when microscopic examination of brain tissuesreveals the telltale neurofibrillary plaques and tangles specific to AD.

The trouble is that AD is only one of many forms of senile dementia,some of which _ unlike AD _ are treatable. Thus, a clear-cutdifferential diagnosis would spare true AD patients futile drugtherapies, and speed up prescribing of such beneficial treatments tonon-AD individuals.

Molecular geneticist and cell biologist Ann Saunders, lead author ofthe Lancet paper, told BioWorld Today that the most common ofsuch AD look-alikes "is multi-drug prescription-taking. As youbecome elderly," she explained, "you start taking blood-pressuremedicine and other drugs, and frequently the combinationinteractions will result in a type of dementia that can be easilycorrected."

Brain tumors, too, she added, produce memory and cognition deficitsthat can be mistaken for AD, as does "an extremely rare condition,vitamin-B12 deficiency."

Every year in the U.S. alone, some 400,000 people are diagnosedwith "possible" AD. What's wanted is a genomic "mark of Cain,"identifying a true AD victim, to the exclusion of others with similarprogressive mental and social disabilities. Put another way, how toget those neurofibrillary plaques and tangles out of the closet and intothe open.

Blowing APOE's Cover

In 1993, molecular neurologist Allen Roses and his colleagues atDuke put the finger on apolipoprotein-E (APOE), a molecule betterknown for its role in managing the body's cholesterol traffic. Theybuilt on earlier showings that the gene encoding APOE exists in threegenetic variants, epsilon-2, epsilon-3 and epsilon-4 (e2, e3, e4).

Of these three alleles, the third, e4, conferred on its bearer a higherrisk of developing AD than the other two. Now in the current Lancetpaper, researchers have quantified these odds for accurate estimatesof the aberrant gene's diagnostic prowess.

For starters, Roses and his co-authors reviewed the records of 67patients at Duke's Memory Disorders Clinic who, over a 10-yearperiod, had received a diagnosis of "probable" AD at the time of theirdeath.

Brain autopsies revealed that 10 of these 67 patients (15 percent) didnot have AD, nor did they have an e4 gene allele. But one-fourth ofthe 57 remaining patients, with verified AD, didn't carry the e4.Three-fourths did.

The epsilion-4 allele, their study showed, had AD specificity andpredictive value of 100 percent. That is, all of the patients with e4had the disease, whereas none of the non-AD individuals carried thee4 version.

"In a clinical setting," said Saunders, "APOE genotyping will identifythree out of four patients who have the disease. It is no help withpatients who do not have an e4."

She added: "This is the first actual measurement of genotyping in aseries that could evaluate misdiagnoses. In short, it can tell aphysician which patients are almost certain to have Alzheimer's."

These results, Roses said, "confirm the rough estimate long made byneurologists that 15 percent of patients diagnosed with AD will notactually have the disease. But it shifts the non-AD individuals into apatient group that can be defined during life." He added: "This hastremendous implications for evaluating drug trials."

Roses also emphasized that this first-ever genetic test for the AD-APOE4 connection needs to be confirmed by much larger patientcohorts. On this score, Saunders observed that Roses will report nextweek to the International Alzheimer's Disease Conference in Osaka,Japan, on a series of 200 patients collected at other university centerswith identical work-ups to Duke's 67.

Athena Offers Duke's Test For AD Suspects Only

Roses made the point that testing the general population for theapolipoprotein E gene is "currently regarded as premature." In fact,when Duke licensed its pending patent on the AD genetic findings toAthena Neurosciences (see BioWorld Today, Mar. 27, 1996, p. 1), itstipulated that the e4 genetic test not be used to predict the disease inasymptomatic people.

"Since rolling the tests out at the Academy of Neurology meeting inMarch of this year," Athena President and CEO John Groom toldBioWorld Today, "we've been talking to neurologists about it. Wedidn't really start detailing them to neurologists until April."

The response, he added, has been, "So far, so good. We'reencouraged by the growth in the number of tests that have been usedfrom month to month, though so far it isn't going to double the stockprice of Elan [which recently acquired Athena]. But I think we havean important product that will become more valuable as time goes on.

"Some neurologists," Groom continued, "are more enthused with ourstory than others. Their sort of standard response has been: `Well, Ican diagnose AD.' And there's no doubt that they can, after a periodof time.

"What these tests offer neurologists is greater clinical information inthe majority of patients, and a guided way of changing the course oftheir former practice.

"Allen Roses' latest paper," Groom went on, "does add quitesignificantly to that, because what Duke did was take a sequentialseries of patients, in which they accepted all comers over a 10-yearperiod that had come through their center."

He concluded: "It's probably one of the best centers in the world forthe diagnosis of AD. Yet even they had this inherent 15 percent errorrate in terms of misdiagnosis, which is certainly higher in terms ofaccuracy than will be achieved in the average neurologist's office." n

(c) 1997 American Health Consultants. All rights reserved.