By David N. Leff

As the debate heats up over the aging baby boomer generation swamping Social Security and Medicare, the rising tide of Alzheimer¿s disease (AD) looms as a warning sign of those times to come.

At present, AD afflicts some 4 million people in the U.S. The Census Bureau projects that by the year 2050, 79 million Americans will be 65 or older (up from 35 million in 2000) and that almost 18 million will be 85 or older. Between those senior-citizen age brackets are the prime-time years in which AD shows its hand, and its symptoms worsen exponentially.

Now it appears that in younger years, the disease keeps those cards close to its chest. In other words, the nerve-cell changes that trigger AD are present long before the first sign of senile memory loss hints that the disease has kicked in.

The specific signs of AD are two proteins ¿ neurofibrillary tangles and beta-amyloid neuritic plaques. They degrade neurons in areas of the brain that control not only memory but also cognition, orientation, judgment, social relations and personal care. All of these mental capabilities wane as AD waxes.

¿It¿s been known for some time,¿ said neuroanatomist Joseph Price, ¿that while plaques and tangles are the hallmarks of AD, they also occur in seemingly normal individuals.¿ Price is professor of anatomy and neurobiology at Washington University in St. Louis.

¿The structures of the brain I have been working on in rats and monkeys,¿ he told BioWorld Today, such as the limbic forebrain, amygdala, frontal cortex and hippocampus, are those most affected in AD.¿

Price is lead author of a research paper in the March issue of The Annals of Neurology, dated March 1, 1999. It is titled ¿Tangles and plaques in nondemented aging and preclinical¿ Alzheimer¿s disease.¿

The study compared annual neurological assessment of 62 initially nonsymptomatic individuals in the pre-AD age bracket with postmortem pathological hallmarks in their brains. ¿We predicted they would fall into at least two groups,¿ Price said. ¿One would be somewhat healthy, aging people who did not show real signs of developing AD. And the other would be people who already had early AD, but had not yet progressed to showing clinical signs.¿

When Price looked for amyloid plaques in the autopsied brains of individuals followed for many years before death, he ¿found no splotches of the abnormal protein in most of the healthy subjects.¿

Clinical neurologist John Morris, the paper¿s senior author, added, ¿We even had a woman who reached age 88 without developing those lesions in the brain.¿

Price did find numerous plaques in the brains of 15 subjects who had displayed only the mildest symptoms of dementia. ¿If you met them on the street,¿ he observed, ¿you would not think them demented, just getting a little old.¿ He made the point that ¿at the earliest clinically detectable stage, the disease is fairly well advanced inside the brain.¿

Quantifying Senile Cognitive Deficits

What made their study possible is the existence since 1984 of a unique neurological testing system, the Clinical Dementia Rating (CDR) scale, developed at Washington University. This takes most of the subjectivity out of current AD diagnosis by refining the nature and severity of symptoms to a fine-grained numerical code. The FDA has recommended that such clinical assessments be included in efficacy testing of antidementia drug candidates.

¿The strength of the CDR rating scale,¿ Price pointed out, ¿is that it¿s able to detect very early changes in cognitive performance, which we now call very mild dementia. Quite frankly, these changes are so mild that mostly you wouldn¿t consider them dementia. But you can also stage this dementia from the very mild state, which we call CDR 0.5 through CDR 1, 2 and 3, with 3 being a state where people have severe problems with memory, recognizing people, knowing where they are, taking care of themselves and so forth.¿

He added: ¿We were particularly interested in what happens before people show any cognitive change ¿ at the CDR-zero stage. Forty of our 62 cases,¿ Price continued, ¿were assessed before death. But to supplement those histories, particularly for younger, nondemented subjects, we collected 23 brains from the university hospital autopsy service, and did retrospective interviews with the spouse or grown child of the deceased. It turns out that you can do a very good CDR assessment just from such an informant.¿

In diagnosing AD by this CDR interview protocol, the co-authors reached an accuracy of 93 percent, as subsequently confirmed by postmortem. Only a brain autopsy can attain a 100 percent score, in differentiating the disease from other forms of dementia. The current criteria for diagnosing AD from an autopsy, Price said, ¿rely primarily on the presence of plaques, especially neuritic plaques that have thickened neuronal processes or neurites within them. The AD determination is possible, probable or definite, depending on the amount of plaques.¿ He added, ¿And there should certainly be tangles within the hippocampus.¿

The CDR itself, Price pointed out, ¿doesn¿t differentiate between AD and any of the other dementias. AD, of course, is overwhelmingly the most common of the dementing conditions.¿

Charting Course To Future AD Therapeutics

Turning to the question of what clinical or therapeutic intervention, if any, do the paper¿s findings indicate, Price observed: ¿Most people would agree on the two prime sites to intervene if we could. One would block the formation of plaque-generating beta amyloid; the other would increase its clearance from the brain.

¿This is something we¿re very much working on,¿ he pointed out. ¿So far we don¿t have any drugs that do this. As we learn more of how exactly amyloids form, it¿s conceivable we could intervene. I think it may be more possible to increase its clearance than prevent its formation.

¿What this paper does indicate,¿ he went on, ¿is that the formation of plaques and tangles begins acting fairly early, before there are any clinical signs. So that if we really want to intervene in the disease and stop it, as opposed to just merely delaying it for a few years, we¿ve got to find treatments that can be applied before there are any clinical signs. I think that¿s the major therapeutic goal in this paper.¿

Price does not propose that CDR testing of elderly individuals who have the slightest trace of memory loss should be extended to the entire neurological community. ¿Unless,¿ he added, ¿you want to detect AD very early. As long as we still have very little we can do about AD, maybe people would be just as well off not knowing.¿

But he added a final thought: ¿One thing I think the biotechnology community could really do is develop a radiological way of assessing amyloid in patients before cognitive changes take place. If we could find some molecule that would bind to amyloid lesions, visualizing it with PET (positron emission tomography) or MRI (magnetic resonance imaging), that would enable drugs to be taken early. At the moment, people talk about it, but there isn¿t any such test.¿ n