No biological test exists to determine whether persons with progressively bad memory problems have Alzheimer’s disease. Such an assay may be closer than many psychiatrists realize, however, and it would probably have to do with brain plaques or brain tangles—major characteristics of Alzheimer’s—or with both.

Not long ago, California and Pittsburgh scientists reported that they had managed, with PET scans and special imaging compounds, to visualize amyloid plaques in the brains of living Alzheimer’s patients. They believe that their techniques might eventually be used to diagnose Alzheimer’s in its very early phase (Psychiatric News, September 8, 2002).

Now German scientists have found, in a small group of subjects, that the cerebrospinal fluid levels of the two proteins that make up Alzheimer’s plaques and tangles appear to be different in persons who have symptoms of Alzheimer’s than in those who do not. If research with more subjects confirms these results, then cerebrospinal fluid levels of the two proteins might pan out as a biological test for Alzheimer’s, they believe.

The investigators are Matthias Riemenschneider, M.D., Ph.D., head of the Laboratory for Neurochemistry and Neurogenetics at the Technical University of Munich, and his coworkers. They reported their results in the November Archives of Neurology.

The proteins of interest are beta-amyloid 42, the material from which Alzheimer’s plaques are composed, and tau, the stuff from which Alzheimer’s tangles are made. During the past few years, Riemenschneider and his coworkers have found that levels of beta-amyloid 42 are lower in the cerebrospinal fluid of Alzheimer’s patients than in healthy subjects, and that levels of tau in the cerebrospinal fluid are higher in Alzheimer’s patients than in healthy subjects. These findings thus made them wonder whether low beta-amyloid 42 levels and high tau levels might also be present in persons making the transition from mild cognitive impairment to Alzheimer’s.

The researchers used newspaper and television announcements to recruit 28 subjects with memory complaints (mild cognitive impairment) for their study. The subjects were given extensive psychiatric and neurological workups to make sure that there were no explanations for their mild cognitive impairment other than possible Alzheimer’s—for example, moderate or severe depression or a vitamin B12 deficiency. The subjects were then given spinal taps to obtain cerebrospinal fluid samples, and their samples were then analyzed for levels of beta-amyloid 42 levels and of tau.

The investigators then used psychological tests to assess the 28 subjects’ cognitive performances 18 months later. The tests suggested that 10 subjects had developed Alzheimer’s; two, frontotemporal dementia; and six, progressive mild cognitive impairment. The remaining 10 had not deteriorated beyond the mild cognitive impairment state.

The scientists then determined whether there had been significantly lower levels of beta-amyloid 42 and significantly higher levels of tau in the cerebrospinal fluid of the 10 subjects who apparently progressed to Alzheimer’s than in the cerebrospinal fluid of the 10 subjects who maintained a stable mild cognitive impairment. The answer was yes, they found.

They also looked to see whether there had been significantly lower levels of beta-amyloid 42 in the cerebrospinal fluid of the six subjects who had developed progressive mild cognitive impairment than in the cerebrospinal fluid of the 10 subjects who maintained a stable mild cognitive impairment. Again the answer was yes.

Thus, low levels of beta-amyloid 42 and high levels of tau in the cerebrospinal fluid might be biochemical markers for the progress of mild cognitive impairment to full-blown Alzheimer’s, Riemenschneider and his colleagues believe.

What’s more, "a biochemical marker for both clinical syndromes—mild cognitive impairment and Alzheimer’s disease—would provide a unifying hypothesis that they are one disorder with variable rates of conversion from mild cognitive impairment to Alzheimer’s," wrote Roger Rosenberg, M.D., editor of the Archives of Neurology, in an accompanying editorial.

Psychiatric News asked Riemenschneider whether he and his team plan to study more subjects with mild cognitive impairment to see whether they can confirm and extend their finding that low beta-amyloid 42 levels and high tau levels signal progression from memory difficulties to Alzheimer’s.

He replied, "What we now want to do—it is rather difficult considering that obtaining cerebrospinal fluid is an invasive approach—but what we now want to do is a population-based study."

The study, "Cerebrospinal Fluid Tau and Beta-Amyloid 42 Proteins Identify Alzheimer Disease in Subjects With Mild Cognitive Impairment," is posted on the Web at http:archneur.ama-assn.org. ▪

Arch Neurol  2002591729