Oldsters who survive long enough to outlive fatal maladies anddeath-dealing trauma will often succumb eventually to Alzheimer'sdisease.
It begins to afflict one in every five to 10 people, on average, whopass their 65th birthday. But Alzheimer's disease is only one ofseveral senile dementias that mark, and blight, the aging process.Neurologists can diagnose and, to a greater or lesser extent, treatthese mental disabilities.
Not so Alzheimer's disease, for which there is no valid therapy, andno absolutely firm diagnosis, short of cerebral autopsy. A confirmingpost-mortem of the Alzheimer's brain reveals its distinguishing sign_ the telltale senile neuritic plaques that disfigure cerebral cortex,amygdala and hippocampus.
The plaques consist of interwoven neuronal filaments wrappedaround an amyloid core. The alleged perpetrator of these amyloiddeposits is apolipoprotein E, (APOE), whose main claim to fame ischaperoning cholesterol around the body. (See BioWorld Today,Nov. 3, 1994, p. 1.)
APOE comes in three allelic persuasions _ numbered two, three andfour. People blessed with APOE2 or APOE3 are less susceptible toAlzheimer's disease than those condemned by APOE4. This Russian-roulette-like genetic variation provides a rough-and-ready clue toAlzheimer's disease prognosis.
It made possible the first study of "Apolipoprotein E type 4 allele andcerebral glucose metabolism in relatives at risk for familialAlzheimer's disease." That's the title of the PreliminaryCommunication reported in a double-issue of the Journal of theAmerican Medical Association (JAMA), dated March 22-29.
Alzheimer's Disease Candidates Tested Two Ways
Psychiatrist Gary Small, of the Alzheimer's Disease Center at theUniversity of California at Los Angeles (UCLA), is the JAMApaper's first author. He and his co-authors advertised widely forelderly volunteers with minor memory complaints, to take part intheir project. Of 912 persons who came forward, they selected 38right-handed participants, ages 40 to 85, from 15 Alzheimer'sdisease-susceptible families. Five of the families had autopsy-confirmed Alzheimer's disease in one or more relatives.
"Nineteen of the 38," Small told BioWorld Today, "were at risk, butdid not have the APOE4 genetic risk factor; 12 who had it did nothave dementia. The remaining seven did."
His study's main insight is that people born with the APOE4 geneversion begin to notice some brain dysfunction, such as mild memoryloss, well before frank clinical symptoms of Alzheimer's diseasedementia surface. The project's salient take-home message is that theprocedures used _ namely, APOE genotyping and positron emissiontomography (PET) _ "may assist in determining the time course forcerebral metabolic progression of the disease . . . and offer anobjective and noninvasive approach to metabolic monitoring duringexperimental therapeutic trials."
Small pointed out that, "This approach of combining geneticassessment and brain imaging assessment also offers a way to identifyideal candidates for experimental interventions, so you can findsomeone before there's been permanent brain damage."
Cerebral metabolism _ the rate at which synapses in the brainoperate _ is a salient measure of higher brain function, ordysfunction. Combined with the APOE allelic profile of an individualat risk of familial Alzheimer's disease it provided an objectivebaseline for assessing propensity of the study subjects forAlzheimer's disease onset and progression.
PET Scans Living Cells
PET scanning quantitated the rate at which the subject's brainsmetabolized a tracer-labeled intravenous infusion of glucose, theprime energy source of cerebration. Small explained: "PET providesinformation on brain function as well as structure, unlike MRI[magnetic resonance imaging] or CAT [computerized axialtomography] which give you only the structure, the abnormalities inthe cell once it's died. PET shows cell dysfunction before death.
"We found that relatives who did not have dementia," Small said,"but who inherited APOE4, had lower brain function than thosewithout APOE4, while the demented patients showed the greatestchanges in brain function."
The National Institute of Mental Health (NIMH) and NationalInstitute on Aging (NIA) funded the UCLA study. NIMH's actingdirector, Rex Cowdry, said its findings may help develop earlydiagnosis of Alzheimer's disease, and "prove useful in thedevelopment of techniques for differentiating between Alzheimer'sdisease and other, eminently treatable, disorders, affecting theelderly, such as depression."
Financial support also came, among others, from the Alzheimer'sAssociation, whose vice president of medical and scientific affairs,Sheryl Williams, stated, "It would be tragic if budget cutbacksprevented science from going on to develop the interventions that arethe payoff for this research."
That payoff, Small pointed out, will depend on further research heand his group are now undertaking.
"Longitudinal follow-up," he said, "will determine if suchhypometabolic patterns in presymptomatic persons indicate that thepathophysiological process begins well before even mild orquestionable dementia is recognized clinically."
He also cautioned against premature clinical application of hisstudy's results: "Because of the relatively small sample size, wecannot as yet identify a specific `cut-off' defining an abnormalparietal metabolic ratio." Such a demarcation, he added, "will requireadditional studies of the effect of [brain] atrophy."
"The parietal region," Small explained, "is part of the cerebral cortexgray matter, the outer part of the brain. It's involved in a variety ofmental functions impaired in Alzheimer's disease _ language,memory, spatial skill, calculation and so on." n
-- David N. Leff Science Editor
(c) 1997 American Health Consultants. All rights reserved.