ADVANCE DIRECTIVES

non-AD dementias? APOE genotyping is the first confirmed adjunctive test that can assist in “ruling in” AD, applicable to about half the patients. Faced with informed consent, the overwhelming number of patients’ families answer “yes. ” Dr. Kandel’s first point also seems contradictory. While stating that she “is very much interested in the individual,” she misinterprets the application of the positive prediction paradigm as an adjunct for accurate individual diagnosis. She states that she “would be wrong as many times as right in stating . [the patient]. did not have AD. ” The absence of an €4 allele does not exclude AD at all, but this situation would now be applicable to less than half of her cases, those who are €4 negative. Dr. Kandel further states that the “presumptive diagnosis is usually correct. ” This accuracy is based on autopsy series, after years of follow-up when other etiologies have shown themselves, and is quite clinically useless. At rhe time of early “presumptive diagnosis,” diagnostic certainly is far less accurate. Dr. Brad Hyman was quoted as stating that “individuals with other types of dementia have at least the same chance of being €4 positive as someone in the general population,” and Dr. Kandel accepts this speculation. However, available data do not support that assertion. In autopsy-confirmed studies, the allele frequency of the non-AD dementia patients is considerably less than the age-matched control population. In the CERAD series, the €4 allele frequency of patients without an autopsy-confirmed primary or secondary diagnosis of definite AD was 0.047, compared with 0.15 for controls. ’ Autopsy-confirmed non-AD demented patients do not have the same allele frequency as observed in the general population. To “beg to differ” usually introduces opinion, not data. Routine neuro-imaging in lieu of a reliable, documented neurological examination infrequently provides useful additional diagnostic information. Multiple imaging studies are frequently performed by subsequent doctors consulted in the family’s desperate quest for an accurate diagnosis. This is expensive. How often has a space-occupying lesion (such as a subdural hematoma) caused dementia of the Alzheimer type in the absence of lateralizing or abnormal neurological signs? Many physicians get by with incomplete or perfunctory neurological examinations, missing subtle or even flagrant neurological signs. The possibility of space-occupying lesions found on CT and/or MRI imaging may justify only one neuro-imaging test. A formal reanalysis of the dementia diagnostic paradigm is needed. (Mayeux et al., manuscript submitted). A codbenefit analysis directly comparing APOE genotyping coupled with a reliable neurological examination with routine imaging would be an interesting and informative study. Finally, I agree that vascular events and AD overlap. AD is frequent and vascular dementia is uncommon. Dementias that appear to start suddenly as a consequence of a vascular event are usually superimposed on AD. That also explains two other findings: (1) clinical diagnosed vascular dementia series sometimes exhibit increased €4 allele freq~ency,’~-~’ and (2) vascular dementia is extremely rare in autopsyconfirmed series of dementia.16. ” I have maintained that APOE genotyping is a useful adjunct that has diagnostic value for more than half the patients (with €4 allele) and is of little diagnostic value for the non-€4 patients. What constitutes a thorough dementia examination is changing. I think it is presumptuous to state that, “I do not believe genotyping will provide much additional information. ” Data, not belief systems, provide more objective guidance in an evidence-based decision process. The potential use of APOE genotyping for pharmacogenetics or in making choices of therapies can only strengthen its usefulness in clinical practice. When practice plans figure out that a good, reliable neurological examination costs a fraction of multiple imaging tests, it may become more difficult to sustain inefficient, but comfortable, traditions.