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CHILDREN OF ALZHEIMER PATIENTS: MORE DATA NEEDED

¹ Department of Psychiatry and Biobehavioral Sciences University of California Los Angeles
² VA Greater Los Angeles Healthcare System
³ Wisconsin Alzheimer's Institute University of Wisconsin, Madison
⁴ Department of Psychiatry and Behavioral Sciences Stanford University School of Medicine Stanford, California

Address correspondence to Lissy F. Jarvik, MD, PhD, Psychiatry & Biobehavioral Sciences, 760 Westwood Plaza, Los Angeles, CA 90095-1759. E-mail: ljarvik{at}ucla.edu

To the Editor:

Children of Alzheimer's disease (AD) patients are at increased risk of developing the disease even if they have not inherited one of the three "Alzheimer genes" (APP, Presenilin 1, or Presenilin 2). Cognitive performance 15 or more years prior to the manifestation of symptoms has been associated with the diagnosis of AD (1–3).

Recently, we examined cognitive performance, 20 years after initial assessment (mean = 19.98 ± 0.30 years), in a convenience sample of 25 adult children of 17 AD patients. All the patients had died; 80% came to autopsy and the diagnosis was confirmed in all. At the time of reexamination, the children ranged in age from 50–82 years (mean = 61.5 ± 8.82). The Wechsler Adult Intelligence Scale (WAIS) and three measures reported sensitive to dementia-related decline (Benton Visual Retention Test, Inglis Paired Associate Learning Test, and the Fuld Object-Memory Evaluation) were included in the reassessment (4).

Only Digit Symbol, a subtest of the WAIS, showed a statistically significant difference between the two assessments, and that decline (12.5%) did not exceed the expected raw score difference between normative samples. Risk factors such as positive family history, age at onset of AD in the parent (AAO), and APOE-e4 were not significantly associated with cognitive change.

We have been unable to find published data specific for children of AD patients either in terms of cognitive change or risk for development of AD. Our previous analyses with this sample combined siblings and children of AD patients and tracked performance for only a few years (i.e., 4 years). The present analysis is the first, to our knowledge, of a 20-year follow-up in children.

The study has a number of limitations.

1. It utilized a small convenience sample and may not be representative of the 132 AD offspring originally evaluated, or of the 86 known surviving offspring (17 of the original 132 are deceased, and for 29 of the original 132, survival status is still unknown). For example, participants with memory complaints may have been less likely to volunteer than those without such complaints. However, some of our participants explicitly stated that memory concerns were the reason they volunteered so promptly. Comparison of the 25 reevaluated participants with the 61 other known survivors failed to reveal statistically significant differences between the two groups in age, education, gender, AAO in parent, family history, and autopsy confirmation. However, 1 of the 61 is known to have developed AD while none of the 25 did so as of the 2002 reassessment.
   
2. The participants, at mean age 61 years, are still younger than the typical age of onset for AD even though first-degree relatives are reported to have 2.5–4 times the general population risk. Data are needed for the 61 previously evaluated known survivors, for the 17 known deceased, and for the 29 whose survival status is still unknown. In addition, current status should be ascertained for those offspring who did not participate previously. Also, independent replication is needed in representative samples.
   
3. The influence of numerous risk factors for AD has not yet been examined, including but not limited to the following: health and diseases (especially vascular and depressive spectrum disorders, head trauma, metabolic and inflammatory disorders), insulin resistance, medications (prescribed and over-the-counter), toxins, metals (aluminum, iron, and zinc), use of anticholinergics, as well as diet, exercise, and education.
   

Notwithstanding these and other limitations of our preliminary data, we wish to bring them to the attention of your readers because of the absence of comparable data in the literature. Longitudinal data on cognitive performance of normal aging do exist. Some have been accumulated in normal aging studies, others in studies concerned primarily with morbidities (e.g., heart disease) or special populations such as twins (e.g., United States veterans, Swedish population samples). Of course, there are data accumulated by researchers throughout the world dealing with Alzheimer families, which contain information on cognitive performance of AD offspring.

We believe that there are important reasons for establishing the risks faced by AD offspring and determining the time course and characteristics of their cognitive changes.

First, many children of AD patients (and there are no readily available data regarding how many AD offspring there are) spend their lives harboring the mistaken belief that they have a very high risk of developing AD themselves. Robust data demonstrating otherwise will hopefully change this misperception.

Second, longitudinal data on the course of cognitive change will help to determine the relative influence of neuronal (and other) initial endowment and subsequent brain activity (e.g., stimulated by education) in the development or protection from the development of AD. Such data may reveal that current cognitive measures need to be augmented. For example, were cognitive change a threshold phenomenon (similar to but much earlier than the manifestation of more overt clinical symptoms of AD), then new approaches might be devised to detect subtle subthreshold changes.

Third, firmly established cognitive markers could assist in evaluating the effectiveness of early interventions as well as preventive approaches. For example, the children of AD patients tend to be aware of new research findings, no matter how preliminary, and many alter their lifestyle accordingly. A few examples are diet, exercise, ginko biloba, alcohol (especially red wine or the extract resveratrol), antioxidants, antiinflammatories, hormones, and other medications (prescribed as well as over-the-counter), the latest being the statins. It is tempting to postulate that such lifestyle changes have already made a difference—that they may delay, if not indefinitely postpone, the manifestations of AD in genetically vulnerable individuals. We need the data to confirm or refute that postulate.

Received May 24, 2004

References

1. LaRue A, Jarvik LF. Reflections of biological changes in the psychological performance of the aged. Age. 1980:;3:29-32.
2. Snowdon DA, Kemper SJ, Mortimer JA, Greiner LH, Wekstein DR, Markesbery WR. Linguistic ability in early life and cognitive function and Alzheimer's disease in late life: findings from the Nun Study. JAMA. 1996:;275:528-532.[Abstract/Free Full Text]
3. Kawas CH, Corrada MM, Brookmeyer R, et al. Visual memory predicts Alzheimer's disease more than a decade before diagnosis. Res Prac Alzheimer Dis. 2003:;60:1089-1093.
4. LaRue A, Matusyama SS, McPherson S, Sherman J, Jarvik LF. Cognitive performance in relatives of patients with probable Alzheimer disease: an age at onset effect? J Clin Exp Neuropsychol. 1992:;14:533-538.[Medline]

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