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A Potential Important Subtype of Familial Alzheimer Disease

Kiri L. Brickell, MBChB; Ellen J. Steinbart, RN, MA; Malia Rumbaugh, MS, CGC; Haydeh Payami, PhD; Gerard D. Schellenberg, PhD; Vivianna Van Deerlin, MD, PhD; Wuxing Yuan, MS; Thomas D. Bird, MD

Arch Neurol. 2006;63:1307-1311.

Background  Genetic influences on the development of late-onset Alzheimer disease (LOAD) are heterogeneous and ill defined.

Objective  To determine the genetic risk factors for LOAD.

Design  We asked the following questions: (1) Does early-onset Alzheimer disease (EOAD) occur in families with predominantly LOAD? and (2) Does the apolipoprotein E (APOE) genotype explain the wide differences in onset age in LOAD families?

Setting  University of Washington Alzheimer Disease Research Center, Seattle.

Participants  A total of 136 kindreds and a separate group of 29 affected parent-child pairs.

Main Outcome Measures  We evaluated the kindreds with familial LOAD for the occurrence of EOAD and the affected parent-child pairs with a 20-year or more difference in the age at onset.

Results  In the 136 kindreds with LOAD, 104 had only late-onset cases (men, 36%), whereas 32 families (24%) had a combination of LOAD and EOAD cases. The 44 EOAD cases in these families accounted for 20% of cases of AD in the 32 families and 6% in all 136 families. The early-onset cases had a mean ± SD onset age of 56.1 ± 3.2 years (range, 45-59 years; men, 50%). Seven (28%) of 25 individuals with EOAD sampled did not have an APOE 4 allele, and 2 of the earliest-onset cases were 3/3. In 29 parent-child pairs with a 20-year or more difference in age at onset, 7 (35%) of the 20 children sampled did not have an APOE 4 allele.

Conclusions  Many LOAD families (approximately 25%) have at least 1 individual with EOAD, and in these individuals, the ratio of men to women is nearly 50%, suggesting a possible subtype of familial AD. The APOE genotype plays an important role in these early-onset cases, but at least one fourth of the risk must represent the influence of other genetic and/or environmental factors. These LOAD families with early-onset cases represent an important resource for investigation of these factors.

Author Affiliations: Department of Neurology, VA Puget Sound Health Care System, University of Washington, Seattle (Drs Brickell, Schellenberg, and Bird and Mss Steinbart and Rumbaugh); Wadsworth Center, New York State Department of Health, Albany (Dr Payami); and Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania Health System, Philadelphia (Dr Van Deerlin and Ms Yuan).

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