Early-onset Alzheimer disease in families with late-onset Alzheimer disease: a potential important subtype of familial Alzheimer disease.
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.


METHODS
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?


METHODS
University of Washington Alzheimer Disease Research Center, Seattle.


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


METHODS
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 epsilon4 allele, and 2 of the earliest-onset cases were epsilon3/epsilon3. 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 epsilon4 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.
Brickell
Kiri L
KL
Department of Neurology, VA Puget Sound Health Care System, University of Washington, 1660 S. Columbian Way, Seattle, WA 98108, USA.
Steinbart
Ellen J
EJ
Rumbaugh
Malia
M
Payami
Haydeh
H
Schellenberg
Gerard D
GD
Van Deerlin
Vivianna
V
Yuan
Wuxing
W
Bird
Thomas D
TD
D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000544:Alzheimer Disease / Q000145:classification* / Q000235:genetics*; D001057:Apolipoproteins E / Q000235:genetics; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D009483:Neuropsychological Tests / Q000706:statistics & numerical data; D012307:Risk Factors
D001057:Apolipoproteins E