Reference
Complete the bibliographic reference for the article according to AJE format.

Category of HuGE information
Specify the types of information (from the list below) available in the article:

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

3. Gene-environment interaction

Study hypotheses or purpose
The authors study hypotheses or main purpose for conducting the study.

Hypothesis:  “Individuals possessing the APOE [epsilon] 4 allele would have a more rapid subclinical pathologic progression and that, in combination with small head circumference, these individuals would be at particularly high risk for earlier onset of Alzheimer’s disease.”

Gene(s)
Identification of the following:

1. Gene name
2. Chromosome location
3. Gene product/function
4. Alleles
5. OMIM #

W

1. Gene: APOE
2. Chromosome location:  19q13.2
3. Gene product/function: Apolipoprotein E
4. Alleles:  4
5. OMIM #: 107741

Environmental factor(s)
Identification of the major environmental factors studied (infectious, chemical, physical, nutritional, and behavioral)

Head circumference

Health outcome(s)
Identification of the major health outcome(s) studied

Alzheimer’s disease – defined as anyone meeting the DSM-IV criteria for dementia and National Institute for Neurological and Communication Disorders and the Stroke/Alzheimer’s Disease and Related Disorders Association’s criteria for probable Alzheimer’s disease at some point during follow-up

1. Case-control
2. Cohort 
3. Cross-sectional
4. Descriptive or case series
5. Clinical trial
6. Population screening

Cohort definition
For study designs 2, 3, and 6, the following are defined, where available:

1. Cohort selection criteria
2. Exclusion criteria
3. Gender
4. Race/ethnicity
5. Age
6. Time period
7. Geographic location
8. Number of participants

1. Cohort selection criteria: Japanese-American individuals aged 65 years and older residing in King County, WA, who were identified in the U.S. census in 1990
2. Exclusion criteria: Subjects with dementia at the baseline visit
3. Gender: 827 male and 1,042 female
4. Race/ethnicity: Japanese American
5. Age: 65+ years
6. Time period: 1992 – not specified
7. Geographic location:  King County, WA
8. Number of participants: 1,869

1. Environmental factor
2. Exposure assessment
3. Exposure definition
4. Number of participants with exposure data (% of total eligible)

1. Environmental factor: Head circumference
2. Exposure assessment: Assessed at baseline using a tape measure
3. Exposure definition: Head circumference measured by placing a measuring tape over the eyebrows and passing it around the head to fit snugly over the most posterior protuberance of the occiput
4. Number of Participants with exposure data: All subjects (100%)

1. Gene
2. DNA source
3. Methodology
4. Number of participants genotyped (% of total eligible) 

1. Gene: APOE
2. DNA source:  Blood sample taken from participants during the first biennial follow-up visit  
3. Methodology: Prepared from buffy-coat preparations by a modification of the salting-out procedures
4. Number of Participants genotyped:  1,111 (59%)

1. Prevalence of gene variant
2. Gene-disease association
3. Gene-environment interaction
4. Gene-gene interaction
5. Genetic test evaluation/monitoring

Table 1: HR*, 95% CI, and p values for lowest tertile of HC**, adjusted for education and APOE status, stratified by sex (Cox model predicting probable AD***)

Variable Model 1, n=549, women Model 2, n=509, men HR 95% CI p HR 95% CI p HC, 1=lowest tertile Education, y APOE*4, 1=y 2.18 0.96 5.57 0.63-7.54 0.75-1.24 1.64-18.85 0.22 0.78 0.006 2.40 1.06 4.02 0.25-22.92 0.81-1.40 0.65-25.0 0.45 0.6 0.14

*HR = hazard ratio
**HC = head circumference
***AD= Alzheimer’s Disease

Table 2: Interaction of APOE  4 and HC, adjusted for education and body mass index (BMI), stratified by sex (Cox model predicting probable AD)

*HC in lowest tertile, APOE 4 positive
**HC in lowest tertile, APOE  4 negative
***HC in upper two tertiles, APOE  4 positive
Reference group: those with HC in upper two tertiles who are APOE 4 negative

Individuals with a head circumference in the lowest tertile (<21.4 in) who also possessed an APOE  4 allele had an increased risk of developing probable AD.

The authors have not provided sufficient evidence that maximal brain size corresponds with the amount of “brain reserve” a person has.  If this concept was true, then all females would have significantly less “brain reserve” than men.  Additionally, there is no concrete evidence that lack of “brain reserve” is predictive of AD.  The lack of evidence brings into question the authors’ rationale for carrying out the study in the first place.

Several Cox proportional hazards models were used in the analysis, but the proportional hazards assumption was not tested for all variables used in the models.  The entire analysis is based on only 59 cases of AD, which doesn’t give very much power to the study.  It is unusual that there was no table presenting the APOE status of the cases by gender, because it appears that the incidence of AD is higher in females in this cohort.  Because of the extreme confounding by gender, all results should have been presented stratified by gender.