APOE4 High Risk

The very high risk of APOE4 carriers.


The lifetime risk of APOE4 carriers is approximatedly 29%, 3.2 fold higher than non-carriers. Furthermore, onset is earlier, frequently in mid seventies in contrast to mid eighties in non-E4 carriers. APOE4 carriers have a different Odds ratio,  age of onset, effect of family history on risk, effect of increased caloric intake on risk, risk of progression from MCI (mild cognitive impairment) to dementia. 

The increased risk is illustrated by following two studies: "APOE e4 lowers age at onset and is a high risk factor for Alzheimer's disease" (Norway) Sando, 2008.(24)

The Odds ratio for E3/E4 vs E3/E3 was 4.2 and the mean age of onset was 75.3 years vs 78.4 without E4 allele. The following chart illustrates the risk:

Odds Ratio for AD in E3/E3, E3/E4, E4/E4 with and without 1st degree relative with dementia

                                                        E3/E3                     E3/E4                      E4/E4

Odds Ratio All AD patients:             1                            4.2                         12.9

OR, No Family History AD:               1                            2.9                         8.1

OR, Family History AD:                     1                            5.9                        18.7

In AD patients without E4, family history does not increase risk of AD. In E4 carriers, there is dramatic increase in risk if family history of AD. In E4 carrier with family history, the Odds Ratio jumps to almost 6 fold increased risk.

                                     AD patients E3 and E4 frequency by Age at onset

                                                            E3                                      E4

Control                                               73%                                   16%

Age 60-69                                           42%                                   51%

Age 70-79                                           50%                                   44%

Age 80-89                                           65%                                   25%

The chart from Sando study shows E4 carriers have much higher percent in younger age groups. In the 60-69 age group, E4 carriers were 51%, although only 16% of population. In contrast in the 80-89 age group, E4 carriers were 25%. This data shows that in the 60-69 age group, APOE4 carriers had an Odds Ratio of 5.6 and Odds Ratio 4.0 in 70-79 age group and odds ratio 1.76 in 80-89 age group. The increasing risk of AD in non-E4 carriers in 80-89 age group and above averages out overall Odds ratio and obscures the greatly increases risk of E4 carriers in 60-79 age group.

This following data is taken from 1993 study published in Science, "Gene dose of Apolipoprotein E type 4 allele and risk of Alzheimer's disease in late onset families, by Corder (1) and data combined with study of late onset sporadic cases by Saunders, a co-author. They studied 42 families with history of late onset AD and followed them till death and confirmed the diagnosis of AD with autopsy. The results from this study are very widely cited as references in the literature. 

One of the most dramatic finding is age of onset. For ApoE 4/4 mean age of onset was age 68 and by age 75, 86% had onset. For carriers with 1 E4 allele, mean age at onset was age 75.5 years. However, 61% had onset by age 75. In contrast, without E4, mean age of onset was 84.3 and by age 75 only 24% were diagnosed with AD.

The result was those with two E4 alleles survived 9.7 years due to very early onset. Those with 1 E4 allele survived 3.1 years. However, those without E4 survived only 0.6 years due to onset in old age.

The second part of story was percent affected. This is summarized in table 3 from Corder and table is here modified. The results of risk combined for men and women was:

 ApoE4 gene dose: 

0:    20.4%; 

1:    46.6%, 

2:    91%. (essentially everybody with 2 doses had AD by age 80) 

The data for men and women are presented in table:

ApoE4 gene dose                    Men                              Women

          0                                       11%                                  26% 

          1                                       39%                                 46.6%

With one E4 gene, risk for men increased 3.5 times and risk for women increased 1.8 times. 

In the Corder study compared to Sando study, big difference is earlier age onset in Sando study in non-E4 group. In Corder study, diagnosis of AD about 9 years sooner, with mean age of 75 instead of 84. The difference Sando study is mean age of non-E4 group was 78.4. 

If you do not have a family history, chance of E4 in general population is about 17%. In sporadic cases of late onset AD (after age 65) 40% of cases usually have one E4. In this study, in sporadic cases E4 was present in 63% of cases. 

The question is if have family history of late onset AD, what is your risk. In this study of 42 families with history of AD, 28% of men and 36% of women had E4 allele. This group accounted for 80% of total of 95 cases of AD. Another 20 cases in this group of families with history of AD did not have E4 gene.


                                 MILD COGNITIVE IMPAIRMENT (MCI)

All subjects with MCI have an increased risk for progression to AD. The paper, "Predictive value of APOE-E4 allele for progression from MCI to AD-type dementia: a meta analysis," Elias-Sonnenschein, 2010,(25) reviewed 35 prospective studies. They concluded, "The APOE-e4 allele is associated with a moderately increased risk for progression from MCI to AD-type dementia." The OR for subjects with MCI who are carriers of APOE-E4 allele to progress to AD-type dementia was 2.29." [compared to MCI without E4]

The following two studies illustrate the risk:

"APOE4 increases the risk of progression from amnestic mild cognitive impairment to Alzheimer's disease among ethnic Chinese in Taiwan", Wang, 2011. (26) Subjects 60 years and older enrolled in memory clinic were evaluated. During the follow-up the E4 carriers had annual conversion rate of 15.9% vs 9.0% for E4--. The mean survival time before conversion was 4.75 years vs 7.2 years for the E4+ vs E4-- patients. The hazard ratio for developing AD was 2.0.

"Conversion to dementia from mild cognitive disorder-The Cache county Study" (Utah), Tschanz, 2006.(27)

All elderly resident (aged 65 or older) were followed for 3 years. 120 participants had mild cognitive impairment at baseline. (51 prodromal AD, proAD); 69 other cognitive syndromes, CS).

3 year conversion rate to AD was 46%.

"In individuals with at least one APOE E4 allele, those with proAD or CS exhibited a 22-25-fold higher risk of dementia than cognitively unimpaired individuals (vs 5 to 10 fold higher risk in those without E4). 

These studies show E4 carriers with MCI have about about a 2 fold increased risk of conversion to AD and mean time was 4.74 years vs 7.2 years in study providing times for conversion. 

Coronary artery disease:

APOE4 carriers also have increased risk of coronary artery disease. For discussion of CAD see Treatment section.