The following chart is Table 2 from "APOE4 magnifies lifestyle risk from dementia", Milia Kivipelto, 2008.(28) This is population based study from Finland in which followed persons from midlife (mean age 51) for mean duration of 21 years and then re-examine at mean age 72. The study is of exceptional value due to early starting age, 21 years follow-up and APOE status. The study looked at physical activity, diet, alcohol use and smoking. All numbers relate to Relative Risk within group.
Active 1.0 1.0
Sedentary 2.4 1.7
Dietary PUFA intake
1st quartile 1.95 1.9
2nd quartile 0.7 0.8
3rd quartile 1.8 0.95
4th quartile 1 1
Dietary SFA intake
1st quartile 1 1
2nd quartile 4.3 1.6
3rd quartile 2.1 1.1
4th quartile 11.3 1.1
Never 1 1
Infrequent 3.8 0.5
Frequent 7.4 0.6
Non smoker 1 1
Smoker 2.0 0.6
The above finding show very dramatic differences between lifestyle risk factors and APOE status. The main effect is APOE4 carriers are far more vulnerable to environmental factors. This was shown most dramatically in intake of saturated fat and alcohol intake. APOE4 carriers showed an 11 fold increase in risk for dementia with increase intake saturated fat compared to E4 persons with lowest intake saturated fat. This was in contrast to non E4 persons which showed no increased risk with highest quartile to lowest quartile within E4-negative group. Likewise, APOE4 carriers showed a 7 fold increase risk from alcohol while non E4 persons showed a reduced risk with alcohol. Other studies have shown a decrease risk for dementia with wine intake, without specify E4 status or with comment that only for E4 negative persons.
The decrease risk for smoking in E4 negative was surprising as other studies have shown increased risk for both groups.
The E4 group also had bigger impact of being sedentary with 2.4 fold increased risk compared to active E4 positive persons.
The most dramatic effect was composite effect. When different risk factor were combined the E4 group in worst quartile had 11.4 fold increase risk. Non- E4 persons showed no composite effect as to various risk factors within their group
Non-E4 persons start with a low risk of dementia and in the age group from 50 to 70 appeared almost invulnerable to lifestyle factors.
APOE4 persons had an overall 2.8 fold increased risk, in this study, compared to non-E4, then within their own E4 group; the most unhealthy life style had a composite 11.4 fold increase in risk of dementia.
Furthermore, the risk of alcohol interacted with E4 positive status to multiply effect in very sharp contrast to non-E4 persons in which alcohol lowered risk.
Non-E4 persons start with a 9% lifetime risk of AD and this study suggested that by increased dietary intake of poly unsaturated fatty acids and regular physical activity they might achieve a small change in their risk compared to other non-E4 persons with unhealthy life style.
APOE4 person start with a 29% lifetime risk of AD and with a healthy or unhealthy lifestyle their risk of dementia might change by 11 fold.
Note: These persons were followed for 21 years, from @ age 50. The persons with healthy lifestyle may have had this same lifestyle their entire adult life. These results do not mean that for APOE4 carriers, adopting a healthy life style at age 50, 60 or 70 will achieve similar benefits.
There are very many studies about nutrition and AD, unfortunately most do not determine APOE status. Without E4 status, the study is of little value to APOE4 carriers. The study might overlook a major risk factor like saturated fat or state something is beneficial like moderate wine intake, while only beneficial to non-E4 persons and harmful for APOE4 carriers. APOE4 carriers need very reliable information about lifestyle and risk of AD that specifically applies to them.
My explanation of why lifestyle magnifies risk as regards APOE4 carriers in the 50-70 age group, is that APOE4 carriers are in latent phase of AD. During latent phase of AD it would be expected that APOE4 carriers would be very much affected by good or bad lifestyle. The explanation would be that lifestyle can increase or decrease mTOR and mTOR drives disease. In contrast, most non-E4 carriers are not in latent phase for most of these years.
If consider that APOE4 carriers may be in latent stage of AD in 25-39 year age group; can see great importance of healthy lifestyle and a lifestyle that reduces mTOR.
There is a major difference between high caloric intake and risk of AD and MCI in E4 carriers versus non-E4 carriers.
This study is of profound significance as to both pathogenesis and treatment of ApoE4 carriers.
As regards treatment; it shows need to avoid excess calories.
Caloric intake is intimately connected to levels of mTOR. Increased caloric intake causes higher levels of mTOR. As regards pathogenesis, this strongly implies increased mTOR is driving factor in development of AD in APOE4 carriers. As regards treatment, it suggests rapamycin will be effective treatment as rapamycin decreases activity of mTOR.
The impact of high caloric intake is of very significant theoretical significance as this effects mTOR levels. The other studies involving rapamycin were primarily in mouse studies. Rapamycin decreases mTOR.
"Caloric intake and the risk of Alzheimer's disease, Luchsinger, 2002. (29)
Conclusion: Higher intake calories may be associated with higher risk AD in individuals carrying the ApoE4 allele. Elderly individuals were followed for mean of 4 years. Individuals in lowest quartile were compared with highest quartile as to risk of AD. For E4 carries HR was 2.3 and for non-E4, the HR was close to 1. Only E4 carriers had increased risk of AD due to high caloric intake.
The second study we examine looks at effect of caloric intake on development of MCI in E4 and non-E4 carriers. Very importantly, MCI is divided into Amnestic and non-Amnestic MCI. "Caloric Intake, Aging, and Mild Cognitive Impairment", Geda, 2013.(30) Caloric intake is divided into tertiles designated as reference (600-1525). Moderate (1526-2142) and High (>2142). Data is presented in modified Table:
Caloric Intake and Odds of Amnestic and non-Amnestic MCI in E4 and non-E4 status
E4 Negative E4 positive
Amnestic MCI Non--Amnestic MCI Amnestic MCI Non-Amnestic MCI
Reference 1.0 1.0 1.0 1.0
Moderate Caloric 1.08 0.3 1.98 0.9
High Caloric 1.76 1.7 5.23 0.73
p < 0.001
The only significant results are association between High calorie diet and Amnestic MCI in ApoE4 carrier. Amnestic MCI has high risk of conversion to dementia in ApoE4 carriers; therefore, this is very important finding.
This study does not prove lowering mTOR with rapamycn will prevent AD; but it certainly shows increasing mTOR with high caloric intake increases risk.