My review of the literature sought to answer the following question: Is use of statins indicated in middle-aged APOE4 carriers to prevent AD.

Various studies involving statins and protection against AD have given inconclusive results. The paper by Betterman (72) shed some light on reasons for this. This study was in cognitively healthy persons 75 and older. The HR for dementia was 0.79 and for HR for AD 0.57. They found  that persons with either MCI or dementia had no significant improvement associated with statins. They also state that in other studies persons with cerebral vascular disease had no prevention of dementia with statins. Also stated, "observational studies have suggested a reduced risk of AD in those treated with statins during MIDLIFE." Therefore to evaluate benefit with statins in midlife need to look at large population studies and exclude studies that focus on elderly.

The Rotterdam study (70) was a large population study. Followed @7000 persons for mean of 9 years. Statin use was associated with decrease risk of AD, (HR 0.54).

Another large population studies was Jick (74), a nested case-control study that collected data from 368 practices in UK, patients 50 and older. The adjusted HR for prescribing statins was  0.29.

A population study from California followed @1700 participants for 5 years and had HR 0.52 for dementia on statin therapy. (75).

A large population study from 3 French cities followed @9000 subjects and found lipid lowering agents are associated with decreased risk of dementia; HR 0.61. (76). 

A Finnish study (77)  followed @17,000 persons over age 60, with 5 year evaluation and had HR 0.42 and concluded lipid-lowering agents may have beneficial effect in dementia prevention. 

The Wolozin study (78) was very interesting because a US VA Affairs database study and information on 4.5 million subjects. They looked at dementia in subjects greater than 65. 

Simvastatin HR 0.46              (Zocor)

Atorvastatin HR 0.91            (Lipitor)

Lovastatin no reduction.

Lovastin and Simvastatin highest level lipophilicity and ability to cross BBB. Simvastin much more potent than Lovastatin.

The explanation is Simvastatin is both potent and crosses BBB. The conclusion was Simvastatin is associated with significant reduction in incident dementia and incident Parkinson's disease. 

To me combination of reduction of BOTH dementia and Parkinson's disease suggest the mechanism may be reduction of inflammation as that is mechanism they both share. 

The Li study looked at statin therapy and risk of dementia in the elderly. They found no significant association between statin use and incident dementia or probable AD. The following was the result of interest:

"A subgroup analysis of participants with at least on APOE-epsilon4 allele who entered the study before age 80 produced adjusted HR of  0.33."

In Wong, a meta-analysis had a RR of 0.70 for pooled results for AD and statin use. Conclusion:"These pooled results suggest that statins may provide a slight benefit in the prevention of AD and all type dementia."

In previously mentioned study on coronary artery disease, Simvastatin reduced risk of death following prior MI specifically in APOE4 group. (63)

APOE4 is associated with higher total cholesterol and LDL. 

Rapamycin therapy, although prevents against thrombosis in atherosclerosis, is associated with increase in cholesterol in blood.

Based upon all these considerations, it appears indicated to include Simvastatin  (Zocor) in treatment formula for APOE4 carriers; both to prevent MI from CAD and prevent cognitive decline.