For a complete discussion of Alzheimer's disease; see website www.alzheimer-prevention.com. which has very detailed discussion of prevention of AD in APOE4 carriers. [The numbers for refererences are from the list of references in that website.]
The evidence indicates that lowering mTOR with rapamycin based treatment will also prevent AD in non-APOE4 carriers as well as in APOE4 carriers.
In my opinion, Rapamycin is primaily indicated in non-APOE4 carriers to slow aging (9,10) and decrease risk of major age-related disease such as atherosclerotic heart disease and cancer. (40-44) As the cornerstone of a general treatment plan to reduce mTOR, rapamycin would also be expected to reduce risk of AD in non-APOE4 carriers.
All of the mouse studies from 2010-2014 were performed on mouse models of AD, unrelated to APOE4. (3-8). It was only in 2015 that the first rapamycin study was done on a mouse model with human APOE4 genes (11). See Mouse Studies.
As noted in Mouse studies and Basic research, there are three major prongs of attack to prevent AD:
a. Prevent deterioration of the microvascular cerebral circulation. (31, 33)
b. Prevent accumulation of amyloid-beta.(22)
c. Prevent accumulation of hyperphosphorylated Tau. (23)
Deterioration of cerebral microcirculation, increased accumulation of amyloid-beta, increased accumulated of hyperphosphorylated Tau, ALL combine to produce the full pathologic and clinical picture of AD.
Hyperphosphorylated Tau is an extremely potent cause of neurodegeneration. Tau is discussed in Basic science section as part of Hit 2. Studies by S. Oddo (7) and JJ Pei (34, 36, 37) shows that elevated mTOR drives Tau pathology. Elevated mTOR causes increased production of Tau, decreased removal of Tau, increased phosphorylation and decreased pruning of phosphate groups.(23)
All rapamycin related actions on Tau are unrelated to APOE4 status.
Amyloid-Beta accumulation is both a major cause of neurodegeneration plus a trigger of further neurodegeneration by increasing mTOR and increasing accumulation of Tau. (23)
Accumulation of Amyloid-B has two main pathways:
(a) decrease in autophagy; (35)
(b) decrease clearance of AB by impaired function of cerebral vascular system. (31, 33)
In the case of non-APOE4 carriers, accumulation of AB may be delayed 20 years compared to APOE4 carriers. In old age, accumulation of AB, both by decrease in autophagy and impairment of cerebral microcirculation can develop. In mouse studies, rapamycin prevented AD-like pathology in mice by increase in autophagy which caused decrease in AB.
Decrease in autophagy is caused by elevated mTOR activity and autophagy is restored by decreasing mTOR activity with rapamycin. (3,4)
The cerebral microvascular system is most directly impacted by APOE4. This autopsy study of human brain examined three groups:
(a) without AD,
(b) APOE3 carriers with AD
(c) APOE4 carriers with AD: (13)
The results were:
APOE3 carriers with AD had more damage to cerebral microvascular system than APOE3 carriers without AD.
APOE3 carriers with AD had less damage to cerebral microcirculation than APOE4 carriers with AD.
APOE3 carriers had same type of findings as APOE4 carriers as regards damage to cerebral circulation, just to a lesser amount.
The main cause of damage to cerebral microcirculation in APOE4 carriers was that transport protein LRP1 did not combine with APOE4. This resulted in loss of function of LRP1 which then triggered the proinflammatory pathway CypA ---> NF-kB---> MMP9 which resulted in damage to BBB and deterioration of microcirculation. (12)
With age, there is a marked decrease in LRP1. In brains with AD, compared to non-AD brains there was a 75% reduction in LRP1 (13). As a consequence of a 75% reduction in LRP1 an APOE3 carrier would sustain the same lack of proper function of LRP1 due to LRP1 being decreased below the physiologic levels required to inhibit CypA. Therefore, the same proinflammatory pathway involving CypA --->NF-KB --->MMP9 causing damage to BBB would apply. The main difference is that in APOE3 carrier, the damage to BBB would not occur until LRP1 was reduced by old age. In the above study of human brains, it was demonstrated that this was indeed the case; just to a lesser degree then in APOE4 brains with AD. (13)
Rapamycin can block this same pathway causing damage to BBB in APOE3 carriers by inhibition of CypA--->NF-kB--->MMP9 pathway (13)
In a very important study in AD model mouse, rapamycin restored vascular integrity and function and improved memory in symptomatic mice. (6). The mode of action of rapamycin was to restore function of nitric oxide synthase and thus increase NO (nitric oxide) release by endothelial cells and vascular dilation. The conclusion was "rapamycin blocked the progression of AD-like cognitive and histopathological deficits by preserving brain vascular integrity and function."(6) This study was most remarkable in that these were symptomatic mice in whom improved cognitive function.
In another study of note, genetic reduction of mTOR activity prevented development of AD type pathology in AD mouse model. (8) Oddo, a leading expert, noted that this study showed major role of elevated mTOR in AD
In the above mouse studies noted, Rapamycin prevented AD type neuropathology unrelated to APOE4.
Mouse studies are divided into section of 6 AD mouse studies without APOE4 gene and 2 mouse studies with human APOE4 gene in mouse. In Basic research sections, the section on AB and Tau these sections apply to both APOE4 carriers and non-E4 carriers.
For the non-APOE4 person who is concerned about the morbidity associated with aging and age-related disease; the suggested approach is to delay aging and delay age-related disease with a rapamycin-based treatment plan. As part of the general plan to delay age-related disease caused by hyperfunction of mTOR; the above evidence suggests rapamycin will also prevent AD.
For persons not on rapamycin therapy, AD starts to become very common after age 85. Therefore, important that in elderly persons on long-term rapamycin-based anti-aging formula; evidence in animal models suggest AD will also be prevented.