In a recent paper about rapamycin and cancer prevention, Mikhail Blagosklonny wrote that rapamycin was the most important new drug since the discovery of antibiotics. Aging is the major risk factor for both cancer and Alzheimer's disease. Rapamycin slows aging. Rapamycin is also an effective drug for both prevention of cancer and prevention of AD. The common factor in aging, cancer, and Alzheimer's disease is TOR (Target Of Rapamycin) and rapamycin targets TOR. [The remarkable scientific research showing how rapamycin prevents AD is discussed in two drop down sections: Mouse and Basic Science. ]
TOR (Target Of Rapamycin) is the command and control of every cell of every living thing on planet earth. TOR has been conserved through 2 billion years of evolution. TOR has evolved to be at the right level from the start of life, through growth and development and through the reproductive years; but after growth and development has stopped, the body changes. According to Mikhail Blagosklonny, TOR is at too high a level for the middle and older years. TOR hyperfunction is driving what we call aging and almost all age-related disease. (40) What the older animal needs is "TOR 2.0," a program update for the aging animal.
Rapamycin is the pharmacological fix for the problem of elevated TOR. (41) Rapamycin directly inhibits TOR. Rapamycin can be used to totally block TOR or to partially block TOR. If ratchet down TOR a small amount, perhaps @ 30% in the older animal, the results are near miraculous. Lowering TOR with rapamycin extends the lifespan of mice 25% (10) and appears to slow what we call aging. In the laboratory, rapamycin prevents cancer, heart disease, Alzheimer's disease, and macular degeneration, (50) plus the majority of other age-related conditions and diseases.(40-47,49)
Recently a study was done in which rapamycin was given to old companion dogs. (48) Some of the dog owners said their old dogs were running about like puppies. Three years ago, at age 72. I felt like one of those old dogs. Since then, I have been on weekly rapamycin for over two years. While I don't feel like a puppy, I do feel very much improved.
This office offers "off-label" use of rapamycin to APOE4 carriers. Extraordinary advances have been made in the understanding of the major role of elevated TOR activity in the pathogenesis of AD. These advances have been made possible by the ability to create transgenic mouse models of AD with human genes. In 2010, it was first shown that Rapamycin prevents AD in transgenic mouse models of AD. (3,4) In 2015 it was shown rapamycin prevents AD in mouse models with the human APOE4 gene having replaced the mouse APOE gene. (11) The results of this basic research is highly suggestive that rapamycin will prevent AD in APOE4 carriers. (15)
Extraordinary scientific advances in the understanding of Alzheimer's disease (AD), in the past 10 years, especially as regards APOE4 carriers suggests that AD can be prevented by early intervention in APOE4 carriers. For the purpose of prevention, late onset AD should be viewed as two different disease with a shared final common pathway. AD in APOE4 carriers is a genetic disease with a large age-related component in contrast to AD in non-APOE4 carriers which is a pure age-related disease. AD in APOE4 carriers is a more homogeneous disease. The two forms of AD overlap in many ways; but are different in others. However, for purpose of prevention, the differences are significant and therefore it is essential that AD in APOE4 carriers be considered as a distinct disease.
This web site is about the prevention of AD in APOE4 carriers. It is likely rapamycin will also prevent AD in non-APOE4 carriers. There is also evidence showing that rapamycin helps protect the brain from age-related cognitive decline in normal aging unrelated to AD. These are reviewed in "Disease and Treatment section. Prevention of AD in non-APOE4 carriers and protection of brain from normal age-related cognitive decline should be addressed in a general anti-aging treatment plan. (See "Rapamycin Based Anti-Aging Medicine at "rapamycintherapy.com".
In contrast to non-APOE4 carriers, who only have a lifetime AD risk of 9% and mean age at diagnosis of 85 years; APOE4 carriers are at much great risk. APOE4 carriers have a lifetime AD risk of 29% and mean age at diagnosis of 75 years. (1)
Also APOE4 carriers begin to experience slight impairment of memory starting prior to age 60.(2) In short, APOE4 carriers have a great unmet medical need which needs to be addressed.
Since 2010, rapamycin has emerged in both transgenetic mouse models of AD and basic science studies as a drug with extraordinary potential to prevent AD. [See Mouse Studies, Basic Science] (3-7) These remarkable studies have not received the media attention they deserve for the possible reason that there have been no follow-up human studies and rapamycin is a generic drug with no press agent.
In 2009, rapamycin did make headlines when rapamycin became the first drug to extend lifespan in a mammal. Most remarkable was that rapamycin was started in a mouse age equivalent to 60 years old in a human. Lifespan in middle age mice was extended 9% and 14% in male and female mice, respectively.(9) In 2014 study lifespan was extended to 23% and 26% in male, female mice, respectively, a study in which in which increased dose and started treatment at earlier age in mouse.(10)
Rapamycin appeared to slow aging and since aging is the major risk factor for AD, there was great interest in the effect of rapamycin on AD. In 2010, two remarkable studies showed rapamycin, if started early, would prevent AD-like pathology and cognitive impairment in transgenic mouse models of AD with human AD genes. (3,4)
Another huge development was 2015 study [Ai-ling Lin] which used transgenic mouse model in which human APOE4 genes replaced the murine genes for APOE. In this ground breaking study, rapamycin was successful in stopping the pathology which leads to development of AD.(11) [See Mouse Studies, APOE4 Mouse]
Two of the most important studies were done by Zlokovic in 2012 and 2015. These two studies demonstrated the basic defect in the ApoE4 lipoprotein which causes cause AD in the APOE4 carrier. The specific finding were demonstrated in a mouse study (12) and the same specific findings related to the APOE4 defect were also demonstrated in post-mortem human brains.(13) [See Basic science]
In my opinion, in regard to basic science, Rapamycin has now reached critical mass, in respect to APOE4 carriers. It has been convincingly shown in the laboratory that rapamycin can prevent AD in APOE4 carriers.
This is time for translation, going from basic science to clinical medicine. However, there are TWO great obstacles; time and money.
Prevention takes a very long time to prove, in contrast to amelioration of a disease, which takes a relatively short time. Proof of prevention can take decades. Leading scientists are now conducting studies to demonstrating that PET scans can act as a surrogate marker to show rapamycin prevents development of AD in APOE4 mouse models.(14) Use of PET scans could reduce time to prove rapamycin can prevent development of AD in APOE4 human carriers from many decades to perhaps less than a decade.
The other great obstacle is money. Rapamycin is a generic drug. There is no pot of gold at the end of the rainbow for a generic drug like rapamycin. Accordingly, the future of human clinical trials as regards rapamycin and prevent AD in APOE4 carrers is uncertain.
Large scale human clinical trials with rapamycin are of great importance. The proof from those studies may lead to preventive treatment for tens of millions of persons at risk due to APOE4.
However, "off-label" treatment may provide the best chance to rescue people today; people who may not have time to wait.
For two of the best reviews of AD, rapamycin and mTOR, by leading researchers are see 2014 paper by Arlan Richardson (22) and 2015 paper by Salvatore Oddo (23).
"mTOR: Alzheimer's disease prevention for APOE4 carriers" is a 2016 paper by Ai-Ling Lin and Arlan Richardson,(15) two of world's leading experts on prevention of AD. [Of the 8 mouse studies discussed in "Mouse studies" section, the names of these two foremost experts appear as major researchers in 6 out of 8 papers.] Their short summary is quoted here as a highly authoritative review of this subject..
"Inheritance of the APOE4 allele is the strongest genetic risk factor for late onset AD. APOE4 carriers accumulate beta-amyloid (AB) and neurofibrillary tau tangles earlier and with more extensive pathology compared to non-carriers. However, decades before the aggregation of AB and tau, cognitively normal APOE4 carries have developed neurovascular deficits, including reduced cerebral blood flow (CBF) and impaired blood brain barrier (BBB) integrity.(12) The above indicates that brain physiology is altered in APOE4 carriers before clinical markers such as AB, tau pathology and memory deficits appear, suggesting that vascular changes predispose APOE4 carriers to developing AD. Therefore, early interventions that can restore neurovascular deficits to normal could be critical in potentially preventing the development of AD-related neuropathology and cognitive impairment."
"In a recent study, using MRI imaging, Lin reported that young asymtomatic APOE4 mice treated with rapamycin had preserved CBF and BBB integrity to the level of wild-type controls.(11) The preserved vasculature was associated with amelioration of incipient learning deficits of the APOE4 transgenic mice. The significance of this discovery is that brain functions are pharmacologically reversible and AD potentially could be prevented in asymptomatic APOE4 carriers."
"Rapamycin is a drug approved by FDA. It has been widely used in clinical setting and was originally used as immunosuppressive agent to prevent rejection of organs in transplant patients." [daily administration required].
"Rapamycin is a mTOR inhibitor. A major breakthrough occurred in 2009 when it was shown that rapamycin, which reduced mTOR signaling, increased the lifespan of mice.(9) In addition, rapamycin has been shown to reduce a variety of cancers in mice as well as atherosclerosis in mouse models fed high fat diets as well as improve immunity in elderly humans.(51) As regards to the human CNS, several studies have shown that inhibition of mTOR by rapamycin treatment improves cognition, slows brain aging, and impedes the neurodegenerative disorders through pathways associated with autophagy, glucose metabolism and mitochondrial functions."
"Lin et.al. demonstrated that mTOR inhibition reduced proinflammatory pathways in brain vasculature that otherwise impair BBB integrity in APOE4 transgenic mice.(11) Loss of BBB integrity is considered one of the initiating events that lead to AD-like pathological cascade in the APOE4 carriers. Restoring BBB integrity is highly associated with improved CBF and preserved learning ability of the APOE4 transgenic mice. "(11)
"In addition, Lin et.al previously reported that inhibition of mTOR activates endothelial nitric oxide synthase and causes release of nitric oxide, a vasodilator, which in turn increases CBF.(6) In mice modeling human AD (hAPP (J20), Lin et al. found that rapamycin restored their CBF and vascular density, which were associated with reduced accumulations of AB and cerebral amyloid angiopathy, and improved memory." (6)
"Collectively, these finding indicate that rapamycin alters neurovascular functions through multiple potential pathways. Because neurovascular defects are one of the earliest events that lead to AD-like pathology, MTOR inhibition might be an effective intervention to preserve brain vascular functions and consequenty slow or prevent the progress of AD development."
"In conclusion, mTOR inhibition has been shown to increase lifespan and healthspan in various species. Rapamycin has been approved by FDA since 1999 for various uses in humans, and these compounds have been given to cancer patients for relatively long periods of time with little change in quality of life. Lin et al. further demonstrate that rapamycin restores and preserves neurovascular functions in APOE4 transgenic mice using MRI.(14) Their results may provide the basis for future AD prevention trials in human APOE4 carriers."
In 1906, Alois Alzheimer first described the main pathologic hallmarks of Alzheimer's disese, extracellular amyloid deposits and intracellular neurofibrillary tangles. These were subsequently identified as amyloid-beta and Tau. For the next 100 years amyloid-beta and Tau were the main focus of AD research and theory.
In 2006 Berislav Zlokovic proposed the neurovascular hypothesis of AD, which has been called the two hit theory. The essence of the Two Hit theory is that vascular impairment precedes neurologic impairment and vascular impairment also causes the increase in amyloid-beta which then triggers Hit 2 which causes overwhelming neurologic damage. The pathologic hallmarks of AD first described by Alois Alzheimer over a hundred years ago are the end result of hit 2 and amyloid-beta and tau interaction. The impairment of cerebral blood blood described above in asymptomatic APOE4 carriers in the 20-39 year old age group constitute the beginning of "HIT ONE". The most important target for prevention of AD in APOE4 carriers is Hit One, damage to the cerebral microcirculation during the latent period.
HIT ONE In APOE4 CARRIERS:
APOE4 carriers produce a defective apolipoprotein, ApoE4. The ApoE4 molecule fails to properly combine with a major cerebral vascular transport carrier, LRP1. This was first discovered in 2008. In contrast to ApoE2 and ApoE3 which form a strong bond with LRP1, ApoE4 forms a very weak bond. This highly specific molecular defect then sets in motion a chain reaction culminating in impairment of regional cerebral blood flow and blood-brain barrier (BBB) breakdown in an age dependent manner. (12, 13)
ApoE4 forming a weak ligand with LRP1 causes elevation of amyloid-beta both directly and indirectly. Directly is LRP1 failure to properly remove amyloid-beta from brain interstitial fluid. Indirectly is APOE4 causes breakdown of BBB and microcirculation which then results in accumulation of amyloid-beta. The combination of impairment of cerebral blood flow and BBB breakdown plus increase accumulation of amyloid-beta triggers the amyloid cascade and full pathologic picture of AD.
In the APOE4 carrier, ApoE4 is not a mere "risk factor"; ApoE4 is the specific cause of the disease.
In the non-APOE4 carrier, age-related changes can cause Hit One. Hit One then triggers Hit 2, which follows the same final common pathway.
AD in APOE4 carriers can be divided into four clinical stages:
Latent: No clinical symptoms
Prodromal: Earliest signs cerebral deficits
MCI (mild cognitive impairment)
The major current focus of clinical medicine is treatment and treatment starts at the late stages of disease, MCI and Dementia. In contrast to treatment, prevention must start at the early stages. the latent and prodromal stages.
The current approach to AD has a rather fatalistic attitude and assumes nothing can be done to prevent AD. I also have a rather fatalistic attitude to AD and believe there is no treatment for AD with dementia and; therefore prevention is required.
For prevention the issue is what are the earliest pathologic events and how can those early events be prevented. Here we look at studies focused on the early stages of AD, the latent and prodromal stages in APOE4 carriers.
Pet scans, using different markers can demonstrate early accumulation of cerebral amyloid deposition
"Apolipoprotein E e4 and age effects on florbetapir positron emission tomography in healthy aging and Alzheimer disease" Fleisher, 2013.(16)
Interpretation: "Cerebral amyloid deposition is associated with APOE4 carrier status in older healthy control subjects and symptomatic AD patients, and increases with age in older cognitively normal individuals. Amyloid imaging positively appears to begin near age 56 in cognitively intact APOE4 carriers and age 76 in APOE4 non-carriers."
This study show APOE4 carriers start showing amyloid accumulation in the brain 20 years before non-E4 carriers. Amyloid accumulation is a major step down the path to AD.
"The Association of APOE genotype with Cognitive function in Persons 35 years or Older", Izaks, 2011.(17)
Abstract: "There was no difference in RFFT (Ruff Figural Fluency test) score between heterozygous APOE e4 carriers and non carriers."
"The results indicated that homozygous APOE e4 carriers aged 35 years or older had worse cognitive function than heterozygous carriers and noncarriers."
"Longitudinal changes in cognition and behavior in symptomatic carriers of the APOE e4 allele", Caselli, 2004.(2)
Participants were age 50 years or older, mean age was 60 years.They were followed over a median period of 33 months.
Among those 50-59 years, E4 carriers showed poorer performance over a mean interval of 33 months in regard to verbal memory and visual memory tests. No differences were found in language, spatial skills or executive function.
Conclusion: "Memory declined in APOE e4 carriers before the symptomatic presentation of MCI in a cohort whose mean age was 60 years over a median period of 33 months." The decline began prior to age 60." (2)
The combination of memory decline and amyloid shows that prior to age 60 many APOE4 carriers have entered the early prodromal stage in contrast to non- E4 carriers.
CEREBRAL BLOOD FLOW, HYPOMETABOLISM:
Three studies, all reporting very similar results, conducted studies of cerebral blood flow using PET scans in APOE4 carriers in middle age.
"Declining brain activity in cognitively normal APOE4 heterozygotes", Reiman 2001. (18) Used PET scan measuring cerebral metabolic rate for glucose (CMRgl) in age group 50-63 over interval 2 years: "The E4 heterozygotes had significant CMRgl declines in the vicinity of temporal, posterior cingulate, and pre-frontal cortex, basal forebrain, parahippocampal gyrus and thalamus, and these declines were significantly greater than those in the E4 noncarriers."
"Correlations between APOE4 gene dose and brain imaging measurements of regional hypometabolism, Reiman, 2005. (19) Age group 47-68, PET scan, CMRgl: "We previously found that cognitively normal late-middle-aged APOE4 carriers have abnormally low CMRgl in the same brain regions as patients with probable Alzheimer's dementia...we now find that E4 gene dose is correlated with lower CMRgl in each of these brain regions."
"APOE epsilon 4 genotype and longitudinal changes in cerebral blood flow in normal aging", Thambisetty, 2010.(20) PET scan using labeled oxygen 15 compared changes in regional blood flow over an 8 year period in E4 carriers older than 55 years.
Results: E4 carriers had greater regional cerebral blood flow decline compared to nonE4 carriers. The affected brain regions were the frontal, parietal and temporal cortices, thoses areas especially vulnerable to pathological changes in Alzheimer disease. The conclusion was "Alzheimer disease is associated with widespread decline in regional cerebral blood flow over time that precedes the onset of dementia."
The following study is different. It studied E4 carriers in the 20-39 age group.
In the following study, the participants were age 20-39 E4 carriers (heterozygotes)
"Functional brain abnormalities in young adults at genetic risk for late onset Alzheimer's dementia" Reiman, 2004.(21)
Abstract: "Like previously studied patients with probably AD and late-middle-aged E4 carriers, the young E4 carriers had abnormally low rates of glucose metabolism bilaterally in the posterior cingulate, parietal, temporal and prefrontal cortex. Carriers of E4 gene have functional brain abnormalities in young adulthood, several decades before the possible onset of dementia."
Amyloid begins to appear at age 56 in contrast to non-E4 carriers in which amyloid begins to appear at age 76.
Memory begins to decline prior to age 60.
Impairment of cerebral blood flow as shown by low rates of glucose metabolism are found in 20-39 age group. (21)
Impairment cerebral blood flow is first change in APOE4 carriers. This change precedes cognitive impairment and accumulation of amyloid.
This finding is demonstrated in cognitively normal human carriers of APOE4.
THIS FINDING OF IMPAIRED CEREBRAL BLOOD FLOW AS FIRST CHANGE IN DEVELOPMENT OF AD IS CONFIRMED IN MOUSE STUDIES USING MICE IN WHOM MOUSE GENES ARE REPLACED WITH HUMAN APOE4 GENES.
This is what makes AD in APOE4 carriers a different disease. They have demonstrable impairment of cerebral blood flow becoming apparent on PET scans in the 20-39 year old age group.
For prevention, the primary target is the deterioration of cerebral blood flow and the microvascular circulatory system.
AD in non-APOE4 carriers is caused by changes that occur in old age.
In contrast to non-APOE4 carriers, the latent stage of AD in APOE4 carriers is apparent in the 20-39 age group by PET scan
APOE4 carriers must know their APOE status.
In general, APOE4 testing is not recommended and even discouraged. I consider this advice extremely paternalistic.
APOE4 carriers very much need prevention; non-APOE4 carriers are at small risk and don't need specific prevention.
Knowing APOE4 status is extremely important for choices involving LIFESTYLE and need for vigilant medical treatment of hypertension and elevated lipids with appropriate statins. (see section on hypertension and statins under Treatment)
Lifestyle choices require knowing the specific risk to you, the individual, involving things like: inadequate physical activity, overeating, overweight, saturated fats, poly unsaturated fats, alcohol, smoking, engaging in contact sports.
Many things, like overeating, sedentary lifestyle, drinking alcohol, eating large amounts of saturated fats, smoking, failure to aggressively treat moderate elevation of blood pressure or elevated cholesterol may be perfectly fine for individuals who are not APOE4 carriers; especially regarding risk of cognitive decline and dementia. APOE4 carriers are very different as regards the risk and benefits of different lifestyles. APOE4 carriers need to know they are at risk and that it is very important for them to adopt a healthy lifestyle for them; a particular lifestyle that will lower risk of AD and cognitive decline specifically in APOE4 carriers. (See Lifestyle section)
As discussed in section regarding age of onset, APOE4 carriers have deterioration of their cerebral microcirculation that can be shown in 20-39 year old age group by PET scan. APOE4 carriers have positive finding for beta-amyloid at age 56, 20 years before non-E4 carriers. It is because of this early onset of disease that APOE4 carriers need to know their E4 status to adopt preventive measure at a appropriate age.
As shown in Lifestyle section, physical activity, high saturated fat intake, alcohol, smoking; can have major impact on risk in APOE4 carrier group. In study which followed the 50-70 age group for twenty years, risk of dementia varied by 11 fold in E4 carriers depending on above lifestyle factors. In contrast, as regards Non-E4 carriers, lifestyle had minimal impact on risk. [see Lifestyle section]
As regards high caloric intake, such a diet had major impact on E4 carriers; but small impact on non-E4 as regards risk of MCI. [see lifestyle]
As regards Diabetes and Obesity; the impact on risk is much greater in APOE4 carriers [see Treatment and Disease section]
An APOE4 carrier may have ongoing latent disease many decades before clinical disease. The latent stage and the prodromal stage are the target for prevention and are very different in APOE4 carriers versus non-E4 carriers.
For purpose of prevention, it is essential that persons who are APOE4 carriers know their APOE4 status. It is essential to understand the nature of AD as regards APOE4 carriers, understand the need for prevention and understand the steps necessary for prevention.
In consideration of long-term use of rapamycin as a prophylactic drug to prevent AD in APOE4 carriers; one major issue might be the question of whether taking weekly rapamycin is a burden or a boon to overall good health, irrespective of whether rapamycin will prevent AD.
Rapamycin is the most robust drug in the history of medicine regarding extension of lifespan. Rapamycin or genetic reduction of mTOR, extends the lifespan in every living thing tested. In a 2014 study rapamycin extended the lifespan 23% and 26% of male and female mice.(10)
In a recent study companion dogs, three months on rapamycin, old dogs were reportedly running around like puppies and had improved cardiac output. (48)
For an understanding of rapamycin as an anti-aging drug, review Mikhail Blagosklonny 2006 paper, "Aging and Immortality" and Rapamycin discussion in "Diagnosis and Treatment".(40)
My personal experience is I have been on weekly rapamycin for 2 years with no significant side-effects. At age 75, I credit Blagosklonny and rapamycin for giving me a new lease on life.
The basic effect of rapamycin is to delay aging and delay onset of age-related disease.
The evidence that rapamycin prevents AD in APOE4 carriers stands on its own, unrelated to evidence regarding lifespan extension. There are extensive animal studies showing rapamycin ameliorates atherosclerosis and stabilizes plaque, (49) thus preventing thrombosis of coronary arteries and acute myocardial infarction. This is important for APOE4 carriers as they are at increased risk of death from coronary artery disease. Interestingly, the same molecular mechanism that prevents AD in APOE4 carriers is the same molecular mechanism which prevents destabilization of plaque and heart attack. The critical step is rapamycin suppression of NF-kB and MMP9. (see Basic science)
There is one most important thing to know is WEEKLY RAPAMYCIN IS NOT DAILY RAPAMYCIN. Daily rapamycin has a well deserved reputation for significant side-effects. It is a mistake to attribute the side-effects of daily rapamycin to weekly rapamycin.
From one perspective, taking rapamycin to prevent AD in APOE4 carriers, based only upon basic science and mouse studies; but without prior human clinical trials, may seen radical. On the other hand, many people, like myself, take weekly rapamycin, without being an APOE4 carrier; but rather take rapamycin to delay aging and prevent age-related disease. (42, 44) From that perspective, being an APOE4 carrier is just another reason in a long list of reasons, to take intermittent rapamycin.
This web site is about early treatment of APOE4 carriers to prevent or ameliorate impairment of regional cerebral blood flow and thus reduce risk of memory impairment, MCI and AD.
APOE4 carriers have a unique opportunity for prevention because:
(1) those at risk can be identified by genetic test for APOE4 allele carriers,
(2) Impairment of the cerebrovascular system develops slowly over many decades, before onset of clinical disease.
(3) Microvascular disease of cerebral capillaries appears to be amenable to prevention, treatment and repair.(6)
The cornerstone of treatment is rapamycin used as a weekly dose. Rapamycin treatment for prevention of AD in APOE4 carriers is "off-label". For that reason this website provides a very detailed and fact based presentation of the scientific research, theory and finding which form the basic science foundation of the rapamycin-based treatment plan.
In mouse models of AD and in cell cultures, blocking mTOR with rapamycin blocks the critical steps in pathogenesis of AD as regards APOE4. (3-8, 11-14)
In humans, conditions which increase mTOR also increase risk of development of AD, especially in APOE4 carriers. A high calorie diet increases mTOR and increases risk of AD. Obesity causes insulin resistance which cause high insulin levels and high mTOR levels and increases risk of AD. Diabetes results in high sugar levels which causes high mTOR levels and diabetes increases risk factor for AD, especially in APOE4 carriers.
The experience in animals using rapamycin to block mTOR and the human conditions in which high mTOR increases risk of AD all suggest that lowering mTOR with rapamycin will lower risk of AD in APOE4 carriers
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