Unified Theory Of Alzheimer’s Disease (UTAD): Implications For Prevention And Curative Therapy, Journal of Molecular Psychiatry, 2016
Any successful Alzheimer’s Disease (AD) therapy … must include the removal of any type of environmental toxin that might inhibit AHN and entertain and aggravate the disease process.
* AHN is Adult Hippocampal Neurogenesis, the ongoing formation of nerve tissue in the brain’s hippocampus from stem cells, throughout life, which I didn’t even know we could do.
Here’s the list of the chemicals they say we should limit our exposure to, and why:
Tobacco smoke diminishes AHN and promotes gliogenesis in rats . Hence, heavy smokers (2 packs a day) have a 2.6 fold increased AD risk . But also electronic cigarettes, even if they would only contain nicotine as an ingredient (which they do not), are unhealthy and most likely AD-promoting, as nicotine impairs neurogenesis and plasticity of hippocampal neurons .
Alcohol intake of two drinks or more per day accelerates AD by about 2 to 3 years and, when combined with heavy smoking (20 cigarettes per day) by about 4 to 6 years. And for those, carrying an ApoE4 allele, which aggravates the consequences of unhealthy lifestyle choices (as detailed above), the onset of AD is on average 10 years earlier . High alcohol intake was shown to efficiently block AHN in an non-human primate model, with the effect lasted for 2 months even after alcohol discontinuation . The lasting alcohol-induced reduction in AHN paralleled an increase in neural degeneration by nonapoptotic mechanisms. Interestingly, abstaining from alcohol was also seen as a risk factor in the past , but this finding has not been confirmed . Hence, drinking small amounts of alcohol might not be statistically harmful, but most likely does not decrease the risk of developing AD.
Trans fatty acids (TFAs), either from processed food (fried products and many fast-food sources) or from whole-fat dairy and ruminant meat products are implicated in AD . Both sources were shown to equally efficiently increase low density lipoprotein (LDL)-cholesterol  and cause negative health effects . TFAs drive the mortality risk from cardiovascular diseases  and increase the rates of cognitive decline in the elderly, again, irrespective of the source [510, 511]. Epidemiological studies starting with healthy participants showed that TFAs raise insulin resistance, blood pressure and cause also chronic inflammation , all well accepted causal risk factors for AD. Furthermore, TFAs inhibit the conversion of n-3 PUFAs into DHA, limiting their accumulation in the brain . DHA depletion has been shown to result in decreased BDNF levels , in impeded productive AHN  and in neuroinflammation . A recent in-vitro study provided convincing evidence that TFAs increase amyloidogenic processing of the amyloid precursor protein (APP), resulting in an overproduction of Aβ . Moreover, TFAs were shown to enhance the oligomerization and aggregation of Aβ. Taken together, high intake of TFAs, independent of the source, might increase the AD risk by many avenues, also causing an earlier onset of the disease.
Nitrosamines cause deficits in motor function and spatial learning, as well as neurodegeneration characterized by lipid peroxidation, increased levels of Aβ and p-tau, neuroinflammation and neuronal insulin resistance . Nitrosamines are found in tobacco smoke. Significant levels of nitrosamines are also produced from nitrites and secondary amines found in many products, like processed meat and cheese preserved with nitrite pickling salt. This is another reason to avoid (mass produced) meat or cheese products.
Bisphenol A (BPA) leads to unwanted hormonal activity and was shown to impair AHN, spatial learning and memory . BPA is found in a variety of common consumer goods like water bottles. Epoxy resins containing BPA are used to line water pipes and for coatings on the inside of many food and beverage cans. Exposure to other bisphenols (B-Z) that are used as replacements (in order to advertise BPA-free products) show similar detrimental effects . Hence BPA-free products are not necessarily safer and support the removal of all bisphenols from consumer merchandise .
Pesticides: Roundup (a glyphosate-based herbicide) was recently shown to increase the lipid-peroxidation, glutamate excitotoxicity and oxidative damage in the hippocampus . The widely used pyrethroid pesticide deltamethrin induces apoptotic signalling in the hippocampus and impairs AHN . Similar effects were observed for Carbofuran, a carbamate pesticide . These neurotoxic effect of widely used chemicals in conventional agriculture argues for the use of organic produced products for the prevention and the treatment of AD .
Aluminium might act as an accelerator of the progression of . Aluminium enhances pro-apoptotic signalling, reduces BDNF in the hippocampus and negatively affects spatial learning in animal models. In fact, every biochemical function in brain cells appears to be affected by aluminium (reviewed in ). In addition, aluminium may play crucial roles as a cross-linker in Aβ oligomerization . Taken together, aluminium exposure should be avoided in prevention and treatment of AD.
Methylmercury (MeHg) competes with selenium for its enzymatic binding sites and acts as a highly specific and irreversible inhibitor of selenoenzymes, which are required to prevent and even reverse oxidative damage throughout the body, in particular the nervous system. Inhibition of selenoenzymes appears to be the proximal cause of the pathological effects known to accompany MeHg toxicity . Dietary selenium intake is inversely related to vulnerability to methylmercury (MeHg) toxicity, which explains why maternal ingestion of foods that contain MeHg in molar excess of Se has adverse child outcomes, whereas eating MeHg-containing but selenium-rich ocean fish results in improved child IQs . Similarly, MeHg intake impairs hippocampal development and AHN  and is associated with delay in cognitive development  and AD . Nevertheless, a recent study showed seafood consumption was associated with less AD neuropathology despite the increased mercury levels . This controversial result might be explained by the fact that both DHA and selenium are contained in high concentration in seafood. Interestingly, in this study, ApoE4 carriers profited most of high seafood intake, or conversely, ApoE4 carriers are more harmed by a deficit in DHA and/or selenium consumption. Taken together, a diet low in MeHg is advised, but at least as important is a diet that keeps selenium and n-3 PUFAs (DHA and EPA) levels sufficiently high.
Iron is essential for many metabolic processes, but, when left unregulated, is implicated as a potent catalyst of reactive oxygen species generation. Iron complexes with ferritin, the major cellular storage of this transition metal . As outlined above, increased ferritin levels in the cerebrospinal fluid (CSF) are negatively associated with cognitive performance and predicted speed of MCI conversion to AD. Since ApoE4 (in contrast to ApoE2 and ApoE3) enhances iron uptake into the brain , carriers who consume large amounts of iron-rich animal products are particularly susceptible to elevated brain iron, enhanced ROS production and AD progression. This might be one of the reasons, why a diet low in animal products reduces AD risk; and pesco-vegetarians have the lowest mortality when compared to other common diets . Individuals with MCI and high CSF-ferritin levels might delay conversion to AD by as much as 3 years by taking a chelating drug like deferiprone , according to the authors of the above mentioned CSF-ferritin-study. An alternative option with less side effects is treatment with α-lipoic acid (ALA) , which was shown to be highly effective in reversing oxidative stress arising from iron overload . Due to the multitude of additional useful properties of ALA for the treatment of AD, ALA will be part of a therapeutic scheme suggested below.
Copper like iron is an essential element for human growth and development. And likewise, excessive intake which leads to free copper contributes to neurotoxicity and impaired spatial memory by specific changes in the expression of synaptic proteins and hippocampal signalling pathways, which causes oxidative stress and neuronal apoptosis . Inorganic copper from drinking water can be directly absorbed and elevate the serum free copper pool, thereby attributing to AD progression . In case of high free copper levels, three regimens are advised: (1) Avoiding water contaminated with copper and supplements, (2) restoring normal zinc levels, as it was shown that elevating zinc levels significantly reduced serum free copper in AD patients  and (3) treatment with free copper-lowering ALA , as will be discussed in more detail below.
Medications: Use of gastric acid inhibitor was significantly associated with the presence of vitamin B12 deficiency , a risk factor for AD. Meanwhile, it was found that these drugs increase the levels of Aβ in the brains of mice and are association with an increased risk of dementia in humans . Increases in incident dementia are associated with long-term use (over three years) of anticholinergic drugs like for example the tricyclic antidepressant doxepin, the antihistamines chlorpheniramine and diphenhydramine, and bladder control drugs like for instance oxybutynin . A case–control study showed an association between the use of benzodiazepines (used for sleep and anxiety control) and the risk of AD . A recent study provided evidence that memory and hippocampal architecture of WeDi-treated rats was particularly vulnerable to short-term treatment with the benzodiazepine midazolam . Again, this short number of examples must suffice to show that there is always the chance that artificial chemicals like many commonly used drugs might interfere with the complex pathomechanisms outlined by the UTAD, thereby increasing AD risk.
I didn’t know that eating dairy and red meat inhibits the conversion of omega-3 PUFAs (short-chain, like in flax seed) into DHA (long chain, like in fish oil), and that it is the trans fatty acids in them which does this. You would need to control for meat-and-dairy eating, and for other sources of trans fats, if you wanted to investigate this conversion. I haven’t seen that done.
Many of these substances (iron, mercury, pesticides, nitrosamines, trans fatty acids) are found in higher amounts in diets that contain a lot of animal foods. Perhaps that is why “a diet low in animal products reduces AD risk.”
This is a great list. We need a public health campaign that seeks to limit exposure to these substances if we are to stem the rising tide of brain diseases. Let us hope that our new President prioritizes this effort.
Another reason this is a great list is that it’s current. For instance:
Manufacturers love to claim “BPA-free!” It’s meaningless.
As a follow up to this older post, does it make sense to switch to a deodorant without aluminum? I’m curious what environmental precautions you take such as avoiding plastics, beyond eating plant-based?
This tiny 2-person study says that aluminum in antiperspirants is poorly absorbed through the skin. Aluminum from food is a bigger contributor. https://www.ncbi.nlm.nih.gov/pubmed/11267710
Sweating seems to be a good route for aluminum disposal. https://www.ncbi.nlm.nih.gov/pubmed/24239230
Even if you do absorb aluminum through the skin, it probably isn’t much (compared to food/drink), you can get rid of some aluminum via kidneys and sweat, and … the contribution of aluminum to Alzheimer’s is still debated.
There was a recent study that found a link between high blood pressure and Alzheimer’s:
When it comes to dementia, I think there’s a lot to recommend a plant-based diet and regular aerobic exercise, and a lot to discourage alcohol and smoking. I think these are bigger players.
Thank you! While I follow a PBD and low/no alcohol, I find gym-based aerobic exercise tedious and don’t live in a walkable or safely bikeable area. Maybe I will look into a treadmill desk like Dr. Greger.
I’ve been reading about jumping rope. It’s supposed to work both upper and lower body, great for heart and bones and balance and coordination. Exercises the brain because you have to be aware of where your body is relative to the rope. Good for posture. Lower impact than jogging.
I’m going to experiment jumping without a rope to see if it’s something I’ll do. I’ll start off at maybe 50 jumps, or maybe 1 minute.
This looked like a nice beginner’s video: