Category Archives: Alzheimer Disease

“A 2017 analysis combined results of 27 studies that looked at the relationship between sleep and cognitive problems, including Alzheimer’s. Overall, poor sleepers appeared to have about a 68 percent higher risk of these disorders than those who were rested, researchers reported last year in Sleep. That said, most studies have a chicken-and-egg problem. Alzheimer’s is known to cause difficulty sleeping. If Alzheimer’s both affects sleep and is affected by it, which comes first?For now, the direction and the strength of the cause-and-effect arrow remain unclear. But approximately one-third of U.S. adults are considered sleep deprived (getting less than seven hours of sleep a night) and Alzheimer’s is expected to strike almost 14 million U.S. adults by 2050 (5.7 million have the disease today). The research has the potential to make a big difference.”

Source: The brain may clean out Alzheimer’s plaques during sleep | Science News

Dead whole fish aren’t very appealing to many folks

I advocate consumption of cold-water fatty fish a couple times per week for long-term protection against heart and brain disease. The protective component of fish may be the omega-3 fatty acids.

On the other hand, much seafood is contaminated with mercury, which can be toxic. So, is the mercury in fish actually toxic to brain tissue of folks eating reasonable amounts of fish?

A recent autopsy study answers, “No.”

Read further for details.

Much more appetizing!

From the Journal of the American Medical Association, 2016 Feb 2;315(5):489-97. doi: 10.1001/jama.2015.19451. “Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults.”

IMPORTANCE:Seafood consumption is promoted for its many health benefits even though its contamination by mercury, a known neurotoxin, is a growing concern.

OBJECTIVE:To determine whether seafood consumption is correlated with increased brain mercury levels and also whether seafood consumption or brain mercury levels are correlated with brain neuropathologies.

DESIGN, SETTING, AND PARTICIPANTS:Cross-sectional analyses of deceased participants in the Memory and Aging Project clinical neuropathological cohort study, 2004-2013. Participants resided in Chicago retirement communities and subsidized housing. The study included 286 autopsied brains of 554 deceased participants (51.6%). The mean (SD) age at death was 89.9 (6.1) years, 67% (193) were women, and the mean (SD) educational attainment was 14.6 (2.7) years.

EXPOSURES:Seafood intake was first measured by a food frequency questionnaire at a mean of 4.5 years before death.

MAIN OUTCOMES AND MEASURES:Dementia-related pathologies assessed were Alzheimer disease, Lewy bodies, and the number of macroinfarcts and microinfarcts. Dietary consumption of seafood and n-3 fatty acids was annually assessed by a food frequency questionnaire in the years before death. Tissue concentrations of mercury and selenium were measured using instrumental neutron activation analyses.RESULTS:Among the 286 autopsied brains of 544 participants, brain mercury levels were positively correlated with the number of seafood meals consumed per week (ρ = 0.16; P = .02). In models adjusted for age, sex, education, and total energy intake, seafood consumption (≥ 1 meal[s]/week) was significantly correlated with less Alzheimer disease pathology including lower density of neuritic plaques (β = -0.69 score units [95% CI, -1.34 to -0.04]), less severe and widespread neurofibrillary tangles (β = -0.77 score units [95% CI, -1.52 to -0.02]), and lower neuropathologically defined Alzheimer disease (β = -0.53 score units [95% CI, -0.96 to -0.10]) but only among apolipoprotein E (APOE ε4) carriers. Higher intake levels of α-linolenic acid (18:3 n-3) were correlated with lower odds of cerebral macroinfarctions (odds ratio for tertiles 3 vs 1, 0.51 [95% CI, 0.27 to 0.94]). Fish oil supplementation had no statistically significant correlation with any neuropathologic marker. Higher brain concentrations of mercury were not significantly correlated with increased levels of brain neuropathology.

CONCLUSIONS AND RELEVANCE:In cross-sectional analyses, moderate seafood consumption was correlated with lesser Alzheimer disease neuropathology. Although seafood consumption was also correlated with higher brain levels of mercury, these levels were not correlated with brain neuropathology.

Source: Association of Seafood Consumption, Brain Mercury Level, and APOE ε4 Status With Brain Neuropathology in Older Adults. – PubMed – NCBI

The following excerpt is boring, so move along now. It’s from a recent review article on all the potential causes and therapeutic options for Alzheimer’s Disease (AD). I post it here so I can find it later. Click the link at bottom to RTWT.

“Lithium is not yet generally recognized as a trace element but several lines of evidence make it a strong candidate. For instance, long-term low-dose exposure to lithium exerts anti-aging capabilities and unambiguously decreases mortality in animal models. In humans, epidemiological studies indicate an inverse correlation between lithium concentration in drinking water and mood, depression and suicide rates, amongst other psychiatric conditions. In a study that compared elderly bipolar patients (who exhibit a higher risk for dementia) who had received chronic lithium treatment, with bipolar patients who had not received lithium, it was shown that the prevalence of the treated group was equivalent to the general, age-comparable population, whereas the non-lithium-treated patients had an incidence of dementia that was six times greater, i.e. 5 % vs. 33 %, respectively. In another study it was shown that lithium treatment resulted in an increase in volumes of the hippocampi in both hemispheres compared to an unmedicated group, an effect that was apparent even after a brief treatment period of about 4 weeks on average. Importantly, intake of lithium not only in standard therapeutic but also in trace doses reduces the risk for dementia, suicide, and other behavioural outcomes, suggesting an pharmacological interference with key regulators of these pathological processes. So, lithium naturally regulates critical cell signalling pathways and a lack of lithium in the diet can therefore cause increased disease risk.It has been shown that lithium modulates negatively the activity of the two kinases GSK-3α and GSK-3β, which might explain both the relative specificity and sensitivity of the effects of low-dose lithium treatment (see below). Since GSK-3β-activation by oligomeric Aβ promotes neuroinflammation, phosphorylation of tau and disturbance of AHN [adult hippocampal neurogenesis], all key mechanisms in the AD process, in inhibition of GSK-3 by lithium results in reduced tauopathy and neurodegeneration in vivo. Likewise, lithium treatment was shown to improve AHN, neuropathology and cognitive functions in a mouse model of AD. Furthermore, such “AD-mice” treated from two months of age had decreased numbers of senile plaques, no neuronal loss in cortex and hippocampus and increased BDNF levels when compared to non-treated transgenic mice. In order to achieve this effect, it was sufficient to give lithium at about one per mill of the high standard-dose therapy in bipolar disorder, a dose which can cause some significant side effects. Hence the authors of the study believe that their data support the use of (virtually side-effect free) microdose lithium in the prevention and treatment of Alzheimer’s disease.Indeed, long-term lithium treatment already provided preliminary evidence of its disease-modifying properties for amnestic MCI [mild cognitive impairment] in a randomised controlled trial, where the lithium-treated group had fewer conversions from MCI to AD. Lithium treatment was associated with a significant decrease in cerebrospinal fluid concentrations of hyperphosphorylated tau and better performance on the cognitive subscale of the Alzheimer’s Disease Assessment Scale and in attention tasks. At a more advanced stage of AD, microdose treatment with only 300 μg lithium administered once daily stabilized the AD patients during the complete evaluation phase of 15 months. For instance, whereas the treated group showed no decreased performance in the mini-mental state examination (MMSE), lower scores were observed for the control group during the same period, with significant differences occurring after three months, and increasing progressively.Importantly, lithium, besides being required for efficient AHN and blocking AD-specific pathological processes, also impacts on cell-rejuvenating autophagy. Lithium was found to inhibit the activity of inositol monophosphatase (IMPase), which leads to a decrease of myo-1, 4, 5-triphosphate (IP3). This reduction of IP3-activity induces autophagy, independent of mTOR. In this context it is important to note that lithium chloride extends the lifespan of the nematode Caenorhabditis elegans, possibly by means of mitochondrial rejuvenation, which suggests that lithium exerts its effects on evolutionary highly conserved mechanisms. Intake of drinking water with comparable low lithium concentrations were found to be inversely correlated with all-cause mortality in a large epidemiological study in Japan. Hence a lack of lithium is linking aging and frailty (all increasing mortality) to disturbed autophagy, and AD to impaired AHN, and, thus, might represent another important and modifiable risk factor in this neurodegenerative disease. Traces of lithium can be ingested in some geographic areas by drinking local tap water or otherwise by consuming commercially available, mineral-rich spring waters, containing suitable concentrations of around 1 mg lithium per litre. Hence microdose lithium intake by means of one or two glasses of such water a day is not only of potential therapeutic value (see below) but also a safe preventive measure, by means of simply reducing an intake-deficit of an important novel trace element.”

Source: Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy

Bonus excerpt:

“Taken together, besides the importance of IMF and physical exercise, also dietary MCTGs [medium-chain trigylcerides] can be an attractive (indirect) source of ketone bodies during the non-fasting state. The intake of coconut oil as a healthy source of MCTGs has additional positive effects on neuronal insulin resistance, neuroinflammation as well as Aβ-toxicity, improves the LDL/HDL-cholesterol quotient by increasing HDL, and ameliorates several others key progression factors of AD. Hence the use of virgin coconut oil is highly recommended as a safe and healthy alternative for polyunsaturated oils for frying and baking and butter and an important part of a comprehensive strategy for the prevention and treatment of AD.”

No need to read the following. It’ll likely bore you to death. I record it here for my own purposes. Alzheimer’s Disease is a huge problem and we desperately need ways to prevent and cure it. Prevention should be easier than cure. BTW, the Mediterranean diet is linked to lower risk of Alzheimer’s Disease.

“The master regulator/inhibitor of autophagy is the mammalian target of rapamycin (mTOR). This intracellular kinase functions as a key signalling node that integrates information regarding extracellular growth factor stimulation, nutrient availability and energy supplies. The fungal metabolite rapamycin was accidently found to block mTOR and became not only the eponym of mTOR but also the main molecular tool to dissect mTOR-function. Rapamycin treatment was found to activate autophagy by inhibiting mTOR, thereby slowing down both aging and cognitive decline of caged mice, suggesting that inefficient autophagy as part of the NRJ-program might be a central element of both processes. Conversely, caging (standard housing) might eliminate an important behavioural cues (like for instance physical activity or intermittent fasting, see below), which leads to unnaturally high activity of mTOR and low activity of peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), the master controller of mitochondrogenesis (see below), thereby inhibiting neuron-rejuvenating and protecting autophagy. Hence the observed aging and cognitive decline in murine models of AD might be regarded as artificial and not reflecting the aging process under natural conditions.

Other behavioural cues that inactivate mTOR are, besides physical exercise, which was shown to promote autophagy of defunct organelles and macromolecules in the brain, chronic caloric restriction (CCR), which is well known to delay aging and extend life-span in essentially all eukaryotic organism. But is CCR a physiological cue or rather an artefact of experimental research that simulates, to some extent, a more natural dietary pattern, namely intermittent fasting (IMF), which from an evolutionary point of view is more natural (see below)? But IMF is experimentally more labour-intensive than CCR and therefore less well studied. Nevertheless, autophagy and in particular mitophagy was found to being activated by CCR through inhibition of mTOR in essentially all species investigated, ranging from yeast, to flies, worms, fish, rodents and even to rhesus monkeys [87], thereby decelerating mTOR-driven aging. CCR not only extends lifespan, it also protects the central nervous system from neurodegenerative disorders, whereas excessive caloric intake is clearly associated with accelerated aging of the brain and increased the risk of neurodegenerative disorders due to suppressed autophagy.

Nevertheless, IMF was shown to create a more robust and steady inhibition of mTOR-accelerated aging and cognitive decline when compared to CCR. This is explained by the fact that the main hormone-like signalling molecules of the metabolic status during IMF, the ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βOHB), are more efficiently generated during fasting than by CCR. These two respiratory fuels can endogenously be produced by the liver in large quantities (up to 150 g/day) from mobilized fatty acids in a variety of physiological or pathological conditions. In humans, basal serum levels of βOHB are in the low micromolar range, but rise up to several hundred micromole after 12 to 16 h of fasting. Importantly, when blood glucose and insulin are low, up to 60 % of the brain energy needs can be derived from ketone bodies, replacing glucose as its primary fuel. Similar high levels of up to 1 to 2 millimole βOHB are reached after prolonged endurance exercise. A physiologically relevant increase in ketone body production is already achieved by fasting overnight, which can even be enhanced if we are physically active before breaking the fasting in the morning. This most likely mimics the situation that faced our foraging ancestors who went out for hunting or gathering food with their stomachs empty.

Since neither long- nor medium-chain saturated fatty acids can pass the BBB, only their transformation into ketone bodies allows our energy-demanding brain to access the largest energy store, our adipose tissue. In fact, ketone body production reduces glucose requirement and preserves gluconeogenic protein stores during fasting, which enables a profound increase in the capacity for survival. Interestingly and again in line with the GMH, elderly generate ketone bodies at least as efficient as younger adults during IMF and the metabolic response to a ketogenic diet appears also to be unaffected by aging.As hinted at above, the observation that IMF is superior to CCR makes also a lot of sense from an evolutionary perspective, as not chronic starvation but rather periodic alteration between fasting and intake of high-caloric meals after successful foraging was ancient normality. Importantly, recent evidence suggests that our phylogenetically conserved genetic program uses the metabolic changes that originate from intermittent fasting (IMF) as a behavioural cue of for [sic] the initiation of subcellular renewal. This is a good thing, since in order to maintain cellular youth, we do not have to starve by CCR. It is sufficient to alternate phases of fasting, which just need to be sufficiently long to induce ketone body production (for instance 12 h overnight) and phases of eating, in which the total energy demand of our body can be met. In contrast, current normality consists of constant feeding pattern, which results in permanent high mTOR activity (and low PGC-1α-levels, see below), which suppresses cellular rejuvenation. A sedentary lifestyle aggravates this pro-aging effect, whereas prolonged physical exercise reduces mTOR-activity, possibly also by increasing ketone body production.”

Source: Unified theory of Alzheimer’s disease (UTAD): implications for prevention and curative therapy