Alzheimer’s disease is an age-related, debilitating progressive disease and is the most common cause of senile dementia. It has been described as “the single most significant health and social crisis in the 21st-century” (1). The world Alzheimer report (2) of 2015 noted that globally there were 46.8 million cases of dementia at a cost of USD 818 billion. The incidence is estimated to be 74.7 globally in 2030 at a cost of USD 2 trillion. By 2050 the number of cases anticipated to rise by 68 percent on the 2015 figure with much of this increase found in low and middle-income countries.
Type 3 Diabetes
Alzheimer’s disease is sometimes termed Type 3 diabetes. It is certainly true that patients with advanced Alzheimer’s disease have very low brain insulin levels. Type 2 diabetes will cause brain insulin resistance, oxidative stress and cognitive impairment, but does not explain the full range of symptoms – hence the term type 3 diabetes (3). While age and genetics are undoubtedly the key risk factors for the disease, factors relating to diet, modern life style and metabolic syndrome may also be very important.
One of the hallmarks of the pathology of Alzheimer’s disease is the formation of neurotoxic beta amyloid plaques. Amyloid beta monomers are produced when two enzymes (beta-secretase and gamma-secretase) cleave amyloid precursor protein (APP) in the neurons. The resulting amyloid beta is then released into brain tissue. It is thought that a specific amyloid beta 42 (AB42)(an amino acid form of amyloid beta) is responsible for the neurotoxic effects. In the healthy brain, amyloid protein acts to help any injury to the brain. However, in Alzheimer’s disease the beta-amyloid monomer miss-folds to produce a beta-amyloid oligomer that is neurotoxic. This mechanism is one of the main targets of pharmaceutical intervention research. Unfortunately, currently licensed drugs only increase levels of the neurotransmitter acetylcholine but have no effect on beta amyloid. Another treatment uses NMDA receptor antagonists (e.g. memantine) which can temporarily improve long term memory in moderate to severe Alzheimer’s patients by increasing the activity of glutamate receptors on the post synaptic neurons.
Tramiprosate (3-amino propane sulphonic acid)
An interesting new discovery is that a small molecule called tramiprosate (3-amino propane sulphonic acid) is able to prevent the miss folding of the amyloid monomer protein. Unusually, the mechanism of action is that the tramiprosate prevents the shape modulation by forming a protective envelope around the native amyloid structure (4). In 2016, phase one trials with a monoclonal antibody treatment called aducanumab were shown to significantly reduce levels of the neurotoxic beta-amyloid oligomer and improve cognition. The drug is now being used in two phase three trials involving a total of 2,700 patients and are due to be completed in 2020 (5). Sadly, another monoclonal antibody treatment, solanezumab, recently failed phase three trials, although it did show improvements in cognition. However, unlike aducanumab, solanezumab only targeted monomeric amyloid beta and not the amyloid oligomers and clumps.
The presence of toxic clumps of amyloid oligomers has been found in brains of individuals as young as 20 years (6).
Another molecular target in the treatment of Alzheimer’s disease is a protein called phosphorylated tau, which binds to structures called microtubules within neurons. The resulting neurofibrillary tangles cause dysfunction of the synapse and eventual death of the neuron. A vaccine has been developed (ACI-35) that stimulates the immune system to produce antibodies that specifically target the tau proteins (5).
Some diets may potentially be able to delay the onset. Observational studies (including the 3C in France) have shown that a high adherence to a Mediterranean diet is able to support cognitive health. In addition, researchers have demonstrated that the omega-3 fatty acids DHA and EPA (not ALA) might support cognitive health (7). An individual’s genetic phenotype, specifically whether or not they possess a pair of the aPoE4 alleles, is an important determinant of the potential beneficial efficacy of such a diet.
Mild Cognitive Impairment (MCI)
The onset of mild cognitive impairment is accompanied by a rise in blood homocysteine levels. Homocysteine is produced within cells from methionine. High levels of blood methionine are widely accepted as a risk factor for the onset of dementia. The rate of cellular production of homocysteine can be reduced if folic acid, vitamin B6 and vitamin B12 are present (8). Prospective studies that increased levels of homocysteine are associated with structural damage to the aging brain, specially damage to white matter microstructure, increased density of neurofibrillary tangles and rates of total brain atrophy. A meta-analysis conducted in 2014 attributed a 22 percent increased risk of the onset of Alzheimer’s disease in healthy elderly with raised homocysteine levels (9). The degree of brain atrophy appears to correlate with homocysteine levels in the elderly, but a recent study using magnetic resonance imaging has shown that B vitamins can support certain key brain structures (10).
The marine omega-3 fatty acid DHA is an important structural component of nerve cells. The levels of DHA in the brain depend on dietary intake. A recent meta-analysis of 12 population studies, including 154,711 participants indicated that an intake of DHA of 0.1g per day significantly reduced the risk of onset of dementia (RR=0.86 ) and Alzheimer’s (RR=0.63), though there did not appear to be a dose response relationship (11). DHA can be metabolized into the oxylipin Neuroprotectin D1 (NPD1), which has been shown to be protective to brain cells exposed to beta amyloid beta 42 oligomers (12).
DHA has been shown to reduce the quantity of both beta amyloid oligomer clumps and neurofibrillary tau protein in Transgenic Alzheimer’s diseased mice (Tg2576) (13). In vitro, DHA has been shown to stabilize amyloid beta 42 monomer in solution, thus hindering any conversion into insoluble aggregates/plaques (14).
Alzheimer’s disease is usually preceded by MCI. In 2010, a report was published on a large, multicentre study with an intervention of 2 g of DHA for 18 months in 400 American Alzheimer’s patients (15). While no benefits could be perceived in the total study population, subset analysis showed that those participants without the ApoE4 gene (some 40 percent of Alzheimer’s patients and 80 percent of general population) had a slower rate of mental function decline.
Jerneren et al. (16) looked retrospectively at the effects of circulating plasma EPA and DHA levels in the VITACOG cohort (17). The VITACOG cohort consisted of 133 individuals aged 70 years or older receiving an intervention of B vitamins. It was shown that the optimal utilization and distribution of marine omega-3 fatty acids requires sufficient B vitamin status and low homocysteine levels (1). Jerneren et al. (18) were able to show that the beneficial effects of B vitamins in reducing brain atrophy were strongly dependent on the patients’ omega-3 status. The tertile with the highest marine omega-3 plasma concentrations (˃590 µmol/L) showed a reduction in atrophy rate of 40 percent in comparison with the placebo group. The subjects in the tertile with the lowest baseline marine omega-3 concentrations (˂390 µmol/L) did not achieve any reduction in the rate of brain shrinkage from the B vitamin supplementation. Alzheimer’s patients become deficient in the phosphatidylcholine (PC) forms of DHA (19). Interestingly, this PC-DHA form is normally generated by the sequential methylation of phosphatidylethanolamine, a process requiring B vitamins.
Antioxidant vitamins may also support cognitive health. The brain has higher vitamin C content than any other organ. Vitamin C is essential for the synthesis of the neurotransmitters dopamine and noradrenaline. Ascorbate may also act as an antioxidant protecting neurons against oxidative stress, particularly because it also is needed for recycling vitamin E to its antioxidant form. Vitamin E is important for proper neuronal functioning and its deficiency leads primarily to neurological dysfunction such as spinocerebellar ataxia and dysarthria. As a potent antioxidant, a free radical scavenger and a constituent of neuronal membranes, vitamin E prevents the oxidation of lipids and fatty acids (20).
This review demonstrates that adjunctive therapy with micronutrients may prove to be beneficial in supporting brain health within an aging population.
Upcoming Event: a conference examining the effect of long-chain polyunsaturated fatty acids (LC-PUFAs) with regard to Alzheimer’s disease will be held in Nancy, France from October 8-11, 2017 https://lipidsandbrain.event.univ-lorraine.fr.