About Alzheimer’s disease
What could be worse than losing your mind, while your body has many years to run? Yet, that is precisely what happens to three in ten people over the age of 70. In Europe alone 1 million people develop impaired memory every year, more than half of which will be later diagnosed with dementia. About 70% of dementia is really Alzheimer’s Disease (diagnosed by a brain scan) with cerebrovascular dementia (a circulation disease) accounting for most other cases. Currently in Britain more than half a million people suffer from Alzheimer’s Disease (AD), costing the National Health Service 23 billion a year. With an ever-ageing population, the prediction is that, by 2030, 20 per cent of people over 65, more than a million people in the UK, will have dementia or AD, the first symptoms of which are depression, irritability, confusion and forgetfulness. In the US the prediction is 13 million sufferers by 2050, according to the National Institute of Health, and 100 million worldwide.
It had previously been thought that age-related cognitive decline began for most people in their 60s. However, a recent research study , which tested the cognitive functions of 7,390 UK civil servants aged 45 to 70 over a 10 year period, found that people started to see a reduction in their memory, vocabulary and comprehension skills from their 40s.
That’s the bad news. The good news is that a number of encouraging research avenues indicate that dementia and Alzheimer’s could be prevented, and possibly halted in the early stages by a comprehensive optimum nutrition approach. One of the reasons this is likely is that only one in a hundred cases of Alzheimer’s is caused by genes. We also know that new brain cells are being made all the time, even in old age and, under the right conditions, new brain cell growth can be encouraged. Current research is focusing on how to encourage not only neurone growth, but also how to enhance the formation of new dendrite connections. But the most exciting frontier is improving your nutrition to prevent memory decline in the first place.
What causes Alzheimer’s?
AD is a complex disease without a single cause, but with many contributors. Many researchers are now converging on the understanding that it is a degenerative inflammatory disease that damages a particular part of the brain called the Medial Temporal Lobe. This may be largely due to the long-term consequence of faulty nutrition plus certain negative lifestyle factors, much like cardiovascular disease, and that any long-term solution must involve fundamental changes to a person’s diet.
The contributing factors may include:
- Raised homocysteine and a lack of B vitamins
- Lack of omega-3 fats
- Metabolic syndrome, insulin resistance, disglycemia and diabetes
- Excessive stress and the stress hormone cortisol
- Acetylcholine and precursor deficiency
- Lack of antioxidant nutrients
- A genetic predisposition
- A lack of an active lifestyle, including physical and mental exercise.
The strongest evidence to date relates to raised homocysteine levels, which both predicts risk and can cause the kind of brain damage seen in Alzheimer’s, caused by lack of B vitamins, especially B12 which is increasingly poorly absorbed with age.
How is your memory and concentration?
Rather than wrongly assuming that failing memory and concentration is an inevitable part of the ageing process it’s better to get tested using our free on line Cognitive Function Test, validated for anyone over the age of 50. This tests all the critical cognitive functions that can decline with age, and tells you what to do about it to reduce age-related cognitive decline. For reasons explained below, if your cognitive function tests below par it is vital to have a homocysteine blood test, available from your doctor or from a private clinic.
Test your memory
Our 15 min cognitive function test can help you identify early signs of cognitive decline, as well as give some personalised dietary and lifestyle guidance to help you take positive steps to prevent Alzheimer’s.
Diet and Nutrition; what works?
Homocysteine and B vitamins
The single, hottest nutritional discovery is that your risk of developing Alzheimer’s is strongly linked to your level of the toxic amino acid homocysteine, which can be measured from a pinprick of blood on a home test kit. The lower your level throughout life, the smaller your chances of developing serious memory decline. Homocysteine is a neurotoxin, capable of directly damaging the medial temporal lobe, which is the area of the brain that rapidly degenerates in AD. Homocysteine is easily lowered with inexpensive B vitamins.
One of the first important studies, published in 2002 in the New England Journal of Medicine, charted the health of 1,092 elderly people without dementia, and measured their homocysteine levels. (1) Eight years later, 111 were diagnosed with dementia, 83 of whom were given the diagnosis of Alzheimer’s. Those with high blood homocysteine levels (above 14 units) had nearly double the risk of Alzheimer’s. There’s also evidence that even before a decline in mental function starts to show up in so-called “healthy” elderly individuals, high homocysteine predicts physical degeneration in certain parts of the brain.
In Scotland, researchers have found that reduced mental performance in old age is strongly associated with high homocysteine and low levels of vitamins B12 and folic acid. Following up participants in the Scottish Mental Surveys of 1932 and 1947, which surveyed childhood intelligence, they found that the most mentally agile had the highest levels of B vitamins and lowest levels of homocysteine; high homocysteine was linked with a 7 to 8 per cent decline in mental performance (2).
A similar Californian study, asked 579 men and women aged 60 and over to keep track of their diet and the supplements they took (3). After nine years, 57 of them developed Alzheimer’s. Those with the highest folate intake, reduced their risk of developing Alzheimer’s by 55 per cent .
A research group led by Dr Teodoro Bottiglieri at the Baylor University Metabolic Disease Center in Dallas, Texas, suggested that low levels of folic acid (which leads to raised homocysteine) may cause brain damage that triggers dementia and Alzheimer’s. Their research has found that one-third of those with both dementia and homocysteine levels above 14 units were deficient in folic acid (4).
Both high homocysteine levels, and low folic acid and B12 levels in blood correlate very well with increasing risk for Alzheimer’s according to a systematic review (5). Another review, in 2008, concludes that of ‘Seventy-seven cross-sectional studies on more than 34,000 subjects and 33 prospective studies on more than 12,000 subjects have shown associations between cognitive deficit or dementia and homocysteine and/or B vitamins’ (6). Homocysteine levels also predict and correlate with rate of cognitive decline (7) as does B12 status (8). There is, therefore, ample evidence to propose that lowering homocysteine by giving appropriate supplemental levels of homocysteine lowering nutrients, including B6, B12 and folic acid, would reduce risk. The main question being at what point in the process is cognitive decline reversible, and what dosage of nutrients confers maximum protection?
But why would homocysteine, and a lack of these B vitamins, predict cognitive decline? The reason for this link may be that the body needs B vitamins to convert the toxic and brain damaging homocysteine into two very useful chemicals called glutathione – an antioxidant – and the amino acid called SAMe. SAMe is vital for ‘methylation’, which is a key chemical process happening millions of times every second, which keeps the brain’s chemistry in balance.
So the theory makes sense but does supplementing with vitamins prevent, or actually reverse memory loss? A study in Holland gave 818 people aged between 50 and 75 either a vitamin containing 800mcg of folic acid a day – almost three times the RDA and the equivalent of 2.5 pounds of strawberries – or a dummy pill (9). After three years supplement users had scores on memory tests comparable to people 5.5 years younger. On tests of cognitive speed, the folic acid helped users perform as well as people 1.9 years younger.
Professor David Smith and his group at the Optima Project at the University of Oxford, investigated the effects of giving B vitamins versus placebo to those with mild cognitive impairment, measuring brain shrinkage with an MRI scan, as well as cognitive function (10). In this study the level of homocysteine, above 9.5 mmol/l, correlated with accelerated brain shrinkage and cognitive decline. Those given folic acid (0.8mg/d), vitamin B12 (0.5 mg/d) and B6 (20mg/d) had a significant reduction in the rate of brain shrinkage. The rate of atrophy in participants with homocysteine above 13 mmol/L was 53% lower in the active treatment group. A greater rate of atrophy was associated with a lower final cognitive test scores.
A study from the University of California, gave homocysteine-lowering B vitamins to those already diagnosed as suffering from mild to moderate Alzheimer’s (11). Patients were not selected on the basis of homocysteine values (average Homocysteine was 9.1mmol/l at baseline), and brain scans were not conducted so it wasn’t as robust as the previous Oxford study. The patients received folic acid (5mg/d), B12 (1mg/d), and B6 (25mg/d over a period of 18 months. No overall difference occurred in rate of cognitive decline in those on the supplements versus placebo. However, when the patients were divided into those with high and low cognitive test scores at the start, those who had milder Alzheimer’s did significantly respond; those taking the B vitamins hardly got worse over 15 months, while those on the placebo showed a steady decline. The average drop in homocysteine over the 18 months was from 9.1 to 6.8µmol/l.
To date, the evidence suggests that, in those with raised homocysteine supplementing something in the order of 1,000mcg of folic acid, 20mg of B6 and 500mcg of B12, can help prevent age-related memory loss and brain shrinkage and may even help those in the early stages of Alzheimer’s disease.
These levels of nutrients are a far cry from the RDA levels, especially for vitamin B12. 500mcg is which is 250 times the RDA and much more than you could ever get by eating a well-balanced diet.
Such high amounts are being used for the simple reason that they work. “The lowest dose of oral cyanocobalamin (B12) required to normalize mild vitamin B12 deficiency older people is more than 200 times the recommended dietary allowance,” concludes a paper by scientist at the University of Wageningen in Holland, one of the top B12 research centres in the world (12).
It certainly makes sense to test your homocysteine level and if it is above 9mmol/l to ensure an optimal intake of B6, B12 and folic acid. There are other nutrients that help lower homocysteine notably zinc, trimethyl glycine (TMG – 1000mg – 2,000mg) and N-acetyl cysteine (NAC – 500mg – 1,000mg). There is also evidence that methylated B12 might be a more effective form of this vitamin. The easiest way to achieve an optimal intake of all these nutrients is by taking a homocysteine lowering supplement containing all these nutrients in these kind of doses.
Side effects? Folic acid supplementation, especially in those with low B12 status, may increase colorectal cancer risk in older people (13). Therefore higher doses, above 400mcg a day, should be used with caution especially in countries that have implemented food fortification with folic acid. It is not known whether this contraindication applies in those also supplementing a combination of homocysteine-lowering nutrients with raised homocysteine.
However, supplementing folic acid on its own can mask the symptoms of B12 deficiency. Hence we recommend only supplementing extra folic acid if you also supplement extra vitamin B12.
Contraindications with medication? Certain drugs are anti-folate. If you are on an anti-folate drug you should discuss with your doctor before taking large amounts of folic acid.
Omega-3 fats are most prevalent in carnivorous, cold water fish such as salmon, tuna, herring and mackerel. According to a study by Dr Martha Morris and colleagues at Chicago’s Rush Institute for Healthy Aging, eating fish once a week reduces your risk of developing Alzheimer’s by 60 per cent (14).
The researchers followed 815 people, aged 65 to 94 years, for seven years and found that dietary intake of fish was strongly linked to Alzheimer’s risk. They found that the strongest link was the amount of DHA, a form of omega 3-fat found in fish. The higher a person’s DHA, the lower their risk of developing Alzheimer’s. The lowest amount of DHA per day that offered some protection was 100 mg. While intake of EPA (another omega-3 fat) did not reach significance, the highest intake of EPA consumed was 30 mg a day. That’s much less than you’d get in one serving of oily fish.
A randomized, double-blind, placebo-controlled, clinical study, gave 900mg of DHA a day for 24 weeks and reported an improvement in learning and memory function in those with age-related cognitive decline (15). In a further trial by the same research group, giving 2g/d of DHA or placebo to 402 subjects with mild to moderate Alzheimer’s disease for a period of 18 months found no cognitive improvement (16).
These studies suggest that DHA may help prevent cognitive decline before the development of Alzheimer’s, but don’t help arrest or slow down Alzheimer’s per se. But why exactly might fish have this protective effect? One theory is that it helps to ease brain inflammation, which, in turn damages brain cells. Omega-3 fats are also a vital component of brain cell membranes and help control calcium flow in and out of cells. This is important because too much calcium inside brain cells is known to contribute to the production of the toxic beta-amyloid protein, which is found in excessive levels in most people who develop Alzheimer’s.
Side effects? None reported.
Contraindications with medication? Omega 3 oils, in large amounts, can thin the blood. This is a benefit however if you are already on blood thinning medication you should discuss this with your doctor first.
Inflammatory reactions invariably mean increased production of oxidants, and hence an increased need for antioxidants such as vitamin A, beta-carotene, and vitamins C and E, all of which have been shown to be low in those with Alzheimer’s. Other antioxidants, including cysteine, glutathione, lipoic acid, anthocyanidins, and co-enzyme Q10 and melatonin may also prove important. In simple terms this means eating a lot more fresh fruit and vegetables – at least six portions a day – and oily fish and seeds.
Vitamin E appears to have a protective effect. A study published in the Journal of the American Medical Association (JAMA) found that the risk of developing Alzheimer’s was 67 per cent lower in those with a high dietary intake of vitamin E, versus those with a low intake (17).
A US study gave 633 disease-free 65-year-olds large amounts of either vitamin E or vitamin C. A small number in each group would have been expected to show the signs of AD five years later. None did (18). Vitamin E appears to not only plays a key role in early prevention in this way, but also in slowing down the progression of the disease. In a study reported in the New England Journal of Medicine in 1997, Alzheimer’s patients received either 2,000iu of vitamin E, a MAO inhibitor, or a placebo (19). Vitamin E was shown to reduce progression most significantly. However, there were weaknesses in this study design and, in a replicate trial people with mild cognitive impairment were randomly assigned to receive 2000 IU of vitamin E daily, 10 mg of a mainstream Alzheimer’s medication daily, or placebo for three years. There were no significant differences in the rate of progression to Alzheimer’s disease between the vitamin E and placebo groups at any point (20).
A study of 4740 Cache County Utah elderly residents found use of vitamin E and C (ascorbic acid) supplements only in combination has been associated with reduced Alzheimer’s prevalence of 78% and incidence 63%. A trend toward lower Alzheimer’s risk was also evident in users of vitamin E and multivitamins containing vitamin C, but there was no evidence of a protective effect with use of vitamin E or vitamin C supplements alone, with multivitamins alone, or with vitamin B-complex supplements. Best results were achieved with 1,000mg of vitamin C and 1,000iu of vitamin E (21).
Side effects? None known, however some studies indicate that high intakes from vitamin E supplements (above 300mg) may increase cardiovascular risk. This is almost certainly to do with the fact that cholesterol-lowering statin drugs interfere with vitamin E’s function as an antioxidant, unless you also take Co-Q10. We recommend supplementing vitamin E with Co-enzyme Q10, and ideally in an all-round antioxidant supplement.
Contraindications with medication? Vitamin E, in large amounts above 300mg may thin the blood. This is a benefit, however if you are already on blood thinning medication you should discuss this with your doctor first. Cholesterol-lowering medications interfere with the body’s ability to use vitamin E. If you are on a cholesterol-lowering medication and wish to take vitamin E also supplement 90mg or more of Coenzyme Q10.
Stress, cortisol and memory loss
Under prolonged stress, the body produces the adrenal hormone cortisol. The research of Professor Robert Sapolsky at Stanford University has shown that although cortisol is a powerful anti-inflammatory hormone, raised cortisol can damage the brain (22). In studies with rats he found that two weeks of induced stress causing raised cortisol levels causes dendrites, those connections between brain cells, to shrivel up (23) . He believes that brain cell loss in ageing and Alzheimer’s may be, in part, due to high levels of cortisol and recommends that corticosteroid drugs should not be used in Alzheimer’s patients for other medical problems like asthma or arthritis.
Using a brain imaging technique, Douglas Bremner of Yale University has shown that the part of the brain responsible for learning and memory is smaller in patients with post-traumatic stress disorder, and that this correlates with poorer memory (24). Researchers at the La Sapienza University have shown that cortisol levels are significantly higher in Alzheimer’s patients than in controls, and correlate with the severity of the disease (25). Linda Carlson and colleagues at McGill University in Montreal have confirmed that in Alzheimer’s patients, the higher the cortisol, the worse their memory (26). They also found that the higher the levels of DHEA the better their memory.
Adrenal exhaustion can also lead to a lack of cortisol, which increases inflammation. It’s a question of balance. All this research implies that the ability to create a lifestyle that minimises prolonged stress is also important for reducing Alzheimer’s risk.
Acetylcholine, enhancers and memory
Whatever the contributory causes to the brain damage seen in Alzheimer’s, once the brain damage occurs, there is memory loss. Understanding how that occurs opens up avenues for treatment.
A memory is not held in one, but in several brain cells joined together in a network. The memory itself is thought to be put into storage by the neurotransmitter acetylcholine, and stored by altering the structure of a molecule called RNA within brain cells. The limbic system, which is the ‘doughnut’ on top of the brain stem, then has to decide if the memory is worth keeping. The amygdala, part of the limbic system, decides about more emotional memories, while the hippocampus decides about others. In Alzheimer’s the hippocampus loses its ability to file memories, resulting in an inability to create new ones. People with Alzheimer’s also show marked deficiencies in acetylcholine, no doubt largely because these acetylcholine-producing brain cells have been damaged or destroyed. Even if a memory is intact, without sufficient acetylcholine one cannot connect one part of the memory with others. For example, you know the face but can’t remember the name.
Most currently prescribed medication for dementia and Alzheimer’s block the breakdown or re-uptake of acetylcholine. An alternative approach would be to supplement the nutrients the brain uses to make acetylcholine in the first place (27). The primary precursor nutrient is phosphatidyl choline, the conversion of which is dependent on pantothenic acid (vitamin B5). However, phosphatidyl choline is synthesised from two other phosphatidyl substrates, reactions dependent on good methylation. That’s where B vitamins, zinc and magnesium are needed. While each of these nutrients has demonstrated mild memory-promoting effects the combined therapeutic effect of these ‘acetylcholine friendly’ nutrients has yet to be adequately explored in the prevention or treatment of AD patients.
Also of interest in the amino acid pyroglutamate, from which various nootropic drugs is derived. Early animal research indicated a potential to increase acetylcholine reception (28). A recent meta-analysis of studies demonstrates a difference between those individuals treated with nootropic medication and those given placebo(29).
Where’s the evidence? Search our evidence database and enter ‘acetylcholine’ and ‘dementia’ into the search field for a summary of studies on acetylcholine enhancers and dementia/Alzheimer’s.
Side effects? None known in reasonable amounts.
Contraindications with medication? None known.
Herbs (Ginkgo biloba)
The herb Ginkgo biloba has also demonstrated potential memory enhancing effects in the elderly. While a systematic review of all research up to 2002 concluded ‘promising evidence of improvement in cognition and function with Ginkgo’ (30), three recent randomized trials on Gingko have failed to confirm earlier positive results for those with cognitive impairment, however one showed mild improvement for those who were not diagnosed with dementia. Ginkgo may therefore have a role to play in prevention (31). A recent review concludes that the results with ginkgo are ‘inconsistent and unconvincing, but not dangerous, for dementia’ (32).
Where’s the evidence? Search our evidence database and enter ‘herbs’ and ‘dementia’ into the search field for a summary of studies on Ginkgo Biloba and Alzheimer’s/dementia.
Side effects? These herbs, in large quantities can reduce blood clotting. On rare occasions nose bleeds have been reported.
Contraindications with medication? Ginkgo biloba can thin the blood. If you are already on blood thinning medication you should discuss this with your doctor first.
- S. Seshadri et al. Plasma homocysteine as a risk factor for dementia and AD. N Engl J Med, vol 346(7), pp. 476-483. (2002)
- P. S. Sachdev et al.. Relationship between plasma homocysteine levels and brain atrophy in healthy elderly individuals. Neurology vol 58, pp. 1539-1541 (2002)
- S. J. Duthie, et al.. Homocysteine, B vitamin status, and cognitive function in the elderly. Am J Clin Nutr, vol 75(5), pp. 908-913 (2002)
- T. Bottiglieri et al.. Plasma total homocysteine levels and the C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene: a study in an Italian population with dementia. Mechanical Ageing Development, vol 122(16), pp. 2013-2023 (2001)
- van Dam F, van Gool, WA;HyperHomocysteinemia and Alzheimer’s disease: A systematic review. Archives of Gerentology and Geratrics, 2009: 48: 425-430.
- Smith AD; The worldwide challenge of the dementias: a role for B vitamins
and Homocysteine? Food Nutr Bull, 2008; 29(2 Suppl): S143–72
- Oulhaj A, Refsum H, Beaumont H et al; Homocysteine as a predictor of cognitive decline in Alzheimer’s Disease. Int J Geriatric psychiatry, 2010; 25(1): 82-90
- Smith AD, Refsum H; Vitamin B-12 and cognition in the elderly. Am J Clin Nutr, 2009: 89(2):707S–11S; Tangney C et al., Biochemical indicators of vitamin B12 and folate insufficiency and cognitive decline. Neurology, 2009;72(4):361–7.
- Durga J, van Boxtel MP, Schouten EG et al; The effect of 3-year folic acid supplementation on cognitive function in older adults in the FACIT trial: a randomized, double blind, controlled trial. Lancet, 2007; 369(1):208-216.
- Smith AD, Smith SM, de Jager CA et al., ‘Homocysteine-lowering by B vitamins slows the rate of accelerated brain atrophy in mild cognitive impairment: a randomized controlled trial’, Public Library of Science ONE, 2010;5(9).
- Aisen PS, Schneider LS, Sano M, Diaz-Arrastia R et al; High-dose B vitamin supplementation and cognitive decline in Alzheimer disease. JAMA, 2008; 300(15):1774–83
- S. J. Eussen et al., Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial, Arch Intern Med, vol 165(10), pp. 1167-72 (2005)
- Smith AD, Young-In K, Refsum H: Is folic acid good for everyone? Am J Clin Nutr, 2008;87:517–33.
- M. Morris, et al.. Consumption of fish and n-3 fatty acids and risk of incident Alzheimer disease. Arch Neurol, vol 60, pp. 940-946 (2003)
- Yurko-Mauro K, McCarthy D, Rom D, et al; Beneficial effects of docosahexaenoic acid on cognition in age-related cognitive decline. Alzheimers Dement. 2010; 6, 456-64.
- Quinn JF, Raman R, Thomas RG, et al; Docosahexaenoic acid supplementation and cognitive decline in Alzheimer disease: a randomized trial. JAMA, 2010; Nov 3;304(17):1903-11.
- M. Morris et al., ‘Dietary intake of antioxidant nutrients and the risk of incident AD’, JAMA, Vol 284(24), pp. 3230-3237. Also see pp.3223-61
- M. Morris et al., ‘Vitamin E and vitamin C supplement use and risk incident Alzheimer disease’, Alzheimer Dis and Assoc Disorders, Vol 12, 1998, pp. 121-6
- M. Sano et al., ‘A controlled trial of selegiline, alpha tocopherol or both as treatment of AD’, New Eng J Med, Vol 336, 1997, pp. 1216-22
- Zandi PP, Anthony JC, Khachaturian AS, et al; Reduced risk of Alzheimer disease in users of antioxidant vitamin supplements: the Cache County Study. Arch Neurol. 2004; Jan;61(1):82-8.
- R. M. Sapolsky, ‘Why stress is bad for your brain’, Science, Vol 273(5276), 1996, pp. 749-50
- R. M. Sapolsky and B. S. McEwen, ‘Stress, glucocorticoids, and their role in the aging hippocampus’, in Treatment Development Strategies for AD, Mark Powley Associates (1986), pp. 151-71
- J. D. Bremner, JD, 1999, Biol Psychiatry, Vol 45(7), 1999, pp. 797-805
- C. Kirschbaum C et al., 1996, Life Sci, Vol 58(17), 1996, pp. 1475-83
- J. W. Newcomer JW et al., 1999, Arch Gen Psychiatry, Vol 56(6), 1999, pp. 527; also see F. Giubilei F et al., 2001, J Neurosci Res, Vol 66(2), 2001, pp. 262-5.
- McDaniel MA et al “Brain-specific” nutrients: a memory cure? Nutrition. 2003 Nov-Dec; 19 (11-12): 957-75
- Birks J ‘Ginkgo biloba for cognitive impairment and dementia’. Cochrane Database Syst Rev. 2002; (4): CD003120.
- van Dongen M et al, ‘Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial’. J Clin Epidemiol. 2003 Apr; 56(4): 367-76; Solomon PR et al ‘Ginkgo for memory enhancement: a randomized controlled trial’ JAMA. 2002 Aug 21; 288(7): 835-40; Mix JA, Crews WD Jr. ‘A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings’. Hum Psychopharmacol. 2002 Aug; 17(6): 267-77.
- Birks J. and Grimley Evans J. ‘Ginkgo biloba for cognitive impairment and dementia’, Cochrane Database Syst Rev, (2):CD003120 (2007).
- Singh-Manoux A, Kivimaki M, Glymour MM, Elbaz A, Berr C, Ebmeier KP, Ferrie JE, Dugravot A. (2012) Timing of onset of cognitive decline: results from Whitehall II prospective cohort study. BMJ Jan 5;344:d7622. doi: 10.1136/bmj.d7622.