Alzheimer’s Disease

Alzheimer’s disease (AD) is a slowly progressive dementia characterized by cognitive decline and behavioral changes. Pathological changes in the brain include atrophy of the cerebral cortex (particularly in the mesial temporal and temporoparietal lobes), the presence of neurofibrillary tangles and senile (amyloid) plaques, a loss of cholinergic neurons in the brain, and reduced activity of choline acetyltransferase (the enzyme responsible for acetylcholine production) in the cerebral cortex and hippocampus. Pathogenesis is not well understood but involves neurotoxicity, inflammation, and, likely, apoptosis.

The disease typically progresses from mild memory impairment to severe cognitive loss with personality and behavioral changes. The patient often experiences language problems (particularly with generation of nouns [dysnomia]), and spatial disorientation is common. AD reduces life expectancy by as much as 50% following initial diagnosis.[1] AD is the sixth leading cause of death among US adults.[2]

Risk Factors

Evidence suggests that AD is associated with the following:

Older age. According to estimates for 2010, there were 4.7 million Americans ≥ 65 years of age with AD, with that rate projected to rise to 13.8 million by 2050.[3]

Family history. Risk is inversely proportional to the age of onset in a first-degree relative.

Genetics. Certain genetic abnormalities (particularly with the presenilin and amyloid precursor protein genes) place some individuals at high risk of early-onset AD. However, these represent only a small fraction of cases. More commonly, late-onset AD is associated with certain subtypes of apo E4, among other genes. Trisomy 21 is also associated with increased risk.[4]

Hypercholesterolemia. There appears to be an association between elevated total or LDL cholesterol concentrations, particularly in middle age, and development of AD. Of the 1,037 postmenopausal women enrolled in the Heart and Estrogen/Progestin Replacement Study, those with LDL cholesterol levels in the top 25% had 76% greater odds of developing cognitive impairment compared with women who had lower LDL levels.[5]

Overweight. Obesity before age 65 has been shown to be an independent risk factor for development of AD.[6],[7]

Sedentary lifestyle. Observational studies and clinical trials show that regular aerobic exercise (e.g., a 40-minute walk 3 times per week) reduces the risk for developing dementia and may reverse shrinkage in the hippocampus and other brain structures.[8][9][10][11]

Hypertension, declining blood pressure over time, cerebrovascular and cardiovascular disease, diabetes, smoking, and persistently elevated alcohol use.[4] All these factors are associated with cerebral atrophy. Excess body weight may exacerbate these factors or lead to cerebral atrophy directly.[12]

Elevated homocysteine and the metabolic syndrome may also increase risk.[13],[14]

Brain trauma. A history of traumatic brain injury may be associated with development of AD.[15]

Poor sleep. Reduced sleep quality, sleep problems, and daytime sleepiness are associated with altered AD biomarkers (beta amyloid, tau, and inflammation) in cerebrospinal fluid.[16]


Pathologic findings cannot be demonstrated except by autopsy (or, rarely, by brain biopsy). A definitive diagnosis of AD is not possible in normal clinical practice. Current evaluation of the patient with suspected AD focuses on identifying potentially reversible disorders that can produce cognitive deficits.

Routine neuroimaging, particularly magnetic resonance imaging, can help rule out certain causes of memory loss, such as vascular dementia, normal pressure hydrocephalus, chronic subdural hematomas, and brain tumors. Occasionally, such conditions are identified even in the absence of other clinical indicators. Therefore, neuroimaging should be considered in all cases of progressive cognitive deterioration. Tests of potential metabolic abnormalities (e.g., hypothyroidism, vitamin B12 deficiency, electrolyte abnormalities) and infection (e.g., neurosyphilis) should be included in the workup. Occasionally, lumbar puncture may be needed, particularly in atypical cases (such as those associated with somnolence or confusion at the outset) or those with rapid progression. Electroencephalography, which is usually normal early in AD, may provide useful clues to alternative diagnosis in unusual cases.

Severe sleep disorders, disorders of liver and renal function, and side effects of various medications can produce cognitive dysfunction, as can depression (pseudodementia). Neuropsychiatric testing may be useful to aid in the diagnosis of AD or to evaluate its progression. Such testing may be particularly helpful if the presentation is atypical. The Diagnostic and Statistical Manual for Mental Disorders, Fifth Edition (DSM5) criteria for diagnosis of AD were updated in 2013.[17]

Overlap with other causes of dementia does occur (e.g., Lewy body dementia and frontotemporal dementia). However, because treatment is generally based on symptoms, biopsy is not commonly performed.


People who exercise, participate in intellectually stimulating activities, and remain active in social networks appear to be at lower risk for AD, and those affected may slow its progression through these activities.[18] Occupational therapy has been shown to improve daily functioning for patients with AD and to reduce caregiver strain.[19] Exercise programs can slow physical and functional decline.[20] Optimizing sleep allows the body to clear out degradative products of neural activity that accumulate during awake hours, such as beta-amyloid and tau proteins, that lead to plaques and tangles in the brain.[21]

Drugs may have a modest effect.

  • Memantine, an N-methyl-D-aspartate receptor antagonist along with galantamine, may slow the loss of mental and physical function. Memantine has modest effects in patients with moderate-to-advanced disease.[22]
  • Nonsteroidal anti-inflammatory drugs (NSAIDs), aspirin, and COX-2 inhibitors are not recommended for use for AD given their lack of efficacy and high risk of side effects.[23]
  • The benefits of cholinesterase inhibitors, such as donepezil, are modest, especially in advanced cases.[24]
  • Ginkgo biloba’s efficacy remains unproven, and it is an unregulated product.[25]
  • HMG-CoA reductase inhibitors (statins) have not been proven to provide a clinically significant benefit in treatment for AD.[26],[27]

Nutritional Considerations

Several epidemiological studies have examined associations between diet and the risk of AD and cognitive decline.[28],[29],[30] The following factors are under study for a possible role in reducing risk:

Cardiovascular Risk Factors

Elevations in cardiovascular risk factors during the midlife period, including hypercholesterolemia, hypertension, obesity, and diabetes, are associated with a significantly greater risk for AD. Individuals with high cholesterol have a risk more than 70% greater, while diabetes and high blood pressure carry a 40% and 31% greater risk, respectively.[31] While observational studies of drug treatment of these risk factors in patients with existing AD have suggested possible benefits, clinical trial data do not support this hypothesis.[32]

Reduced Saturated Fat, Cholesterol, and Trans Fats

Ecological data have shown that the availability of animal products is more highly correlated with AD than any other types of foods.[33] The prospective Chicago Health and Aging Project reported that persons consuming the most saturated fat (compared with the least) had more than twice the risk of developing AD, with similar findings for trans fats.[34] Saturated fat is particularly abundant in dairy products and meat. Trans fats are found in many snack foods and, in traces, in dairy products. Other studies have also implicated saturated fats in the cognitive decline that precedes AD.[31]

The mechanism may relate to the influence of dietary fat on blood cholesterol concentrations. As noted above, midlife hypercholesterolemia is associated with risk for AD. Cholesterol forms the core of the neuritic plaques that are a well-known feature of this disease; indeed, a primary role for the amyloid precursor protein is the clearance of excess cholesterol from the brain.[29] Oxidized cholesterol, found in ghee, powdered milk, meat, cheese, and eggs, has also been suggested as a contributor to AD due to its apparent ability to cross the blood-brain barrier, leading to neuro-inflammation and free radical formation.[35],[36] In addition, animal products are chief dietary sources of advanced glycation end products that are now thought to play a key role in the pathogenesis of AD.[37]

In contrast, higher intakes of unsaturated fats and a higher ratio of unsaturated to saturated fat are associated with a significantly lower risk for either cognitive decline or AD.[38] A meta-analysis of fish and omega-3 fatty acid intake found that higher compared with lower intake of fish was associated with a 36% lower risk of AD.[39]

Both longitudinal studies and meta-analyses have revealed cognitive benefits from what is referred to as a Mediterranean diet.[40],[41],[42] Definitions of such a diet vary from one study to another, but the diets are generally lower in animal products, higher in plant-derived foods, and may include some oil, wine, or other regional products. Studies have shown a similar benefit from both traditional Japanese diets and diets that focused on higher intakes of vegetables, fruits, nuts, fish, and poultry and a lower intake of high-fat dairy animal foods.[35] Soy foods, frequently used in Asian cuisine, may be particularly beneficial as a replacement for animal products. They are free of cholesterol, lower in saturated fat than animal products, and have also been associated with benefits on cognitive function in postmenopausal women.[43]

Presumed explanations for the benefits of these diets include their low content of saturated and trans fats, their high content of antioxidant-containing foods, and, in Mediterranean regions, the use of olive oil, which contains oleocanthal, a phytochemical that appears to inhibit the fibrillization of tau protein, deposits of which are a characteristic of AD.[44]

Maintaining Healthy Weight

A study showed that individuals who were overweight before age 65 had a roughly 40% greater risk for dementia compared with normal-weight individuals; however, overweight after this age is associated with a lower risk.[6]

Consuming Vitamin E-Rich Foods

The Chicago Health and Aging Project reported that, in older people followed over a 4-year period, AD developed in 14.3% of those whose vitamin E intake was low, but in only 5.9% of those in the highest category of dietary (non-supplement) vitamin E.[45]

Similarly, in a Dutch study including 5,395 people aged 55 and older, those who got the most vitamin E cut their risk of developing AD and other forms of dementia over the next decade by about 25%.[46]

Studies have shown that patients with AD and cognitive impairment have lower blood levels of all forms of vitamin E found in foods (4 tocopherols and 4 tocotrienols) when compared with cognitively normal persons. While each form shows different biological properties that may offer neuroprotective effects in AD, α-tocotrienol (not alpha-tocopherol, the types used in AD studies) is the most neuroprotective form of vitamin E.[47]

LLower concentrations of γ- and α-tocopherols are also found in CNS tissue of AD patients, compared with normal controls, and may be associated with AD neuropathology.[48] A controlled clinical trial of high-dose vitamin E (alpha-tocopherol, 2,000 IU/day for roughly 2 years) found a significant benefit for AD patients. This study used the Alzheimer’s Disease Cooperative Study/Activities of Daily Living (ADCS-ADL) Inventory score, which assesses ability to perform activities of daily living in AD patients. Investigators found that the ADCS-ADL scores declined by roughly 3 units less in the vitamin E group than in the placebo group, a difference that was superior to memantine as well.[49]

Increased Vitamin C

Studies have found that blood levels of vitamin C were lower in patients with both mild cognitive impairment and AD, when compared with controls. In addition, individuals with higher vitamin C intakes (through diet and low-level supplementation of 500 mg/day or less) may have slower rates of cognitive decline than do persons with low intakes, thereby raising the possibility that long-term consumption of diets high in vitamin C-containing foods can reduce the risk for AD.[50]

In AD patients, no benefit was found in a 16-week study of a combination of vitamin C and E, lipoic acid, and Coenzyme Q10.[51] In contrast, a study in which AD patients were given a combination of an antioxidant (lipoic acid) and an omega-3 supplement over 12 months resulted in less decline in the Mini-Mental State Examination (MMSE) and Instrumental Activities of Daily Living (IADL).[52]

Micronutrient Adequacy

A systematic review and meta-analysis found that AD patients had significantly lower blood levels of vitamins A, B12, C, E, and folate and non-significantly lower levels of vitamin D and zinc when compared with individuals without AD. Similar results were found even in AD patients who were not considered malnourished.[46] Given the large number of nutrients AD patients are lacking, a multiple vitamin supplement may be of benefit, provided it omits iron and copper, as noted below.

Avoiding Excess Copper

A meta-analysis examining copper levels in serum, plasma, and cerebrospinal fluid concluded that AD patients have a higher body copper burden than do normal individuals.[53] In addition, a higher than normal amount of this copper is unbound from its carrier (ceruloplasmin) in these patients, as a result of alterations in copper metabolism seen in AD patients. The consequence, apparently, is an increase in unbound copper in the brain.[54] This is of concern because brain copper increases with age and upregulates the expression of the amyloid beta precursor protein (AβPP) protein and increases the aggregation and neurotoxicity of Aβ.[55]

Avoiding Excess Iron

Some evidence suggests that excess iron may contribute to AD risk. Patients with AD have elevated iron levels in several brain areas affected by this disease, and an excess of iron in the brain is associated with beta-amyloid (Aβ) plaque formation.

Iron transport through the blood-brain barrier is usually tightly controlled.[56] However, a damaged blood-brain barrier has been implicated in the development of this disease and may precede the development of clinical symptoms. A Western diet has been linked to a compromised blood-brain barrier, thereby providing a possible mechanism by which iron could accumulate in the brain.[57] In the AD Neuroimaging Initiative cohort study, ferritin levels predicted the conversion from mild cognitive impairment to AD. Ferritin levels were also strongly associated with cerebrospinal fluid levels of apolipoprotein E and were elevated by the APOE-ɛ4allele, revealing that elevated brain iron adversely impacts disease progression.[58]

Copper and iron are often added to multiple vitamin-mineral supplements. It may be prudent to choose supplements that omit these minerals.

Adequate Vitamin D Status

Vitamin D deficiency is associated with global cognitive impairment in adults, and a meta-analysis found the risk to be more than 20% greater for AD and dementia in persons whose vitamin D blood levels were in the deficient range (< 50 nmol/L) compared with individuals above this level.[59],[60] In addition, patients with AD are significantly more likely to have vitamin D deficiency than normal individuals.[61]

Avoiding Aluminum

Aluminum exposures can be neurotoxic, and studies have shown associations between aluminum in drinking water and AD risk.[62] Unlike iron and copper, there is no requirement for aluminum in human biology. Nonetheless, the role of aluminum in AD remains controversial.[63]

Moderate Alcohol Consumption

Although alcohol intake as low as 20 g/day (1.25 servings) is a known risk factor for certain cancers, hypertension, and several other diseases, a meta-analysis found a roughly 30% lower risk for AD and a 25% lower risk for dementia in light to moderate alcohol consumers, compared with nondrinkers.[64],[65]

Benefits of moderate alcohol consumption, if any, are thought to derive from cardiovascular risk factor reduction (reducing platelet aggregation or modifying serum lipids) or through acetylcholine release in the hippocampus.[66] However, hippocampal insulin resistance has been found in patients with AD, and moderate alcohol consumption is known to enhance insulin sensitivity.[67],[68]


A 2010 study suggested that coffee might reduce Alzheimer’s risk. Over a 21-year period, a study including 1,409 people found that high coffee drinkers had 64% less risk of developing Alzheimer’s disease, and benefits were seen even among people carrying the APOE e4 allele.[69]

However, a much larger prospective study, including 398,646 UK Biobank participants, aged 37-73 years, showed that high daily coffee consumption was associated with a significant loss of gray matter and increased risk of dementia. Those drinking more than 6 cups per day had a 53% increased risk of dementia, compared with those drinking 1-2 cups per day.[70]


See Basic Diet Orders chapter.

Physical and occupational therapy consultation for home safety evaluation and needs assessment.

What to Tell the Family

A diet low in saturated fat, trans fats, and cholesterol, moderate in iron and copper, and high in dietary fiber and vitamins E and C may reduce the risk of AD, in addition to helping prevent other age-related debilitating diseases. It is not yet clear that diet changes can alter the course of AD that has already been diagnosed.

Safety precautions for AD patients are always important. Connection with social services or a support group may also help ease the burden of care for a person with AD. Although routine genetic testing is not typically recommended, family members may want to be tested for the presence of the apo E4 allele. At minimum, they should be encouraged to mitigate their future risk of AD by noting the above recommendations.


  1. Larson EB, Shadlen MF, Wang L, et al. Survival after initial diagnosis of Alzheimer disease. Ann Intern Med. 2004;140(7):501-9.  [PMID:15068977]
  2. Xu J, Murphy SL, Kochanek KD, Arias E. Mortality in the United States, 2018. Centers for Disease Control and Prevention. Accessed April 29, 2020.
  3. Hebert LE, Weuve J, Scherr PA, et al. Alzheimer disease in the United States (2010-2050) estimated using the 2010 census. Neurology. 2013;80(19):1778-83.  [PMID:23390181]
  4. Kivipelto M, Helkala EL, Laakso MP, et al. Apolipoprotein E epsilon4 allele, elevated midlife total cholesterol level, and high midlife systolic blood pressure are independent risk factors for late-life Alzheimer disease. Ann Intern Med. 2002;137(3):149-55.  [PMID:12160362]
  5. Yaffe K, Barrett-Connor E, Lin F, et al. Serum lipoprotein levels, statin use, and cognitive function in older women. Arch Neurol. 2002;59(3):378-84.  [PMID:11890840]
  6. Pedditizi E, Peters R, Beckett N. The risk of overweight/obesity in mid-life and late life for the development of dementia: a systematic review and meta-analysis of longitudinal studies. Age Ageing. 2016;45(1):14-21.  [PMID:26764391]
  7. Profenno LA, Porsteinsson AP, Faraone SV. Meta-analysis of Alzheimer's disease risk with obesity, diabetes, and related disorders. Biol Psychiatry. 2010;67(6):505-12.  [PMID:19358976]
  8. Colcombe SJ, Erickson KI, Scalf PE, et al. Aerobic exercise training increases brain volume in aging humans. J Gerontol A Biol Sci Med Sci. 2006;61(11):1166-70.  [PMID:17167157]
  9. Erickson KI, Voss MW, Prakash RS, et al. Exercise training increases size of hippocampus and improves memory. Proc Natl Acad Sci USA. 2011;108(7):3017-22.  [PMID:21282661]
  10. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med. 2006;144(2):73-81.  [PMID:16418406]
  11. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer disease. JAMA. 2009;302(6):627-37.  [PMID:19671904]
  12. Gustafson D, Lissner L, Bengtsson C, et al. A 24-year follow-up of body mass index and cerebral atrophy. Neurology. 2004;63(10):1876-81.  [PMID:15557505]
  13. den Heijer T, Vermeer SE, Clarke R, et al. Homocysteine and brain atrophy on MRI of non-demented elderly. Brain. 2003;126(Pt 1):170-5.  [PMID:12477704]
  14. Seshadri S, Beiser A, Selhub J, et al. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002;346(7):476-83.  [PMID:11844848]
  15. Shively S, Scher AI, Perl DP, et al. Dementia resulting from traumatic brain injury: what is the pathology? Arch Neurol. 2012;69(10):1245-51.  [PMID:22776913]
  16. Sprecher KE, Koscik RL, Carlsson CM, et al. Poor sleep is associated with CSF biomarkers of amyloid pathology in cognitively normal adults. Neurology. 2017;89(5):445-453.  [PMID:28679595]
  17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition (DSM-5). Arlington, VA: American Psychiatric Publishing; 2013.
  18. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life might protect against dementia. Lancet Neurol. 2004;3(6):343-53.  [PMID:15157849]
  19. Graff MJ, Vernooij-Dassen MJ, Thijssen M, et al. Community based occupational therapy for patients with dementia and their care givers: randomised controlled trial. BMJ. 2006;333(7580):1196.  [PMID:17114212]
  20. Forbes D, Forbes SC, Blake CM, et al. Exercise programs for people with dementia. Cochrane Database Syst Rev. 2015;4:CD006489.  [PMID:25874613]
  21. Xie L, Kang H, Xu Q, et al. Sleep drives metabolite clearance from the adult brain. Science. 2013;342(6156):373-7.  [PMID:24136970]
  22. Reisberg B, Doody R, Stöffler A, et al. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med. 2003;348(14):1333-41.  [PMID:12672860]
  23. Jaturapatporn D, Isaac MG, McCleery J, et al. Aspirin, steroidal and non-steroidal anti-inflammatory drugs for the treatment of Alzheimer's disease. Cochrane Database Syst Rev. 2012;2:CD006378.  [PMID:22336816]
  24. Courtney C, Farrell D, Gray R, et al. Long-term donepezil treatment in 565 patients with Alzheimer's disease (AD2000): randomised double-blind trial. Lancet. 2004;363(9427):2105-15.  [PMID:15220031]
  25. Birks J, Grimley Evans J. Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev. 2007.  [PMID:17443523]
  26. Feldman HH, Doody RS, Kivipelto M, et al. Randomized controlled trial of atorvastatin in mild to moderate Alzheimer disease: LEADe. Neurology. 2010;74(12):956-64.  [PMID:20200346]
  27. Sano M, Bell KL, Galasko D, et al. A randomized, double-blind, placebo-controlled trial of simvastatin to treat Alzheimer disease. Neurology. 2011;77(6):556-63.  [PMID:21795660]
  28. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol. 2004;3(10):579-87.  [PMID:15380154]
  29. Gillette Guyonnet S, Abellan Van Kan G, Andrieu S, et al. IANA task force on nutrition and cognitive decline with aging. J Nutr Health Aging. 2007;11(2):132-52.  [PMID:17435956]
  30. Donini LM, De Felice MR, Cannella C. Nutritional status determinants and cognition in the elderly. Arch Gerontol Geriatr. 2007;44 Suppl 1:143-53.  [PMID:17317448]
  31. Meng XF, Yu JT, Wang HF, et al. Midlife vascular risk factors and the risk of Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2014;42(4):1295-310.  [PMID:25024338]
  32. Valenti R, Pantoni L, Markus HS. Treatment of vascular risk factors in patients with a diagnosis of Alzheimer's disease: a systematic review. BMC Med. 2014;12:160.  [PMID:25385407]
  33. Grant WB. Using Multicountry Ecological and Observational Studies to Determine Dietary Risk Factors for Alzheimer's Disease. J Am Coll Nutr. 2016;35(5):476-89.  [PMID:27454859]
  34. Morris MC, Evans DA, Bienias JL, et al. Dietary fats and the risk of incident Alzheimer disease. Arch Neurol. 2003;60(2):194-200.  [PMID:12580703]
  35. Gamba P, Testa G, Gargiulo S, et al. Oxidized cholesterol as the driving force behind the development of Alzheimer's disease. Front Aging Neurosci. 2015;7:119.  [PMID:26150787]
  36. Poli G, Biasi F, Leonarduzzi G. Oxysterols in the pathogenesis of major chronic diseases. Redox Biol. 2013;1:125-30.  [PMID:24024145]
  37. Angeloni C, Zambonin L, Hrelia S. Role of methylglyoxal in Alzheimer's disease. Biomed Res Int. 2014;2014:238485.  [PMID:24734229]
  38. Morris MC, Tangney CC. Dietary fat composition and dementia risk. Neurobiol Aging. 2014;35 Suppl 2:S59-64.  [PMID:24970568]
  39. Wu S, Ding Y, Wu F, et al. Omega-3 fatty acids intake and risks of dementia and Alzheimer's disease: a meta-analysis. Neurosci Biobehav Rev. 2015;48:1-9.  [PMID:25446949]
  40. van de Rest O, Berendsen AA, Haveman-Nies A, et al. Dietary patterns, cognitive decline, and dementia: a systematic review. Adv Nutr. 2015;6(2):154-68.  [PMID:25770254]
  41. Cao L, Tan L, Wang HF, et al. Dietary Patterns and Risk of Dementia: a Systematic Review and Meta-Analysis of Cohort Studies. Mol Neurobiol. 2016;53(9):6144-6154.  [PMID:26553347]
  42. Berti V, Walters M, Sterling J, et al. Mediterranean diet and 3-year Alzheimer brain biomarker changes in middle-aged adults. Neurology. 2018;90(20):e1789-e1798.  [PMID:29653991]
  43. Cheng PF, Chen JJ, Zhou XY, et al. Do soy isoflavones improve cognitive function in postmenopausal women? A meta-analysis. Menopause. 2015;22(2):198-206.  [PMID:25003621]
  44. Swaminathan A, Jicha GA. Nutrition and prevention of Alzheimer's dementia. Front Aging Neurosci. 2014;6:282.  [PMID:25368575]
  45. Morris MC, Evans DA, Bienias JL, et al. Dietary intake of antioxidant nutrients and the risk of incident Alzheimer disease in a biracial community study. JAMA. 2002;287(24):3230-7.  [PMID:12076219]
  46. Devore EE, Grodstein F, van Rooij FJ, et al. Dietary antioxidants and long-term risk of dementia. Arch Neurol. 2010;67(7):819-25.  [PMID:20625087]
  47. Mangialasche F, Westman E, Kivipelto M, et al. Classification and prediction of clinical diagnosis of Alzheimer's disease based on MRI and plasma measures of α-/γ-tocotrienols and γ-tocopherol. J Intern Med. 2013;273(6):602-21.  [PMID:23343471]
  48. Morris MC, Schneider JA, Li H, et al. Brain tocopherols related to Alzheimer's disease neuropathology in humans. Alzheimers Dement. 2015;11(1):32-9.  [PMID:24589434]
  49. Dysken MW, Sano M, Asthana S, et al. Effect of vitamin E and memantine on functional decline in Alzheimer disease: the TEAM-AD VA cooperative randomized trial. JAMA. 2014;311(1):33-44.  [PMID:24381967]
  50. Harrison FE. A critical review of vitamin C for the prevention of age-related cognitive decline and Alzheimer's disease. J Alzheimers Dis. 2012;29(4):711-26.  [PMID:22366772]
  51. Galasko DR, Peskind E, Clark CM, et al. Antioxidants for Alzheimer disease: a randomized clinical trial with cerebrospinal fluid biomarker measures. Arch Neurol. 2012;69(7):836-41.  [PMID:22431837]
  52. Shinto L, Quinn J, Montine T, et al. A randomized placebo-controlled pilot trial of omega-3 fatty acids and alpha lipoic acid in Alzheimer's disease. J Alzheimers Dis. 2014;38(1):111-20.  [PMID:24077434]
  53. Ventriglia M, Bucossi S, Panetta V, et al. Copper in Alzheimer's disease: a meta-analysis of serum, plasma, and cerebrospinal fluid studies. J Alzheimers Dis. 2012;30(4):981-4.  [PMID:22475798]
  54. Squitti R, Siotto M, Polimanti R. Low-copper diet as a preventive strategy for Alzheimer's disease. Neurobiol Aging. 2014;35 Suppl 2:S40-50.  [PMID:24913894]
  55. Harris CJ, Voss K, Murchison C, et al. Oral zinc reduces amyloid burden in Tg2576 mice. J Alzheimers Dis. 2014;41(1):179-92.  [PMID:24595193]
  56. Peters DG, Connor JR, Meadowcroft MD. The relationship between iron dyshomeostasis and amyloidogenesis in Alzheimer's disease: Two sides of the same coin. Neurobiol Dis. 2015;81:49-65.  [PMID:26303889]
  57. Hsu TM, Kanoski SE. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia. Front Aging Neurosci. 2014;6:88.  [PMID:24847262]
  58. Ayton S, Faux NG, Bush AI, et al. Ferritin levels in the cerebrospinal fluid predict Alzheimer's disease outcomes and are regulated by APOE. Nat Commun. 2015;6:6760.  [PMID:25988319]
  59. Annweiler C, Montero-Odasso M, Llewellyn DJ, et al. Meta-analysis of memory and executive dysfunctions in relation to vitamin D. J Alzheimers Dis. 2013;37(1):147-71.  [PMID:23948884]
  60. Shen L, Ji HF. Vitamin D deficiency is associated with increased risk of Alzheimer's disease and dementia: evidence from meta-analysis. Nutr J. 2015;14:76.  [PMID:26231781]
  61. Annweiler C, Llewellyn DJ, Beauchet O. Low serum vitamin D concentrations in Alzheimer's disease: a systematic review and meta-analysis. J Alzheimers Dis. 2013;33(3):659-74.  [PMID:23042216]
  62. Campdelacreu J. Parkinson disease and Alzheimer disease: environmental risk factors. Neurologia. 2014;29(9):541-9.  [PMID:22703631]
  63. Frisardi V, Solfrizzi V, Capurso C, et al. Aluminum in the diet and Alzheimer's disease: from current epidemiology to possible disease-modifying treatment. J Alzheimers Dis. 2010;20(1):17-30.  [PMID:20378957]
  64. Rehm J, Gmel G, Sempos CT, et al. Alcohol-related morbidity and mortality. Alcohol Res Health. 2003;27(1):39-51.  [PMID:15301399]
  65. Anstey KJ, Mack HA, Cherbuin N. Alcohol consumption as a risk factor for dementia and cognitive decline: meta-analysis of prospective studies. Am J Geriatr Psychiatry. 2009;17(7):542-55.  [PMID:19546653]
  66. Beydoun MA, Beydoun HA, Gamaldo AA, et al. Epidemiologic studies of modifiable factors associated with cognition and dementia: systematic review and meta-analysis. BMC Public Health. 2014;14:643.  [PMID:24962204]
  67. Pitt J, Thorner M, Brautigan D, Larner J, Klein WL. Protection against the synaptic targeting and toxicity of Alzheimer's-associated Aβ oligomers by insulin mimetic chiro-inositols. FASEB J. 2013;27:199–207.
  68. Hätönen KA, Virtamo J, Eriksson JG, et al. Modifying effects of alcohol on the postprandial glucose and insulin responses in healthy subjects. Am J Clin Nutr. 2012;96(1):44-9.  [PMID:22648716]
  69. Eskelinen MH, Kivipelto M. Caffeine as a protective factor in dementia and Alzheimer's disease. J Alzheimers Dis. 2010;20 Suppl 1:S167-74.  [PMID:20182054]
  70. Pham K, Mulugeta A, Zhou A, et al. High coffee consumption, brain volume and risk of dementia and stroke. Nutr Neurosci. 2021.  [PMID:34165394]
  71. Comabella M, Caminero AB, Malhotra S, et al. TNFRSF1A polymorphisms rs1800693 and rs4149584 in patients with multiple sclerosis. Neurology. 2013;80(22):2010-6.  [PMID:23624563]
  72. Heron M. Deaths: leading causes for 2010. Natl Vital Stat Rep. 2013;62(6):1-96.  [PMID:24364902]
Last updated: August 2, 2021