Amyloid Beta is the main culprit in Alzheimer's Disease.  However, what causes it to accumulate is less clear.  Recent research suggests that the normal system transporting beta-amyloid across the blood-brain barrier may be defective. Abnormal beta-amyloid-24 fragments form and bind to ABAD in the mitochondria and destroy mitochondial functioning.  Another possibility is that circulatory problems to the brain may be the most important factor.  Many individual factors appear to influence the risk of developing Alzheimer's. 

Some factors that play a causative role covered below are: 1) small brain size and lower intelligence, 2) cholesterol, 3) low omega-3 fatty acids (low fish intake, etc.), 4) head trauma, 5) obesity, 6) occupational exposure to pesticides, and 7) smoking.  Certain vitamin deficiencies (folic acid, B-12, and possibly vitamin D), and diabetes may also be involved. 

Aluminum: Dietary Aluminum Associated with AD in One Study But Not Another: 46 Patients were matched with controls. The adjusted Risk Ratio was 8.6 (760% more risk for Alzheimer's disease) for dietary aluminum which is found in pancake mixes, waffle mixes, biscuits, muffins, cornbread, corn tortillas P<.025. It is also in American cheese, chocolate pudding, salt, and chewing gun. Age Ageing 3/99 28:205. But, another study found no association with dietary aluminum or water or medicines in J Epid Comm Health 6/95 in 109 matched. The use of antacids containing aluminum hydroxide (Maalox, etc.) increase aluminum blood levels by 100-200%! J Inorg Biochem. 1998 Feb 15;69(3):171-6.

Aluminum in Drinking Water Bad, Calcium Good: 3777 French over age 64 were studied. Calcium in drinking water was inversely related to dementia. There was no relationship for Fl, Fe, Zn, Cu, or Mg. High aluminum was related to dementia if the water had a lower pH and lower silica. Bordeaux, Epidemiol 5/96;7:281

Aluminum Drinking Water Aluminum Linked to AD in 9 Studies: Nine out of 13 published epidemiological studies of Al in drinking water and AD have shown statistically significant positive relations. Given the difficulty in producing high-quality data for the occurrence of AD and also for Al exposure, with the resulting unavoidable misclassification errors biasing any true association towards the null value, these studies are remarkably consistent. Brain Res Bull 2001 May 15;55(2):187-96

 Apolipoprotein E and Clusterin Protective: Apolipoprotein E (apoE) and clusterin, appear to act as "chaperones" orchestrating the clearance of potentially hazardous molecules such as amyloid out of the brain. Ironically, these proteins also have been implicated in a key stage of plaque formation. David Holtzman, Neuron 1/22/04. Plaques form when the protein amyloid beta (Abeta) is converted from its soluble to its insoluble form and coalesces into hair-shaped threads called fibrils due to being unable to dissolve or be cleared out of the brain. Both apoE and clusterin promote the formation of these fibrils. In mice genetically engineered to develop Alzheimer's disease-like brain plaques, those without either apoE or clusterin developed fewer fibrils. However, in mice lacking both proteins, more plaques were present. Moreover, fibrils in animals lacking both proteins developed significantly earlier in life and resulted in the more advanced amyloid plaques, similar to early onset hereditary Alzheimer's. In addition to increased amounts of Abeta in brain tissue, there are also abnormally high levels in the fluid surrounding individual brain cells and in the fluid surrounding the entire brain. In contrast, levels of Abeta in the blood are not abnormally high.

Brain Blood Flow Factor in Dementia: Using MRIs to examine the brains of 17 elderly patients with dementia after age 75 related to Alzheimer's or Parkinson's disease, 16 seniors of the same age with optimal cognitive function and 15 healthy younger individuals, the average cerebral blood flow in the healthy young individuals was 742 milliliters (mL) per minute vs. 443 mL per minute in dementia vs. 551 mL per minute in seniors with optimal brain function. Aart Spilt, et al. Leiden University, Netherlands. Radiology 9/05.

Brains Small and Education Low Increases AD: James Mortimer of Univ San Francisco's Institute on Aging found that nuns who completed 16 or more years of education or whose head circumference was in the upper two-thirds were four times less likely to be demented than those with both smaller head circumferences and lower education. Head circumference a good indicator of the volume or size of the brain. No association between education or head circumference and the presence of severe brain abnormalities characteristic of Alzheimer's disease pathology. Higher education or a larger brain does not decrease the chances of Alzheimer's brain abnormalities, but rather allows the brain to function at a higher level despite the presence of these abnormalities. Head circumference is completely determined by age 12, at which time maximum brain size is attained. Elderly people can delay or even prevent the onset of dementia by keeping their brains active. 294 Catholic sisters for whom data on head circumference were available every year for 10 years. The nuns were tested for their cognitive abilities and completion of daily living tasks, and 111 were diagnosed with dementia. 60 autopsied brains.

By-Pass Heart Surgery Increases Risk of Alzheimer's: In a 5-year follow-up study, 5,216 people who underwent coronary artery bypass graft surgery (CABG) were compared to 3,954 people who had a percutaneous transluminal coronary angioplasty (PTCA). Over 5 years, 78 who had bypass surgery and 41 who had angioplasty developed Alzheimer's disease. The coronary bypass patients had a 70 percent increased risk of developing Alzheimer's disease. Show some heart surgery patients experience memory problems immediately following the procedure. However, at a one-year follow-up most patients regain cognitive function. Heart bypass surgery represents a traumatic insult to the brain, particularly by reducing oxygen supply to the brain and increasing the stress response. Assessment of the Emergence of Alzheimer's Disease Following Coronary Artery Bypass Graft Surgery or Percutaneous Transluminal Coronary Angioplasty. Todd A. Lee, et al. Boston University. Journal of Alzheimer's Disease 9/2005:7(4).

Cardiovascular and Peripheral Arterial Disease Increase Alzheimer's: In a 5.4-year follow-up study of 3,602 adults with brain MRI scans and no dementia, excluding those with strokes and controlling for apolipoprotein E allele status, age, race, sex, education, Mini-Mental State Examination score, and income, dementia was higher in those with prevalent cardiovascular disease (CVD), particularly in the subgroup with peripheral arterial disease (PAD): 34.4 per 1,000 person-years for those with CVD, vs. 22.2 per 1,000 person-years without a history of CVD. For those with PAD: 57.4 vs 23.7 per 1000 person-years, a 140% increase. Dementia and Alzheimer's disease incidence in relationship to cardiovascular disease in the cardiovascular health study cohort. Newman AB, et al. University of Pittsburgh. J Am Geriatr Soc. 2005 Jul;53(7):1101-7.

Cholesterol: Low Natural Cholesterol More Cognitive Difficulties: In 1894 adults from the Framingham Heart Study who were free of dementia and stroke and who received total cholesterol (TC) determinations over an 18-year period, the higher the TC, the better the measures of verbal fluency, attention/concentration, abstract reasoning, and a composite score measuring multiple cognitive domains. Those with "desirable" TC levels (<200 mg/dL) performed less well than those with borderline-high TC levels (200-239 mg/dL) and participants with high TC levels (over 240 mg/dL). Serum cholesterol and cognitive performance in the Framingham Heart Study. Elias PK, Elias MF, et al. Boston University. Psychosom Med. 2005 Jan-Feb;67(1):24-30.

Cholesterol Increases Tangles: High cholesterol levels also increase the rate at which the amyloid beta peptides break off and form the tangles that kill brain cells. High cholesterol increases the production of another protein, apolipoprotein E (APOE), which is mainly responsible for transportation of cholesterol out of the cell. Researchers discovered that too much APOE results in the accumulation of free cholesterol, which is toxic to human nerve cells. Georgetown, 6/24/02, Vassilios Papadopoulos

Cholesterol and Heart Disease: Often a forerunner of AD, beta-amyloid increased in cholesterol-fed rabbits and was decreased by HMG Co-A reductase inhibitors (statins). Microsc Res Tech 2000 Aug 15;50(4):287-90

Cholesterol: HDL Good Cholesterol Higher, Mental Functioning Higher: Study of 139 elderly at least 95 years old. Plasma HDL levels correlated significantly with MMSE (r =.32; p <.0001). Each decrease in plasma HDL tertile (74.9, 50.6, and 36.8 mg/dl) was associated with a significant decrease in MMSE (23.4, 17.7, and 12.4; p <.04 for each plasma HDL tertile). As expected, increased plasma apolipoprotein A-I and decreased plasma triglyceride levels were also correlated with a significantly superior cognitive function. Plasma HDL levels highly correlate with cognitive function in exceptional longevity. Atzmon G, Gabriely I, et al. J Gerontol A Biol Sci Med Sci 2002 Nov;57(11):M712-5, Albert Einstein.

Copper Elevated Independent of Ceruloplasmin: In 47 patients with AD, 24 patients with vascular dementia (VaD), and 44 healthy controls, copper (p < 0.001), peroxides (p = 0.026), and ceruloplasmin (p = 0.052) were increased and TRAP (total peroxides, antioxidants, and other peripheral markers of inflammation) was decreased (p = 0.006) in patients with AD, while no other markers of inflammation were altered. The calculation of the ratio between copper and ceruloplasmin suggested the presence in the serum of AD patients, but not of VaD or normal controls, of a large pool of non-ceruloplasmin-bound copper. Excess of serum copper not related to ceruloplasmin in Alzheimer disease. Squitti R, Pasqualetti P, et al. Rome, Italy. Neurology. 2005 Mar 22;64(6):1040-6.

Copper-Zinc Superoxide Dismutase Elevated: All of 32 AD patients had elevations early in disease. Lowered successfully with chelator for 24 weeks. No correlation with APOE genotype or SOD activity. U Rome. Red blood cell copper, zinc superoxide dismutase activity is higher in Alzheimer's disease and is decreased by D-penicillamine. Rossi L, Squitti R, et al A. Neurosci Lett. 2002 Aug 30;329(2):137-40. 

Copper Serum and Peroxide Levels Up; Penicillamine Not Retard Progression: Small Rome study of 18 pt DB PC 6 months. Copper and peroxide levels both markedly up in AD with p<.0001for each! Oxidative stress also somewhat higher p<.05. Penicillamine helped lowered oxidative stress somewhat but no impact on disease progression. D-penicillamine reduces serum oxidative stress in Alzheimer's disease patients. Squitti R, Rossini PM, Cassetta E, Moffa F, Pasqualetti P, Cortesi M, Colloca A, Rossi L, Finazzi-Agro A. Eur J Clin Invest. 2002 Jan;32(1):51-9

Copper, Zinc, & Iron Blamed for Amyloid: Clioquinol Chelator Might Help: Dyshomeostasis of copper, iron, and zinc has been detected, and the mismanagement of these metals induces beta-amyloid precipitation and neurotoxicity. Chelating agents offer a potential therapeutic solution to the neurotoxicity induced by copper and iron dyshomeostasis. Currently, the copper and zinc chelating agent clioquinol represents a potential therapeutic route that may not only inhibit beta-amyloid neurotoxicity, but may also reverse the accumulation of neocortical beta-amyloid. A Phase II double-blind clinical trial of clioquinol with B12 supplementation. Duke. Current status of metals as therapeutic targets in Alzheimer's disease. Finefrock AE, Bush AI, Doraiswamy PM. J Am Geriatr Soc. 2003 Aug;51(8):1143-8

Copper in Water Increases Plaques in Rabbits: Rabbits on high cholesterol diet given water laced with 1/8^th the maximum allowable human level developed AD like plaques in AD typical areas of the brain. 8/14/03 Sparks and Schreurs, Proceedings of the National Academy of Sciences

Depression: Alzheimer's with Depression More Brain Damage: The brains of 52 deceased patients with Alzheimer's disease without a lifetime history of major depression were compared with the brains of 50 patients with AD with a lifetime history of major depression. Brains of patients with AD with a lifetime history of depression showed much higher levels of both plaque (P<.005) and tangle (P<.002) formation within the hippocampus than brains of patients with AD without a history of depression. Those with a history of depression had more rapid cognitive decline than patients without a history of depression (P<.004). Within the group of patients with AD with a history of depression, those who had depression at the time of first diagnosis of AD had more pronounced neuropathological changes in the hippocampus (P<.006). Increased hippocampal plaques and tangles in patients with Alzheimer disease with a lifetime history of major depression. Rapp MA, et al.  Mount Sinai School of Medicine. . Arch Gen Psychiatry 2006 Feb;63(2):161-7.

Depression Not Linked to Alzheimer's Decline: In a 12-year prospective epidemiological study of 1265 adults over age 66 without dementia at baseline, 171 developed dementia. Depressive symptoms were not associated with rate of cognitive decline over time in either group. Depressive symptoms are cross-sectionally associated with cognitive impairment but not subsequent cognitive decline. Depressive symptoms and cognitive decline in late life: a prospective epidemiological study. Ganguli M, et al. University of Pittsburgh. . Arch Gen Psychiatry 2006 Feb;63(2):153-60.

Diabetes Increases Risk of AD: In a study of 2600 adults ages 40-65 in the Israeli Ischemic Heart Disease followed for almost 40 years, the mental status of 1892 participants was determined, and 652 were identified as possibly demented. This was confirmed in 309 subjects (16.3 percent). Those with diabetes during the study were 2.83-times more likely to develop dementia than those without diabetes. MS Beeri, et al. Mount Sinai, New York. Neurology, November 23, 2004.

Head Trauma Causes AD: Head trauma causing unconsciousness or 24 hours of amnesia in the 20's causes a four fold increase in AD later in life. AP 10/24/00.

Head Trauma Increases AD: A report released in 2000 by the National Institute on Aging compared the cases of World War II soldiers and found those who suffered moderate head injuries during the war were twice as likely to develop Alzheimer's. Those who had severe injuries were four times as likely to develop the condition. A 2002 study found mice with head trauma developed dementia sooner and had beta amyloid deposits. J Neuroscience

Head Trauma from Falls in Elderly Increases Dementia: 325 elderly with MMSE of over 25 were followed-up for 9 years. Then, 152 persons (81% of survivors) were examined for dementia. Eight persons sustained a traumatic brain injury (TBI) and 34 developed dementia. Brain injury was associated with a 180% increased risk of younger age at detection of dementia even when adjusted for sex and educational status (low educational status significantly associated with dementia); HR = 2.8. In a population scoring > or =28 points in the baseline MMSE an apolipoprotein E (ApoE) epsilon4 phenotype was also associated with a 256% increased risk of younger age at the time of detecting dementia; HR=3.56, and the effect of brain injury and ApoE epsilon4 phenotype was synergistic; HR=7.68. Fall-related brain injuries and the risk of dementia in elderly people: a population-based study. Luukinen H, Viramo P, et al. University of Oulu, Finland. Eur J Neurol. 2005 Feb;12(2):86-92.

Hyperthyroidism: Subclinical Cases with Low TSH May Cause AD: 1843 adults over 55 in prospective Rotterdam study found that those with low TSH at baseline had 3 times the risk of AD two years later (RR=3.5). Those with antibodies to thyroid peroxidase and low TSH had RR of 23! : Clin Endocrinol (Oxf) 2000 Dec 19;53(6):733-737

Immune: AD Increased T-Lymphocyte Interleukin 6 Receptor Binding: AD patients were found to have a definite increase in this binding compared to healthy controls. Seems related to immune function. Paolo Bongioanni, U Pisa, Arch Neurol 55:1305-8, ’98

Infectious Disease Not a Cause: antibody titres to Adenovirus, Chlamydia Group B, Coxiella burnettii, Cytomegalovirus, Herpes simplex virus, Influenza A, Influenza B, Measles and Mycoplasma pneumoniae were measured in 33 patients with a clinical diagnosis of Alzheimer's disease, and in 28 non-demented controls suffering from functional psychiatric disorders. No statistically significant differences. Age Ageing 1987 Sep;16(5):311-4. A study from Allegany Univ found PCR for Chlamydia in 17 of 19 AD brainsMed Microbiol Immunol (Berl) 1998 Jun;187(1):23-42, but three other studies failed to find any evidence at all.

Infection: Viral History of CMV or Herpes Doubles AD Risk but not Chlamydia p. or Mycoplasma p.: A history of infection with at least two of the viruses -- two strains of herpes and cytomegalovirus -- were about twice as likely to show significant mental decline during the one-year study as those infected with one or none of the pathogens. Both herpes and cytomegalovirus are known to damage brain cells, so infection with either or both could lead to loss of neurons, and eventually dementia. Timo Strandberg, of the University of Helsinki followed 383 elderly men and women with varying stages of blood vessel disease. More than 80 percent had a history of heart disease and 37 percent had had at least one stroke. The researchers looked for signs of infection with three common viruses: herpes simplex 1, which causes cold sores; its sexually transmitted sibling herpes simplex 2; and cytomegalovirus, which can be harmful to babies in the womb but typically causes no problems for healthy adults. Blood tests revealed that 48 people had evidence, in the form of proteins called antibodies, to one or none of the viruses; 229 had antibodies to two of the microbes; and 106 had signs of infection with all three viruses. At the start of the study 58 people, or 15 percent, had cognitive trouble. Those with antibodies to three viruses were 2.5 times more likely to fall into this group compared to people with fewer or no infections. The greater the level of antibodies, the more severe the dementia. In 12 mo. f/u, history of infection was strongly linked to the likelihood of mental decline. Chlamydia pneumoniae and mycoplasma p. both common but presences of antibodies not related to dementia. 9/03 Stroke

Lead Levels Associated with Lower Mental Functioning in Elderly: Using the MMSE score of < 24 as a measure of cognitive functioning, increased levels of lead in bone (odds ration 2.1)and blood (OR 3.4) are inversely associated with cognitive performance among older men. Lead exposure might accelerate age-associated cognitive decline. Among subjects in the lowest quartile of patella lead levels, MMSE score decreased by 0.03 points per year, whereas in the highest quartile, MMSE score decreased by 0.13 points per year. Similar interactions were found between blood lead levels and age. Harvard. Lead exposure biomarkers and mini-mental status exam scores in older men. Wright RO, Tsaih SW, et al. Epidemiology. 2003 Nov;14(6):713-8

Lead Levels Linked to Memory Deficiencies in Adults: The neuropsychological effects of lead exposure were examined in 39 adult outpatients. Lead blood levels ranged from 1 to 65.6 microg/l (mean 27.4). Although the neuropsychological test results of all patients were within the normal range, there were significant correlations between blood lead levels and the speed of information processing for working memory. Working memory deficiencies in adults associated with low-level lead exposure: implications of neuropsychological test results. Kunert HJ, Wiesmuller GA, et al. University of Aachen, Germany. Int J Hyg Environ Health. 2004 Dec;207(6):521-30.

Lipid Peroxidation May Play a Role: The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains. Compared with controls, researchers found a significant increase of metabolites of 12/15LOX in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. Activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, implicates 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD. Elevation of 12/15 lipoxygenase products in AD and mild cognitive impairment. Yao Y, et al. University of Pennsylvania. Ann Neurol. 2005 Jul 21

MEOX2: Alzheimer's Has Decreased MEOX2 Which Helps Form Blood Supply to Brain Tissue: In a study of endothelial cells from the lining of blood vessels in the brain, taken from autopsy samples from people with Alzheimer's, researchers found that expression of MEOX2, or mesenchyme homeobox 2, also known as GAX, was low in the cells of those with Alzheimer's. When there are low levels of MEOX2 expression, the affected cells cannot form any form of blood supply system, and so die. It also increased the level of a protein that removes amyloid beta peptide, the toxin that builds up in brain tissue in Alzheimer's disease. Restoration of the gene expression level in the human brain cells was found to stimulate the formation of new blood vessels. In further studies, one copy of the gene was deleted in mice, creating damage similar to that seen in the brains of people with Alzheimer's. Berislav Zlokovic, et al. University of Rochester. Nature Medicine 8/21/05.

Microglia Attack Amyloid with 4 Proteins Driving Inflammation: April, 2003, J Neuroscience, Case Western Reserve. Molecules play a critical role in making the brain think it is under attack from these plaques, triggering immune cells in the brain. Microglial cells detect plaques, made of beta amyloid, the microglial do not follow through on the attack, but remain inflamed. When microglia undergo this activation, they secrete various inflammatory toxins killing neurons. Maria E. Bamberger, found that the microglial cells use an ensemble of at least four different receptor proteins to bind to the amyloid. Each one of these receptor proteins act together at the same time to drive the inflammation.

Mitochondrial Defects Common in AD: Defects in mitochondrial oxidative phosphorylation have frequently been associated with Alzheimer's disease (AD), and both inherited and somatic mtDNA mutations have been reported in certain AD cases. Sixty-five percent of the AD brains studied had the T414G mutation, whereas this mutation was absent from all controls. Alzheimer's brains harbor somatic mtDNA control-region mutations that suppress mitochondrial transcription and replication. Coskun PE, Beal MF, Wallace DC. University of California, Irvine. Proc Natl Acad Sci U S A. 2004 Jul 20;101(29):10726-31

Mitochondria of Alzheimer's Have Impaired Calcium Transport: Study found this. Impaired transport leads to increased sensitivity of oxigenic free radicals. Kumar, U Saskachetwan, Life Sci ’94;54:1855

Mitochondria: APP Fragment Blocks Mitochondria: A 50 amino acid segment of APP seals off mitochondria in affected neurons, resulting in an "energy crisis" and buildup of toxins that causes cells to die. The A-beta portion hangs outside the mitochondria and get clipped off and builds up. This pathway, the first specific biochemical explanation for pathologies associated with Alzheimer's, is detailed in the April 14, 2003, Journal of Cell Biology.

Mitochondria: Abeta-bound ABAD Blocks NAD: Mitochondrial dysfunction is a hallmark of beta-amyloid (Abeta)-induced neuronal toxicity in Alzheimer's disease (AD). Abeta-binding alcohol dehydrogenase (ABAD) is a direct molecular link from Abeta to mitochondrial toxicity. Abeta interacts with ABAD in the mitochondria of AD patients. The crystal structure of Abeta-bound ABAD shows substantial deformation of the active site that prevents nicotinamide adenine dinucleotide (NAD) binding. An ABAD peptide specifically inhibits ABAD-Abeta interaction and suppresses Abeta-induced apoptosis and free-radical generation in neurons. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer's disease. Lustbader JW, Cirilli M, Lin C, Xu HW, Takuma K, Wang N, Caspersen C, Chen X, Pollak S, Chaney M, Trinchese F, Liu S, Gunn-Moore F, Lue LF, Walker DG, Kuppusamy P, Zewier ZL, Arancio O, Stern D, Yan SS, Wu H. Columbia University. Science. 2004 Apr 16;304(5669):448-52

Myelin Breakdown by Toxic Protein Possible Primary Cause: UCLA researcher George Bartzokis' theory: Myelin is a sheet of lipid, or fat, with very high cholesterol content -- the highest of any brain tissue. The cholesterol allows myelin to wrap tightly around axons, insulating these neural "wire" connections. As the brain continues to develop in adulthood and as myelin is produced in greater quantities, cholesterol levels in the brain grow and eventually promote the production of a toxic protein. The protein attacks myelin, and eventually leads to the brain/mind-destroying plaques and tangles visible years later. Genetic factors couple with the brain's own developmental process of increasing cholesterol and iron levels degrade the myelin. Complex connections that take the longest to develop and allow humans to think at their highest level are among the first to deteriorate as the brain's myelin breaks down in reverse order of development. Neurobiology of Aging 1/04.

Nerve Growth Factor May Be Involved: Dysfunction of nerve growth factor (NGF) and its high (TrkA) and low (p75NTR) affinity receptors underlies the selective degeneration of the nucleus basalis (NB) cholinergic cortical projection neurons in end stage Alzheimer disease (AD). The number of choline acetyltransferase-containing neurons remains stable despite a significant reduction in NGF receptor-positive cells in people with mild cognitive impairment (MCI). However, there is a loss of cortical TrkA in the face of stable p75NTR and increased proNGF levels, the precursor molecule of mature NGF, in early AD. Depending upon the cellular context these changes may result in increased pro-apoptotic signaling, cell survival, or a defect in retrograde transport mechanisms. Alterations in NGF and its receptors within the cholinotrophic NB system in early AD suggest that NGF-mediated cell signaling is required for the longterm survival of these neurons. Therapeutic neurotrophic intervention might delay or prevent NB neuron degeneration and preserve cholinergic cortical function during prodromal AD.

Niacin Low in Diet Linked to Dementia: Dementia can be caused by severe niacin insufficiency. In a 6-year follow-up study of 6158 Chicago adults over age 64, energy adjusted niacin intake had a protective effect on development of AD and cognitive decline. In a logistic regression model, relative risks for AD from lowest to highest quintiles of total niacin intake were: 1.0 (referent) 0.3, 0.3, 0.6, and 0.3 adjusted for age, sex, race, education, and ApoE e4 status. Niacin intake from foods was also inversely associated with AD (p = 0.002).

Overweight Have Brain Atrophy: In a study of 114 adults ages 40-66 given MRI studies, brain volume decreased as BMI increased. Increased diastolic blood pressure was associated with poorer episodic learning. Michael Ward et al. BMC Neurology 2005, 5:23 

Overweight and Obesity in Midlife Increase Risk of Dementia: In a Kaiser Permanente study of 10,276 Californians in their 40s and followed for 27 years, obese people were 74% more likely to develop dementia while those who were merely overweight were only 35% more likely. Skin fold thickness was more accurate for men than BMI. BMJ 4/30/05.

Overweight Increases AD in females: 392 elderly Swedish with an 18 year follow-up found that for each unit BMI over 25, 36% increase AD at age 79-88. Effect not found for males. Those getting AD had BMI 3.6 units higher. Gustafson, Goteborg U., An 18-year follow-up of overweight and risk of Alzheimer disease. Gustafson D, Rothenberg E, Blennow K, Steen B, Skoog Arch Intern Med. 2003 Jul 14;163(13):1524-8

Overweight Increases Risk of Dementia 25 Years Later: In a study of 7402 men ages 47-55 followed for 27 years, 3.4% developed dementia. The relationship between BMI and dementia was J-shaped, and men with a BMI between 20 and 22.5 had the lowest risk. After adjustment for smoking, blood pressure, serum cholesterol level, diabetes mellitus, and social class, the risk increased 73% in men who had a BMI of 22.5-25, 93% for 25-27.5, 130% for 27.5-30, and 154% for those who were obese (BMI 30.00 or greater)(P = .03). Men with a BMI less than 20.00 had a nonsignificantly 119% elevated risk. Overweight and obesity could be major preventable factors in the development of dementia. Body mass index, other cardiovascular risk factors, and hospitalization for dementia. Rosengren A, Skoog I, et al. Sahlgrenska University, Goteborg, Sweden. Arch Intern Med. 2005 Feb 14;165(3):321-6. 

Oxidation May Play a Role: 4-hydroxy-2-trans-nonenal (HNE), an aldehydic product of membrane lipid peroxidation, is increased in AD brain. The alpha class of glutathione S-transferase (GST) can detoxify HNE and plays an important role in cellular protection against oxidative stress. The export of the glutathione conjugate of HNE is required to fully potentiate the GST-mediated protection. The multidrug resistance protein-1 (MRP1) and GST proteins may act in synergy to confer cellular protection. Oxidative modification of GST and MRP1 in AD brain by immunoprecipitation of GST and MRP1 proteins suggest that HNE is covalently bound to GST and MRP1 proteins in excess in AD brain. HNE may be an important mediator of oxidative stress-induced impairment of this detoxifying system and may thereby play a role in promoting neuronal cell death. Augmenting endogenous oxidative defense capacity through dietary or pharmacological intake of antioxidants may slow down the progression of neurodegenerative processes in AD. Oxidatively modified GST and MRP1 in Alzheimer's disease brain: implications for accumulation of reactive lipid peroxidation products. Sultana R, Butterfield DA. University of Kentucky. Neurochem Res. 2004 Dec;29(12):2215-20.

Oxidative Damage Increased in Mild Cognitive Impairment: In a study of patients with mild cognitive impairment, the amount of protein carbonyls, thiobarbituric acid-reactive substances (TBARS), and malondialdehyde in the superior and middle temporal gyri (SMTG) and cerebellum found elevated levels of protein carbonyls (25%), malondialdehyde (60%), and TBARS ( 210%) in the SMTG of individuals with MCI and early AD vs normal control subjects. The elevation in TBARS was associated with the numbers of neuritic but not diffuse plaques. Levels of protein carbonyls increased as delayed verbal memory performance declined. Oxidative damage occurs in the brain of subjects with mild cognitive impairment, suggesting that oxidative damage may be one of the earliest events in the onset and progression of Alzheimer disease. Evidence of increased oxidative damage in subjects with mild cognitive impairment. Keller JN, et al. University of Kentucky. Neurology. 2005 Apr 12;64(7):1152-6 

Oxidative Damage in AD: Oxidative stress forms nitrotyrosine by perioxydation of nitrate, and neurotoxic to NMDA. It is found in neuorfibillary tangles which are also common to Parkinson’s and ALS. Good, Mt. Sinia, Am J Neurol 7/96: 149:21

Pesticide Exposure Occupationally Linked: In men, the relative risks of developing Parkinson's disease and Alzheimer's disease for occupational exposure assessed by a job exposure matrix were 5.63 and 2.39, respectively, after confounding factors were taken into account. No association was found with having a primary job in agriculture or with environmental pesticide exposure, nor was an association found in women. Bordeaux. Neurodegenerative diseases and exposure to pesticides in the elderly. Baldi I, Lebailly P, Mohammed-Brahim B, Letenneur L, Dartigues JF, Brochard P. Am J Epidemiol 2003 Mar 1;157(5):409-14.

Smoking Doubles Dementia: In a study of 6870 adults over age 54 with 2.1 years of follow-up found smoking increased with risk of dementia by 120% (RR 2.2), especially for those without the apoE-4 allele (360% or RR 4.6).  Those with the allele had no increased risk from smoking. Ott, Erasmus Univ, Lancet, ’97;351:1840. Apolipoprotein E (apoE) is a major apolipoprotein in the CNS, mediating the transport of cholesterol, phospholipids and their fatty acids, particularly in reparative mechanisms during neuronal injury.

Smoking More than Doubles AD: A study of 2820 adults over age 59 followed for two years found a total of 121 incident cases of dementia, of which 84 (69%) were Alzheimer's disease, 17 (14%) were vascular dementia, and 21(17%) were other dementia. Compared with never smokers, current smokers had a 172% increased risk of Alzheimer's disease (RR = 2.72) and 98% increased risk of vascular dementia (RR = 1.98) adjusting for age, sex, education, blood pressure, and alcohol intake. Compared with light smokers, the adjusted risk of Alzheimer's disease was significantly (156%) increased among smokers with a medium level of exposure (RR = 2.56), with an even higher 203% risk of Alzheimer's disease in the heavy smoking group (RR = 3.03). A 2-year follow-up study of cigarette smoking and risk of dementia. Juan D, Zhou DH, Li J, Wang JY, Gao C, Chen M. Chongqing, China.  Eur J Neurol. 2004 Apr;11(4):277-82

Smoking Causes Mental Decline in Nondemented Elderly: 17,610 persons over age 64 were followed for 2.3 years and 11,003 were retested. Mini-Mental State Examination (MMSE) score of persons who never smoked on average declined 0.03 point/year. The adjusted mental decline of former smokers was twice as fast (0.03 point greater) and of current smokers four times as fast (0.13 point greater) compared to never smokers (p < 0.001). Higher cigarette pack-year exposure was correlated with a significantly higher rate of decline. Effect of smoking on global cognitive function in nondemented elderly. Ott A, Andersen K, Dewey ME, Letenneur L, Brayne C, Copeland JR, Dartigues JF, Kragh-Sorensen P, Lobo A, Martinez-Lage JM, Stijnen T, Hofman A, Launer LJ; EURODEM Incidence Research Group. Erasmus University, the Netherlands. Neurology. 2004 Mar 23;62(6):920-4

Smokers’ Memory Already Impaired in 50s: UK study of 5346 born in 1946 and tested 21 times found that verbal memory in smokers deteriorated much more rapidly between 40s and 50s. Those who stopped smoking, esp before age 43, had much less damage. Richards, American Journal of Public Health 2003;93. 5/29/03, Univ College London. Damage worse for over 1 pack/d

SAMe: Theory of SAMe shortage: This theory proposes that hypomethylation caused by a shortage of s-adenosylmethionine might play a role in Alzheimer's and Parkinson's diseases. Med Hypotheses 2000 May;54 (5):774-6. B-12 and folate vitamins occupy a key position in the remethylation and synthesis of S-adenosylmethionine (SAMe), a major methyl donor in CNS; therefore, deficiencies in either of these vitamins lead to a decrease synthesis of SAMe and increase in Homocysteine, which otherwise is methylated to methionine. S-adenosylmethionine is involved in numerous (35) methylation reactions involving proteins, phospholipids, DNA, and neurotransmitter metabolism. SAM found reduced 67% - 84% in Alzheimer brains, but normal in Parkinson’s disease. severe reduction in levels of this essential biochemical substrate would be expected to compromise seriously metabolism and brain function in patients with Alzheimer's disease. :J Neurochem 1996 Sep;67(3):1328-31. Lower methionine S-adenosyltransferase Km in RBCs of AD patients corrected by giving B-12, folate, and SAM 200BID. support the hypothesis that aberrations in the B12 dependent transmethylation reactions might be involved in the pathogenesis of dementia, and suggest that the evaluation of erythrocyte MAT activity may be a useful marker for the detection of such an aberration. U Uppsala. Eur Neuropsychopharmacol 1995 Jun;5(2):107-14. SAMe has antidepressant properties, and preliminary studies indicate that it may improve cognitive function in patients with dementia. Treatment with methyl donors (betaine, methionine and SAMe) is associated with remyelination in patients with inborn errors of folate and C-1 (one-carbon) metabolism. These studies support a current theory that impaired methylation may occur by different mechanisms in several neurological and psychiatric disorders. S-adenosylmethionine decarboxylase (SAMDC), a key regulatory enzyme of polyamine biosynthesis, in autopsied brain from 13 patients with Alzheimer's Disease (AD). As compared with the controls, mean enzyme activity was increased by 37-96% in all seven examined brain regions with statistically significant increases in temporal cortex (%), frontal cortex (%) and hippocampus (%). The elevated SAMDC may have occurred as part of a generalized polyamine response to brain injury, which has been previously described in experimental animal conditions. Above-normal SAMDC activity implies increased levels/metabolism of spermidine and spermine, two polyamines which are involved in neuronal regeneration, growth factor production, and activation of excitatory N-methyl-D-aspartate preferring glutamate receptors. Our data suggest the involvement of the polyamine system in the brain reparative and/or pathogenetic mechanisms of AD. Neurosci Lett 1993 May 14;154(1-2):141-4. S-Adenosylmethionine, which has antidepressant properties, raises brain 5-hydroxytryptamine (and serotonin). One old study reported rx AD pts with SAMe and found improvement in membrane fluidity but no change in AD. J Clin Psychopharmacol 1988 Feb;8(1):43-7. Since SAMDC is a key regulatory enzyme in the synthesis of spermidine and spermine, the marked increase in SAMDC activity in the neonate and the sustained high enzyme levels throughout adulthood, imply a role for these polyamines in both development and mature brain function. SAMDC increased in AD. Above-normal SAMDC activity implies increased levels/metabolism of spermidine and spermine, two polyamines which are involved in neuronal regeneration, growth factor production, and activation of excitatory N-methyl-D-aspartate preferring glutamate receptors. Our data suggest the involvement of the polyamine system in the brain reparative and/or pathogenetic mechanisms of AD. Neurosci Lett 1993 May 14;154(1-2):141-4. deficiency of S-adenosylmethionine is critical to the development of demyelination in cobalamin deficiency. J Inherit Metab Dis 1993;16(4):762-70

Testosterone Lower with Alzheimer’s in Small Autopsy Study: Osteoporosis and the loss of muscle mass, strength and function (sarcopenia) linked to decreased testosterone levels is called ADAM, or androgen deficiency in aging males. Androgens are male sex hormones. Using brain tissue from 45 deceased males, brain levels of testosterone were significantly lower in Alzheimer’s subjects. Estrogen levels were affected by neither advancing age nor Alzheimer’s. Testosterone protects neurons from injury, and it reduces levels of beta-amyloid, JAMA 9/22/04 Christian Pike, et al. USC

Vaccine of Amyloid Beta Decreased in Mice: In mice, vaccination decreased amyloid deposits and signs of dementia. Nature 2000 Dec 21-28;408(6815):982-5. Ed: Unfortunately, humans developed side-effects from a vaccine and the human experiment had to be stopped.  Other studies are still on-going.

Transporter Difficulty: Normally, amyloid beta protein, the protein thought to cause Alzheimer's disease, leaves the brain and crosses the blood brain barrier, which is a wall of blood vessels that feed the brain and regulate the entry and exit of brain chemicals. But in persons with Alzheimer's disease, apparently due to a transporter problem in the barrier, amyloid beta protein becomes blocked in the brain and can't make it across the blood brain barrier. The more amyloid beta protein accumulates, the tougher it is for the blood brain barrier to move it out. Wm Banks, St. Louis Univ, 10/03 Neuroscience.

Valproic Acid (Depakene or Depakote) Dementia Case: A case of reversible dementia in a 72 year old female caused by valproic acid medication is reported. Walstra, Ned Tidjschr Geneeshkd 2/97

White Matter Lesions Associated with Cognitive Impairment: Deary of the University of Edinburgh in Scotland reports in the Amer Psychological Ass 3/23/03 a study of 89 Scottish tested at age 11 and again at age 78. The number of white-matter lesions in the brain contributed 14% of the variance in cognitive scores; early IQ scores contributed another 14%. Lesions were associated somewhat with with presence of high blood pressure.

Naprilysin Gene Therapy Helps in Mice: Naprilysin is a protein that normally breaks down beta-amyloid. Using an HIV modified vector, the naprilysin gene was injected and successfully decreased beta-amyloidlevels by 50%. Salk Institute, J Neurosci 3/15/03

Thomas E. Radecki, M.D., J.D.

 modern-psychiatry.com