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Risk factors are abnormalities that are indicators of a greater likelihood of disease but they are not necessarily causes of the disease. The below are risk factors either for dementia in general or Alzheimer's specifically. These include decreased hearing, reduced awareness, low bone mineral density, high CRP (inflammation), low cholinesterase activity, dental cavities, depression, untreated diabetes, high homocysteine, APOE-e4 gene, folate recepter gene polymorphism, lack of nighttime melatonin peak, low IQ, certain atrophy on MRI (hippocampus, general), late onset schizophrenia, high tau and low amyloid in CSF, strokes, low free testosterone, low walking speed, and white matter hyperdensities on MRI. Auditory Dysfunction, Central Type, Precedes Some AD: The presence of a central auditory speech-processing deficit had 900% increased risk, i.e., an age-adjusted risk ratio for probable Alzheimer's disease of 10.8. The estimated risk ratio adjusted for age, gender, education level, apolipoprotein allele E4 presence, and hearing level was 23.3 or 2200% ! In all, 740 dementia-free Framingham patients were measured for symmetric hearing thresholds and followed. A central auditory speech-processing deficit was defined as a score of 50% of less correct on the Synthetic Sentence Identification with Ipsilateral Competing Message test in at least one ear with normal word recognition ability in both ears. The test had a positive predictive value for subsequent probable Alzheimer's disease of 47% but the sensitivity was only 17.5%. In other words, half of those with a defective test developed dementia, but only one of out six who developed dementia had had a defective test. J Am Geriatr Soc 2002 Mar;50(3):482-8 Awareness: Lack of Awareness a Predictor: Patient's lack of awareness of mild cognitive functional deficits identified by informants strongly predicts a future diagnosis of AD. Neurology 2002 Mar 12;58(5):758-64 Bone Mineral Density When Low Strongly Associated with Increased Verbal Memory Impairment: With adjustment for age, sex, and other covariates, the prevalence ratios of verbal memory impairment for each increased bone mineral density quintile were 1.00, 0.64, 0.65, 0.55, and 0.44, respectively (p for trend < 0.001). Am J Epidemiol 2001 Nov 1;154(9):795-802 C-Reactive Protein Low = Low Dementia: In a 25 year follow-up Honolulu of Japanese-Americans of a subset of 1050 men found that those in the lowest quartile of CRP blood levels had 1/3 the rate of dementia. These relations were independent of cardiovascular risk factors and disease. CRP is a non-specific marker of inflammation. Early inflammation and dementia: a 25-year follow-up of the Honolulu-Asia Aging Study. Schmidt R, Schmidt H, et al. Ann Neurol 2002 Aug;52(2):168-74; CT Scans Measure Progression: Study of 18 with AD and controls found 2.4% more atrophy in one year vs. 0.4% in controls. Arch Neurol 2000;57;339 Cholinesterase Activity Decreased in Early Alzheimer's: Cholinesterase (ChE) activity was measured in lymphocytes, erythrocytes and platelets. Both early-AD and AD patients had lower AChE activity in lymphocytes compared to control subjects (p < 0.0001). Erythrocyte AChE activity was higher in patients with vascular dementia (p = 0.004). Low ChE activity in lymphocytes was the best discriminator for AD. Blood Cells Cholinesterase Activity in Early Stage Alzheimer's Disease and Vascular Dementia. von Bernhardi R, Alarcon R, et al. Pontificia Universidad Catolica de Chile, Santiago, Chile. Dement Geriatr Cogn Disord. 2005 Jan 25;19(4):204-212 Dental Caries More Common in Demented: In a 1-year follow-up community study of over 100 elderly living in community with dementia vs. controls, dental cavities were more common in the demented. Caries incidence and increments in community-living older adults with and without dementia. Chalmers JM, Carter KD, Spencer AJ. Gerodontology 2002 Dec;19(2):80-94 Unipolar and Bipolar Depressed at Greater Risk for Dementia than Patients with Diabetes or Osteoarthritis: A Danish study of all hospitalizations in the nation followed the data for 2,007 patients hospitalized with mania, 11,700 depression, 81,380 osteoporosis, and 69,149 diabetes. Researchers calculated the risk of later hospitalization for dementia. U Copenhagen. Increased risk of developing dementia in patients with major affective disorders compared to patients with other medical illnesses. Kessing LV, Nilsson FM. J Affect Disord 2003 Feb;73(3):261-9 Depression Somewhat Higher AD Risk: 1,953 AD and 2,093 unaffected relatives in Research in Alzheimer's Genetic Epidemiology Study were studied. There was an association between depression symptoms and AD (adjusted OR, 2.13). In families where depression symptoms first occurred within 1 year before the onset of AD, the association was higher (OR, 4.57), while in the families where the depression symptoms first occurred more than 1 year before the onset of AD, the association was lower (OR, 1.38). In families where depression symptoms first occurred more than 25 years before the onset of AD, there was still a modest association (OR, 1.7). Arch Neurol 2003 May;60(5):753-9 Green RC; Cupples LA; Kurz Diabetes Causes Mental Impairment in Senior Citizens; Treatment Helps: In a study of 18,999 ex-nurses in Boston ages 70-81, women with diabetes were at 25-35% more likely to do poorly on cognitive testing. Odds of poor cognition were particularly high for women who had had diabetes for a long time (over 14 years) (1.52). In contrast, women with diabetes who were on oral hypoglycemic agents performed similarly to women without diabetes, while women not using any medication had the greatest odds of poor performance (1.71) compared with women without diabetes. Prospective study of type 2 diabetes and cognitive decline in women aged 70-81 years. Giancarlo Logroscino. BMJ 2004;328:548 (6 March) Glycogen Synthase Kinase-3 (GSK3) Sometimes Involved: Glycogen synthase kinase-3 (GSK3) is a key component of a large number of cellular processes and diseases. Several mechanisms play a part in controlling the actions of GSK3, including phosphorylation, protein complex formation, and subcellular distribution. These are used to control and direct the far-reaching influences of GSK3 on cellular structure, growth, motility and apoptosis. Dysregulation of GSK3 is linked to diabetes and/or insulin resistance, and Alzheimer's disease. The glamour and gloom of glycogen synthase kinase-3. Jope RS, Johnson GV. University of Alabama at Birmingham. . Trends Biochem Sci. 2004 Feb;29(2):95-102 Homocysteine Increase Linked to Increased MMSE: In a study of 2,871 stroke-free adults from The Northern Manhattan Study, homocysteine levels were related to age, renal function, and B12 deficiency. Those with B12 deficiency had tHcy levels five points higher (9.4 vs 14.4 nmol/L). Mean MMSE scores differed by age, sex, and race-ethnic group. Those with hypertension, diabetes, cardiac disease, and B12 deficiency had lower MMSE scores. In multivariate analyses, elevated tHcy was associated with lower mean MMSE scores for those older than 65 but not for those 40 to 64. Adjusting for B12 deficiency and sociodemographic factors the mean MMSE was 2.2 points lower for each unit increase in the log tHcy level. Adding vascular risk factors to the model did not attenuate this effect (mean MMSE -2.2 points). Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study. Wright CB, et al. Columbia University. . Neurology. 2004 Jul 27;63(2):254-60 Homocysteine Increase Not Linked to AD in Study: In 679 elderly without dementia followed for 3,206 person-years, 237 developed Alzheimer’s dementia. High homocysteine levels were not associated with AD and were not related to a decrease in memory scores over time. Plasma homocysteine levels and risk of Alzheimer disease. Luchsinger JA, Tang MX, Shea S, Miller J, Green R, Mayeux R. Columbia University. Neurology. 2004 Jun 8;62(11):1972-6. Ed: This is a large, prospective study which increases its reliability. Homocysteine Linked to Alzheimer's and Aggravated by Methylenetetrahydrofolate Reductase Polymorphism: Homocysteine metabolism is influenced by genetic polymorphisms of the methylenetetrahydrofolate reductase (MTHFR 677 C-->T and 1298 A-->C) and transcobalamin genes (TCN1 776 C-->G ). We evaluated the association of homocysteine with Alzheimer's disease (AD) and the influence of related polymorphisms and APOE, in 180 cases and 181 controls from southern Italy. Homocysteine (upper tercile) was associated with AD risk, with an odds ratio of 2.8 (p=0.0008), which was increased 2.2- and 2.0-fold by MTHFR 677T (OR 6.28, p < 0.0001) and APOE epsilon4 (OR: 5.60, p=0.0361), respectively. In conclusion, association of homocysteine with AD was aggravated by MTHFR 677T and APOE epsilon4 alleles. Homocysteine and methylenetetrahydrofolate reductase polymorphism in Alzheimer's disease. Anello G, Gueant-Rodriguez RM, Bosco P, Gueant JL, Romano A, Namour B, Spada R, Caraci F, Pourie G, Daval JL, Ferri R. Italy. Neuroreport. 2004 Apr 9;15(5):859-61 Homocysteine Up in Dementia: ACP J Club 2002 Sep-Oct;137(2):76 Homocysteine Said High in AD: Matched study of 30 ADs found homocysteine much higher (P<.0001) and correlated with low B-12 without signs B-12 difficiency. Low B-12 a cause of high homocyst. Claims aberrant B-12 tissue delivery a cause of AD. North Wales. Int J Geriatr Psychiatry 1998 Apr;13(4):235-9. S-Adenosylmethionine and S-adenosylhomocysteine levels were normal in occipital cortex of patients with idiopathic Parkinson's disease (n = 10), suggesting that the decreased S-adenosylmethionine levels in Alzheimer's disease are not simply a consequence of a chronic, neurodegenerative condition. Reduced S-adenosylmethionine levels could be due to excessive utilization in polyamine biosynthesis. J Neurochem 1996 Sep;67(3):1328-31; 2/14/2002 NEJM Boston U study Framingham 935 people with 8 yr f/u average age 76 at start. 30% homocysteine over 14 micromoles, i.e., high. At f/u 111 with dementia, 83 of which AD. Those with high homocysteine at beginning were twice as likely to develop dementia, including AD. Homocysteine Increased in CVD: There was more cerebral vascular disease found in highest quartile of serum homocysteine. NEJM ’95 332:286-91 Hyperphosphorylated Tau Excellent Marker: CSF level of tau phosphorylated at Ser-396/Ser-404 is a promising diagnostic marker of AD. China. Am J Pathol 2002 Apr;160(4):1269-78 Inflammatory Proteins Modestly Elevated in AD and Vascular Dementia: From 6,713 subjects who were free of dementia, a random subcohort of 727 subjects and 188 cases who had developed dementia at follow-up, researchers found high levels of alpha1-antichymotrypsin, interleukin 6, and, to a lesser extent, C-reactive protein were associated with an increased risk of dementia; rate ratios per standard deviation increase were 1.49, 1.28, and 1.12, respectively. Similar associations were observed for Alzheimer disease, whereas rate ratios of vascular dementia were higher for alpha1-antichymotrypsin and C-reactive protein. Soluble forms of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were not associated with dementia. Inflammatory proteins in plasma and the risk of dementia: the rotterdam study. Engelhart MJ, Geerlings MI, Meijer J, Kiliaan A, Ruitenberg A, van Swieten JC, Stijnen T, Hofman A, Witteman JC, Breteler MM. Erasmus Medical Center, Rotterdam, The Netherlands. Medial Temporal Lobe Atrophy Predicts Alzheimers: During a six-year period, 45 subjects older than 60 years underwent neuropsychometric tests and MRI baseline and at two or more follow-up evaluations. Cognitive decline occurred in 13 (29%). The best predictor of cognitive decline was MTL atrophy. Accuracy was 89% (in 40 of 45 subjects); specificity was 91% (in 29 of 32 subjects), and sensitivity was 85% (in 11 of 13 subjects). Henry Rusinek, NYU, Radiology. 12/2003;229:691-696 Melatonin: Nighttime Peak Blunted; More with Dementia; Less in Centenarians: Elderly, ages 66-94, demented or not, exhibited a flattened circadian profile, because of the suppression of the nocturnal peak. This was greater in demented individuals and significantly correlated with the severity of the cognitive impairment. As in young controls, in centenarians the aMT6s excretion was significantly higher at night than during the day. In centenarians, ages 100-107, the maintenance of the circadian organization of melatonin secretion may suggest that the amplitude of the nocturnal peak and/or the persistence of a prevalent nocturnal secretion may be an important marker of biological age and of health status. Qualitative and quantitative changes of melatonin levels in physiological and pathological aging and in centenarians. Magri F, Sarra S, et al. University of Pavia, Italy. J Pineal Res. 2004 May;36(4):256-61; Melatonin in a large Chinese study began falling after age 59. Chronobiol Int. 2002 Nov;19(6):1171-82. Another smaller Chinese study reports decreases after age 40. J Pineal Res. 2003 Jan;34(1):11-6. Supplement levels are typically far higher than endogenous levels. Mental Ability in Childhood Predicts Independent Living Elderly: Independent functioning at age 77 was strongly predicted by mental ability at age 11. Age and Ageing, 2000;29:583 Mental Ability: Higher IQ and Verbal Ability Predicts Slower Mental Decline: In a study of 2,058 adults born in 1946 and tested for verbal ability at age 15 and retested for reading ability at age 53, ability in childhood was inversely associated with decline in memory (OR = 0.09, P = 0.005) and search speed ( = 0.11, P < 0.005), independent of educational attainment, occupational social class, and a range of health indicators. The adult reading test was also significantly and negatively associated with decline in these outcomes (for memory = 0.19, P < 0.001; and for search speed) independent of educational attainment, social class, and childhood ability. Both childhood and adult higher IQ independently predict a slowed rate of mental decline. Cognitive ability in childhood and cognitive decline in mid-life: longitudinal birth cohort study. Marcus Richards. BMJ 2004;328:552 (6 March) Mental Activity Low Before Alzheimers: Between ages 40-60, people who were less active in their leisure time activities were three to four times more likely to have Alzheimer's disease. Robert Friedland, associate professor of neurology, psychiatry, and radiology at Case Western, Am Acad Neurol Meeting 9/18/00. Mental Activity: Rate of Cognitive Decline Predicts Death: After age 70, a more rapid cognitive decline was a strong, independent predictor of earlier death in Dutch follow-up study of 211 elderly. Am J Epid 11/90 MRI Helps Predict: Volume of entorhinal area predicted conversion to AD 3 years later with converters 37% less volume reflecting neuronal loss. Albert MGH 4/00 Annals Neurol; Volume of hypocampus measured by MRI may be decreased decades before memory loss with neurofibrills and tangles just beginning. Nun Study of 678 nuns ages 75-102 with brain autopsies. U S. Fla & U Ky. Neurology 5/02 Neuroticism Scale Scores Predict AD: A Rush-Presbyterian 4.9 year follow-up in the Religious Orders Study of 797 nuns 75 or older found that higher scores on the neuroticism scale were linked to an increased risk of dementia at follow-up. Persons in the 90th percentile on the test were twice as likely to develop AD as those in the 10th percentile. Neurology 2003;61:1479-1485 Osteoprotegerin a Marker for Vascular and Alzheimer Dementia: Elevated level of osteoprotegerin (OPG), a pleiotropic cytokine involved in bone metabolism, is associated with coronary heart disease and higher cardiovascular mortality. Cardiovascular disorders are recognized risk factors for dementia. OPG concentration of 39 VaD patients, 36 AD patients, and 39 non-demented controls found OPG levels were positively related to age in both demented and non-demented persons. OPG concentrations were significantly higher in both VaD (median: 4.75 pmol/l; P<0.0001) and AD (median: 4.02 pmol/l; P=0.0278) compared to non-demented controls (median: 3.24 pmol/l). After allowance for confounding factors (age, gender and APOE epsilon4 allele), plasma OPG levels remained independently associated with the presence of VaD (OR = 2.51; P=0.0009) and AD (OR = 2.17; P=0.0126). These results further support the hypothesis that vascular factors may not only play a role in the pathogenesis of VaD but also in the pathogenesis of AD. Plasma osteoprotegerin as a biochemical marker for vascular dementia and Alzheimer's disease. Emanuele E, Peros E, Scioli GA, D'Angelo A, Olivieri C, Montagna L, Geroldi D. University of Pavia, Italy. Int J Mol Med. 2004 Jun;13(6):849-53 Perivascular Space Enlargement Increased with Worse Mental Ability: The abnormal channels are known as enlarged perivascular spaces, rare in young, healthy adults, are very common in older people, and in conditions such as diabetes, Parkinson's disease, and high blood pressure. The enlarged perivascular spaces might be an indicator of overall brain shrinkage, or they might reflect specific damage to brain tissue around blood vessels. In 100 healthy elderly males, more enlarged perivascular spaces was linked to worse mental ability. Joanna Wardlaw et al, Edinburgh University. J Neurol NeuroSurg Psychiatry 12/05. Schizophrenia Late Onset Prelude for Alzheimer's: 27 who developed schizophrenia at age 50 or above, with Mini-Mental State Examination (MMSE) scores were 20 or above. 19 followed-up 5 years later. Compared with those of 34 normal controls, 24 of whom were re-examined after 5 years. Average age of both groups exceeded 70 years. At 1-year follow-up, there was no evidence of decline in either group. At 5 years, however, nine schizophrenia patients were diagnosed with dementia. Five met criteria for Alzheimer's disease, one for vascular dementia, and three for dementia of unknown type. None of the controls had dementia. Over 5 years, mean MMSE scores declined from 25.5 to 19.0 in the schizophrenic patients, but only from 29.7 to 29.2 in the normal subjects (p < 0.001). Schizophrenic individuals who did not develop dementia hadobal Assessment of Functioning scores increased from 41.4 to 61.6 during follow-up, which was attributed to resolution of psychosis. Given that about half of the patients with schizophrenia did not become demented, the authors maintain that late-onset schizophrenia is a heterogeneous syndrome. Br J Psychiatry 2003;183:213-219. Spinal Tap High Tau, Low Beta-Amyloid: Trey Sutherland, US National Institute of Mental Health performed spinal taps on 136 Alzheimer's patients and 72 people without. Patients with the disease had less than half the normal level of beta amyloid while their tau levels were more than double those of people without the disease. This pattern was found in 90% of Alzheimer's patients involved in the study. JAMA 4/23/03 Stroke Increases Risk of AD 60%: A study of over 1,700 Medicare patients found that those who had had strokes were 60% more likely to develop Alzheimer's that those without strokes. Lawrence Honig, Richard Mayeux, Columbia, Arch Neurol 12/03. High Testosterone, Low Sex Hormone-Binding Globulin Protective: Data prospectively collected in the Baltimore Longitudinal Study of Aging on 574 men ages 32-87 and free of AD were followed for 19.1 years. 54 were diagnosed with AD. Serum total testosterone and sex hormone-binding globulin (SBHG) were not associated with AD. However, the free androgenization index (FAI) (dividing serum testosterone by sex hormone-binding globulin) was inversely associated with AD onset. There was a 26% reduction in the risk of AD with each 10-unit increase in FAI, suggesting a protective effect of testosterone. In the second study, Gian Benedetto Melis of the University of Cagliari, Italy, compared hormone levels in 32 men and 64 women with AD to those in 32 men and 72 women without AD. Subjects' BMI ranged between 20 and 22. SHBG levels were significantly higher and FAI was significantly lower in subjects with AD, both men and women. Unbound testosterone can cross the blood-brain barrier, where it can work as an androgen or be converted to estrogen, which is supported by previous research showing a beneficial effect of estrogen on the central nervous system. Testosterone supplements are not warranted at this point to protect against AD. Neurology 1/27/2004;62:188-193,301-303. Walking Speed Best Predictor Elderly Dependency: Maximum walking speed was most sensitive in predicting future dependence for those ages 65-74, while usual walking speed was most sensitive for people age 75. Walking speed was the best physical performance measure for predicting the onset of functional dependence in a Japanese rural older population. Prospective 6 year study. Age and Ageing, 29:441-446, 9/00 White Matter Hyperdensities Common in AD: 81 AD patients and 19 healthy volunteers of comparable age were given MRIs and neurological testing. Images were segmented into grey matter, white matter, and cerebrospinal fluid. AD patients had significantly more white matter hypertensities (WMH) than controls (p<0.05). WMH preferentially involved the frontal lobes (70%), were inversely correlated with grey matter cortical volume (R(2) = 0.23, p<0.001), and were significantly associated with vascular risk factors and with a worse performance on memory tasks. White matter hyperintensities are significantly associated with cortical atrophy in Alzheimer's disease. Capizzano AA, Acion L, et al. Buenos Aires. J Neurol Neurosurg Psychiatry. 2004 Jun;75(6):822-7 White Matter Hyperdensities Strong Hereditary Pattern in Non-Demented: In a previous study of normal elderly male twins, the heritability of quantitative white matter hyperintensity (WMH) volume has been estimated to be high (0.73). Brain magnetic resonance scans were performed on 1330 stroke- and dementia-free individuals (mean age 61) in the offspring of the Framingham study. Individuals with a history of multiple sclerosis, stroke, dementia, or other neurological condition including traumatic brain injury were excluded from this analysis. WMH heritability was 0.55 (P<0.0001). Heritability among women was 0.78 (P<0.0001) whereas heritability among men was 0.52 (P<0.0003). Heritability varied as average age increased, with a peak of 0.68 (P<0.0001) in individuals aged 55 or older. Genetic Variation in White Matter Hyperintensity Volume in the Framingham Study. Atwood LD, Wolf PA, et al. Boston University. Stroke. 2004 May 13 Thomas E. Radecki, M.D., J.D.
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