Risk Factors for Dementia (of special interest to the 10/66 research programme)

Cardiovascular risk factors and cardiovascular disease

An updated analysis of protective and risk factors of dementia (including developmental and early-life risk factors, psychological factors, lifestyle, and cardiovascular risk factors) was published in the World Alzheimer Report 2014 on Dementia and Risk reduction. It is available here.

Recent research suggests that vascular disease predisposes to AD as well as to vascular dementia (1). In short (2-4) and longer latency (5,6) incidence studies, smoking increases the risk for Alzheimer's disease. Inverse associations from case-control studies are thought to be explained by prevalence-incidence bias, with smoking influencing dementia-specific mortality (7). Diabetes is also a risk factor (8), and in longer term cohort studies, midlife hypertension (9,10) and hypercholesterolemia (10)are associated with AD onset in later life. Aggregated cardiovascular risk indices incorporating hypertension, diabetes, hypercholesterolaemia and smoking incrementally increase risk for dementia incidence whether exposure is measured in midlife (6) or a few years before dementia onset (4). Recent studies report associations between metabolic syndrome and incident cognitive decline (11), and insulin resistance and impaired executive function (12), but the role of the metabolic syndrome is as yet little explored. Despite occasional negative findings from large prospective studies (13,14), the accumulated evidence for a causal role for CVRF and CVD in the aetiology of dementia and AD is very strong. This has led to the hypothesis that atherosclerosis and AD are convergent disease processes (15), with some common pathophysiological and aetiologic factors (APOE e4 polymorphism, hypercholesterolaemia, hypertension, hyperhomocysteinaemia, diabetes, metabolic syndrome, smoking, systemic inflammation, increased fat intake and obesity).

1. Hofman A, Ott A, Breteler MMB, et al. Atherosclerosis, apolipoprotein E, and prevalence of dementia and Alzheimer's disease in the Rotterdam Study. Lancet 1997;349:151-154.
2. Ott A, Slooter AJC, Hofman A, et al. Smoking and risk of dementia and Alzheimer's disease in a population-based cohort study: the Rotterdam Study. Lancet 1998;351:1841-1843.
3. Juan D, Zhou DH, Li J, Wang JY, Gao C, Chen M. A 2-year follow-up study of cigarette smoking and risk of dementia. Eur J Neurol 2004 Apr;11:277-282.
4. Luchsinger JA, Reitz C, Honig LS, Tang MX, Shea S, Mayeux R. Aggregation of vascular risk factors and risk of incident Alzheimer disease. Neurology 2005 Aug 23;65:545-551.
5. Tyas SL, White LR, Petrovitch H, et al. Mid-life smoking and late-life dementia: the Honolulu-Asia Aging Study. Neurobiol Aging 2003 Jul;24:589-596.
6. Whitmer RA, Sidney S, Selby J, Johnston SC, Yaffe K. Midlife cardiovascular risk factors and risk of dementia in late life. Neurology 2005 Jan 25;64:277-281.
7. Hill G, Connelly J, Hebert R, Lindsay J, Millar W. Neyman's bias re-visited. J Clin Epidemiol 2003 Apr;56:293-296.
8. Ott A, Stolk RP, van HF, Pols HA, Hofman A, Breteler MM. Diabetes mellitus and the risk of dementia: The Rotterdam Study. Neurology 1999 Dec 10;53:1937-1942.
9. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia [see comments]. Lancet 1996;347:1141-1145.
10. Kivipelto M, Helkala EL, Laakso MP, et al. Midlife vascular risk factors and Alzheimer's disease in later life: longitudinal, population based study. BMJ 2001 Jun 16;322:1447-1451.
11. Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of cognitive decline. JAMA 2004 Nov 10;292:2237-2242.
12. Abbatecola AM, Paolisso G, Lamponi M, et al. Insulin resistance and executive dysfunction in older persons. J Am Geriatr Soc 2004 Oct;52:1713-1718.
13. Yip AG, Brayne C, Matthews FE. Risk factors for incident dementia in England and Wales: The Medical Research Council Cognitive Function and Ageing Study. A population-based nested case-control study. Age Ageing 2006 Jan 13.
14. Bursi F, Rocca WA, Killian JM, et al. Heart Disease and Dementia: A Population-based Study. Am J Epidemiol 2006 Jan 15;163:135-141.
15. Casserly I, Topol E. Convergence of atherosclerosis and Alzheimer's disease: inflammation, cholesterol, and misfolded proteins. Lancet 2004 Apr 3;363:1139-1146.

Nutritional factors

a) Research on micronutrients and dementia in developed countries has focussed upon antioxidants (1) with less attention towards deficiencies in vitamin B12 and folate, which result in hyperhomocysteinaemia; only four small incidence studies (2-5), all underpowered and with inconsistent findings. Two out of three studies testing for an effect of folate were positive (2, 3), in one case independent of homocysteine (2). B12 was associated in only one out of four studies (3).

b) Overt hypothyroidism is a potentially reversible cause of dementia. Sub-clinical hypothyroidism (raised TSH levels with normal T4) is more prevalent, affecting up to 20% of older people in developed countries. It is associated with elevated total cholesterol and progression to overt hypothyroid disease, possibly also CVD (6). It was strongly associated with risk for dementia in one cross-sectional study (7). Conversely, a small incidence study reported a strong association with sub-clinical hyperthyroidism (low TSH) (8).

1. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol 2004 Oct;3:579-587.
2. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005 Sep;82:636-643.
3. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 2001 May 8;56:1188-1194.
4. 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 Feb 14;346:476-483.
5. Crystal HA, Ortof E, Frishman WH, Gruber A, Hershman D, Aronson M. Serum vitamin B12 levels and incidence of dementia in a healthy elderly population: a report from the Bronx Longitudinal Aging Study. J Am Geriatr Soc 1994 Sep;42:933-936.
6. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004 Jan 14;291:228-238.
7. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry 1996 Oct 15;40:714-725.
8. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol (Oxf) 2000 Dec;53:733-737.

Ethnic Differences and Research in Admixed Populations

Previous research indicates strong and consistent ethnic differences in the incidence of dementia and stroke, in shared risk factors for atherosclerosis and dementia (lipid metabolism, hypertension, metabolic syndrome, APOE genotype), and in risk associations between certain of these risk factors and these outcomes.

• Dementia - The age-specific prevalence (1) and incidence (2) of dementia in Nigeria are both very low. A further notable finding is the apparent lack of an association between APOE genotype and dementia (3), confirmed in Kenya (4). Those with African ancestry tend to have a higher prevalence of APOE e4, but African Americans, other populations of west African ancestry, and Hispanics, all show weak and inconsistent associations with AD (5). There is a robust association between APOE genotype and AD in Europeans (5) and south Asians (6).
• Stroke, Heart disease and CVD risk factors - In the South London Stroke study (7) age and sex adjusted stroke incidence was higher among black (African Caribbean) residents, with a RR of 2.2 (1.8-2.8). In the USA incidence was higher among African Americans and Hispanics (8,9). These differences may be partly explained by elevated blood pressure levels (10). In the North Manhattan Stroke Project, both relative risks and population attributable fractions varied across white, black and Hispanic ethnic groups for the major stroke risk factors (11). Conversely, African Caribbean migrants in the UK have a low risk of heart disease despite a high prevalence of metabolic syndrome, attributed to a low prevalence of smoking and low triglyceride levels (10).

Measurement of individual admixture proportions (the proportions of the individual’s genome that are of African, European, and Native American ancestry) is now feasible, and studying the relationship of disease risk to admixture proportions is the most direct way to distinguish genetic from environmental explanations for ethnic variation in disease risk (12).

1. World Population Prospects: The 2002 Revision - Highlights. New York: United Nations; 2003.
2. Luchsinger JA, Mayeux R. Dietary factors and Alzheimer's disease. Lancet Neurol 2004 Oct;3:579-587.
3. Ravaglia G, Forti P, Maioli F, et al. Homocysteine and folate as risk factors for dementia and Alzheimer disease. Am J Clin Nutr 2005 Sep;82:636-643.
4. Wang HX, Wahlin A, Basun H, Fastbom J, Winblad B, Fratiglioni L. Vitamin B(12) and folate in relation to the development of Alzheimer's disease. Neurology 2001 May 8;56:1188-1194.
5. 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 Feb 14;346:476-483.
6. Crystal HA, Ortof E, Frishman WH, Gruber A, Hershman D, Aronson M. Serum vitamin B12 levels and incidence of dementia in a healthy elderly population: a report from the Bronx Longitudinal Aging Study. J Am Geriatr Soc 1994 Sep;42:933-936.
7. Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA 2004 Jan 14;291:228-238.
8. Ganguli M, Burmeister LA, Seaberg EC, Belle S, DeKosky ST. Association between dementia and elevated TSH: a community-based study. Biol Psychiatry 1996 Oct 15;40:714-725.
9. Kalmijn S, Mehta KM, Pols HA, Hofman A, Drexhage HA, Breteler MM. Subclinical hyperthyroidism and the risk of dementia. The Rotterdam study. Clin Endocrinol (Oxf) 2000 Dec;53:733-737.
10. Hall KS, Hendrie HH, Brittain HM, et al. The development of a dementia screeing interview in two distinct languages. International Journal of Methods in Psychiatric Research 1993;3:1-28.
11. Development of the World Health Organization WHOQOL-BREF quality of life assessment. The WHOQOL Group. Psychological Medicine 28(3):551-8, 1998 May.
12. Kaufer DI, Cummings JL, Ketchel P, et al. Validation of the NPI-Q, a brief clinical form of the Neuropsychiatric Inventory. J Neuropsychiatry Clin Neurosci 2000;12:233-239.
13. Smith SC, Lamping DL, Banerjee S, et al. Measurement of health-related quality of life for people with dementia: development of a new instrument (DEMQOL) and an evaluation of current methodology. Health Technol Assess 2005 Mar;9:1-iv.