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Stockholm Gerontology Research Center Karolinska Institute
The Division of Geriatric Medicine Huddinge University Hospital,
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly. The prevalence and incidence of AD approximately doubles every five years after the age of 65 years. The estimated prevalence rates are 1% in people aged 60–64 years, increasing to over 25% in those who are 85 years and over.
As the longevity of the general population increases, AD is becoming an enormous public health problem. It has been estimated that the number of AD patients will quadruple by 2050 unless a means for prevention or cure is found.(1) From the same projections it has been proposed that interventions that could postpone disease onset by five years would decrease the projected prevalence of AD by 50%. Thus, it is important to try to identify modifiable risk factors for AD.
Risk factors for AD
Until recently, age and family history were the only well-established risk factors for AD. Epidemiological studies have lately, however, revealed many potential modifiable risk factors for the disease. The main proposed risk factors and protective factors for AD are summarised in Tables 1 and 2.
Basic biological data suggest that oestrogen may have neuroprotective and neurotrophic functions and play a protective role against many disturbances characteristic of AD. Also, epidemiological studies have suggested that hormone replacement therapy (HRT) may reduce the risk of AD.(2) However, many of these studies have been hampered by methodological limitations, and randomised clinical trials are needed to assess the health benefits and risks of HRT. A large trial of oestrogen plus progestin (Women’s Health Initiative) was stopped recently because of the side-effects of HRT. Future research is needed to clarify the benefits and risks of oestrogens used in Europe, and to find out which forms of oestrogen or oestrogen receptor modulators would possess the most beneficial effects without significant health risks.
Over the last decade, epidemiological evidence has been accumulating that vascular risk factors and indicators of vascular disease may be associated with AD. In particular, hypertension and hypercholesterolaemia have gained a considerable amount of attention because they may represent common and potentially modifiable risk factors for AD. Recently, three long-term population-based follow-up studies (follow-up times from 9 years to 25 years) have shown that hypertension earlier in life increases the risk of AD later in life.(3–5) It has also been reported that high serum cholesterol values at midlife increase the risk of AD later in life.(5–6) The risk of AD related to treatable risk factors – hypertension and cholesterol – appears also to be greater than the risk related to the apolipoprotein E (ApoE) e4 allele, which is the most important genetic risk factor for AD so far. Effective interventions for hypertension and raised cholesterol might reduce the risk of AD from 8–11-fold to as low as twofold, even if the patient is an ApoE e4 carrier.(7) Blood pressure and cholesterol values often fall before the manifestation of dementia. These changes may explain, at least in part, the inconsistent/negative results from earlier cross-sectional or short-term follow-up studies on this issue.
Many cohort studies have also reported an association between AD and other clinical vascular disorders, such as cardiovascular and cerebrovascular diseases, and diabetes mellitus. A high homocysteine level, another cardiovascular risk factor, has also been suggested as a risk factor for AD.
Potential for pharmacological interventions
In the Systolic Hypertension in Europe (Syst-Eur) trial, active treatment of isolated systolic hypertension with nitrendipine, a calcium channel blocker, was found to halve the incidence of AD.(8) Besides this randomised, placebo-controlled study, some observational studies have reported that antihypertensive medication may protect against dementia.(9)
Three recent clinical studies have reported significantly reduced rates (up to 70%) of dementia and AD in patients who had used statins as cholesterol-lowering drugs.(10–12) In addition to reducing cholesterol levels, statins appear to have a variety of mechanisms of action that may be beneficial for the central nervous system and be associated with a reduced risk of AD, including endothelial protection via actions on the nitric oxide synthase system, antioxidant, anti-inflammatory and antiplatelet effects, and immunomodulatory effects.
It may be that early interventions reduce the risk of AD, and that statins and antihypertensive drugs could be more effective in preventing the disease than in treating it. Pathological studies have shown that AD neuropathology may start to develop in midlife, suggesting that pathological cascades leading to AD could have already started at that time.(13) However, the theoretical background and preliminary data suggest that statins may also be beneficial in slowing the progression of AD. A recent randomised, placebo-controlled, double-blind pilot study reported that simvastatin decreased beta-amyloid levels in the cerebrospinal fluid and slowed the progression of disease in normocholesterolaemic patients with mild AD.(14) However, long-term trials in larger populations are needed to clarify whether statins really can slow the progression of cognitive symptoms of AD. These trials are on their way.
There is increasing evidence that AD has many modifiable risk factors. Elimination or treatment of any of the risk factors may decrease or delay the incidence of the AD, and thus prevention of AD, at least in part, is likely to be possible. Vascular risk factors, especially hypertension and serum cholesterol values earlier in life, seem to have an important role in the development of AD as suggested both by epidemiological studies and studies that have reported a decreased incidence or prevalence of AD in persons receiving antihypertensive or lipid-lowering drug treatments.(9) These findings are also supported by experimental studies.
It is important to notice that many of the other proposed risk factors for AD (such as diabetes and smoking) may be vascular-related.(15) The data available should be considered as sufficient evidence to emphasise the need for clinical interventions to control vascular risk factors more effectively, particularly as there are already clear indications to treat hypertension and hyperlipidaemia (because of cardiovascular and cerebrovascular sequelae), as well as a number of means of treatment. Proper treatment may not only increase the chances of escaping cardiovascular morbidity and mortality, but may also increase the chances of escaping AD.
The finding that the risk related to modifiable vascular factors appears to be greater than that associated with the ApoE e4 allele gives further reason for optimism about future prevention strategies for AD. It is also possible that other lifestyle-related factors like high antioxidants, low-fat diet and active life may decrease the risk of AD.
Future studies will reveal whether lowering homocysteine levels with folate and vitamin B12 supplements will help to prevent AD. Future studies are also needed to evaluate whether some forms of oestrogen, anti-inflammatory drugs and antioxidants have a role in prevention. Combining multiple approaches and drug regimens may be a future strategy in both prevention and treatment of the disease.