SCIENCE REVISITEDObviously this is not a satisfying answer for clinicians or patients, and it is important to emphasize that the panel did not conclude that risk factor modification has been proven ineffective. For a variety of reasons, many important risk factors have not been “put to the test” in a controlled clinical trial. The challenge for clinicians is to find a practical course between false claims and therapeutic nihilism in making recommendations for cognitive health. We will attempt to chart such a course here by reviewing relevant risk factors, then reviewing completed clinical trials attempting to modify these risk factors, then reviewing published projections of the benefits of risk factor modification, and finally concluding with recommendations that are practical, concrete, and inarguably beneficial for general health even if unproven for cognitive health.
Alzheimer’s disease and vascular risk
In considering the prominence of vascular risk factors in the following list of dementia risk factors, it is important to remember that all large risk factor studies rely on clinical, rather than pathological, diagnosis of Alzheimer’s disease, and even pathologically confirmed Alzheimer’s disease includes some degree of concomitant cerebrovascular disease. In fact, several studies have emphasized that concomitant cerebrovascular disease increases the likelihood of “clinical expression” of dementia. In other words, risk factors for Alzheimer’s disease (AD) are not necessarily risk factors for Alzheimer-specific lesions like plaques and tangles, but may include risk factors for subclinical cerebrovascular disease, which in turn modifies the expression of AD.
What are the best established modifiable risk factors for Alzheimer’s dementia?
Hypertension
Several systematic reviews have found that the effect of hypertension upon dementia risk appears to be age dependent. Midlife hypertension consistently increases the risk of late-life dementia, while the effect of late-life hypertension upon dementia risk is less clear, possibly because of the confounding effects of medication and iatrogenic hypotension. Pooled results from systematic studies yielded a relative risk of 1.61 for AD among subjects with midlife hypertension.
Smoking
Although some early studies surprisingly found a reduced incidence of dementia in smokers, more recent longitudinal studies have consistently found an increased incidence of dementia in smokers. The most comprehensive metaanalysis to date found a relative risk of 1.59 for AD among active smokers.
Depression
Depression has consistently been identified as a risk factor for Alzheimer’s and dementia, with some studies finding that onset of first depression in later life carries the strongest risk of dementia. Two recent metaanalyses have found that any history of depression is associated with a two-fold increase in the risk of Alzheimer’s disease or dementia with relative risks ranging from 1.87 to 2.03.
Physical inactivity
One systematic review of physical inactivity and cognitive function observed that 20 out of 24 longitudinal studies found that physical inactivity was associated with some level of cognitive impairment. A second systematic review examined the association between physical inactivity and dementia in 16 studies, and found a relative risk for all-cause dementia of 1.39 and for Alzheimer’s disease of 1.82 in the most physically inactive individuals compared to the most active.
Cognitive inactivity
Although it is intuitive to think that cognitive exercise is critical to brain health, the variables are much more difficult to quantify in this area and the literature is consequently more limited. However, one systematic analysis compared dementia risk in subjects according to whether or not they engaged in “cognitively stimulating leisure activities” and found that subjects who engaged in such activities had a reduced risk of dementia, with an estimated relative risk of 0.5.
Dietary factors
Obesity
There appears to be a parallel between obesity and hypertension in terms of the effects of age upon risk factor modification. As with hypertension, studies of midlife obesity consistently find an increased risk of Alzheimer’s disease in obese subjects with a relative risk estimated at 1.59, while late-life obesity does not appear to be a robust risk factor. In this case, the post facto explanation is that early disease-associated weight loss masks the effect of obesity upon brain health in late life.
Diabetes mellitus
Diabetes mellitus has been associated with an increased risk of dementia in several studies. One metaanalysis of nine prospective studies found a relative risk of AD of 1.39 and all-cause dementia of 1.47 in diabetics, while a second metaanalysis of eight prospective studies found a relative risk of 1.54 for all-cause dementia in diabetics.
Hypercholesterolemia
Several studies have reported an increased risk of Alzheimer’s disease and all-cause dementia in patients with hypercholesterolemia. There is some evidence from animal models and cerebrospinal fluid (CSF) biomarker studies to indicate that statins may have effects on AD pathology rather than on concomitant vascular pathology, but clinical trials have been disappointing to date.
Low omega 3 fatty acid intake
Some (but not all) population-based studies have shown a reduced risk of AD in individuals who consume higher levels of fish, which are rich in the omega 3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the latter of which is the most abundant polyunsaturated fatty acid (PUFA) in the brain. Animal studies have suggested that DHA intake modifies AD pathology, but clinical trials have been disappointing.
Low antioxidant intake
Several risk factor studies have provided evidence that consumption of vitamin E, vitamin C, or the combination is associated with a reduced risk of AD. As with statins and omega 3s, however, clinical trials have been discouraging to date.
B vitamin-related hyperhomocysteinemia
Elevated serum homocysteine, which in many cases is a reflection of B vitamin status, has been associated with increased risk of stroke, dementia, and AD. Trials of B vitamins for the treatment or prevention of AD have shown successful reduction of serum homocysteine, but mixed effects on cognitive outcomes.
Trace metals
Patients and family members continue to ask about the effects of environmental aluminum upon AD risk since this was reported in the 1970s, but research on this topic has not borne out the “aluminum hypothesis” and most people in the field no longer consider aluminum a relevant factor.
However, some more recent evidence has implicated copper intake in the pathogenesis of AD, with both epidemiological and animal studies suggesting an interaction between dietary copper and dietary lipids.
Medications
Non-steroidal antiinflammatory drug usage
More than 20 studies of the effect of NSAID use upon dementia risk have concluded that NSAID users have a lower risk of Alzheimer’s dementia compared to non-users. The remarkable consistency of this epidemiological finding has led to controlled clinical trials which will be discussed in the next section.
Estrogen
It is difficult to believe that as recently as the late 1990s, review articles were concluding that estrogen replacement therapy at menopause had great potential for the prevention of AD. The opinion regarding estrogen for dementia prevention has since been dramatically reversed on the basis of clinical trials. Interestingly, investigators in this area are now postulating that there may be a “critical period” for estrogen use in midlife, so that estrogen may be a third dementia risk factor which cannot be fully appreciated without careful consideration of interactions with age of exposure.
What modifiable risk factors have been evaluated in controlled clinical trials?
Many clinical trials have been designed and conducted on the basis of the flawed hypothesis that the pathogenic mechanisms which initiate AD continue to operate after dementia is manifest. In other words, many clinical trials based on the risk factor data just described tested the hypothesis that risk factor modification would slow the rate of progression of established AD, rather than testing whether risk factor modification would prevent AD. The reasons for this phenomenon are practical: trials to slow the rate of progression of AD require far fewer subjects, shorter periods of observation, and less money than prevention studies.
Related posts:
Diagnosis and Differential Diagnosis of Dementia
An Approach to the Problem of Normal Pressure Hydrocephalus
Depression: Cause or Complication of Cognitive Decline?
After the Diagnosis: Continuing Neurological Care of the Outpatient with Dementia
Using Psychotropic Medications to Manage Problem Behaviors in Dementia
Young Onset Dementia: How Much Diagnostic Testing is Enough?
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
