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Risk factors for cognitive decline and dementia

Risk factors for cognitive decline and dementia
Author:
Eric B Larson, MD, MPH
Section Editor:
Steven T DeKosky, MD, FAAN, FACP, FANA
Deputy Editor:
Janet L Wilterdink, MD
Literature review current through: Dec 2022. | This topic last updated: Nov 01, 2019.

INTRODUCTION — Dementia is a disorder that is characterized by impairment of cognition, typically involving memory and at least one other cognitive domain (language, visuospatial, executive function). These must represent a decline from previous level of function and be severe enough to interfere with daily function and independence. As the global population ages, dementia prevalence is expected to rise substantially over the next several decades, especially in low- to middle-income countries.

Two major reports released in 2017 review the literature on potentially modifiable risk factors for dementia and highlight strengths and weaknesses in the available data to support the impact of risk factor modification on dementia incidence [1-3]. While the overall evidence is generally of low quality and does not support any single intervention as effective in delaying or preventing dementia, there is optimism that intensive risk factor modification, especially during midlife (age 45 to 65 years), has the potential to delay or prevent a substantial number of dementia cases worldwide. In support of this, large population-based studies indicate that the incidence of dementia has declined in high-income countries over the last several decades [4-9].

The Lancet Commission estimates that approximately 35 percent of dementia cases are attributable to a combination of nine potentially modifiable risk factors [1]:

●Low educational attainment

●Midlife hypertension

●Midlife obesity

●Hearing loss

●Late-life depression

●Diabetes

●Physical inactivity

●Smoking

●Social isolation

This topic will review the risk factors associated with cognitive decline and dementia. The risk factors for Alzheimer disease (AD) and the diagnosis, prevention, and treatment of dementia are discussed separately. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease" and "Prevention of dementia" and "Treatment of Alzheimer disease" and "Treatment of vascular cognitive impairment and dementia".)

AGE — Age remains the strongest risk factor for dementia, particularly for Alzheimer disease (AD). The incidence of AD approximately doubles every 10 years after the age of 60 years. Overall, approximately 85 percent of dementia cases are in adults 75 years of age and older [10,11]. Dementia is estimated to be present in one-half to two-thirds of nursing home residents. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Incidence and prevalence' and "Palliative care: Nursing home", section on 'Patient characteristics'.)

Studies estimating dementia incidence in the very old have been limited by low numbers in this age group. A number of studies have found that dementia incidence continues to increase with age after 85 years [12-15]. These cumulative increases in incidence rates result in the prevalence of dementia approaching or exceeding 50 percent in individuals over 90 years.

AD and other neurodegenerative dementias also occur, albeit rarely, in younger patients. The reported incidence of AD in one study from England was 4.2 cases per 100,000 person-years among individuals aged 45 to 64 years [16], while the overall incidence of early-onset dementia in this and another study was 11 to 13 cases per 100,000 person-years for adults younger than 64 years [16,17]. Among 235 individuals aged 17 to 45 years diagnosed with dementia in Rochester, Minnesota, neurodegenerative disease accounted for 31 percent of cases [18]. (See "Early-onset dementia in adults".)

GENETIC FACTORS — The genetic risk factors for dementia are studied best in Alzheimer disease (AD) because it is the most prevalent dementia and data from large numbers of cases are available.

Genetic risk plays an important role in AD, even in so-called sporadic or late-onset cases. A parental history of dementia is associated with an approximately twofold increase in the relative risk of dementia and AD, independent of known genetic factors [19,20]. Risk estimates gradually decline with advancing parental age at diagnosis of dementia, with little to no increased risk when a parent is diagnosed after the age of 80 years [20].

The genetic basis for AD is understood most clearly in the early-onset form; while it accounts for less than 1 percent of cases, it follows an autosomal dominant inheritance pattern related to mutations in genes that alter amyloid-beta (Aβ) protein production, aggregation, or clearance, including amyloid precursor protein (APP), presenilin 1 (PSEN1), and presenilin 2 (PSEN2).

The genetic basis of late-onset AD is more complex, with susceptibility likely conferred by a variety of more common but less penetrant genetic factors such as apolipoprotein E (APOE) alleles interacting with environmental and epigenetic influences. The genetic basis of AD is discussed in detail separately. (See "Genetics of Alzheimer disease".)

A family history of dementia is commonly present in patients with frontotemporal dementia (FTD) as well. Mutations in genes such as C9ORF72, MAPT, and GRN together explain approximately 15 percent of familial FTD. (See "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Genetic factors'.)

MILD COGNITIVE IMPAIRMENT — Mild cognitive impairment (MCI) may be considered a risk factor for dementia in that it is often a precursor state to dementia. This topic is discussed in detail separately. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment" and "Mild cognitive impairment: Prognosis and treatment", section on 'Progression to dementia'.)

ISCHEMIC OR HEMORRHAGIC STROKE — Approximately 10 percent of patients develop new-onset dementia after a first stroke, and up to one-third of patients develop dementia after recurrent stroke [21-23]. Risk factors for dementia in patients with stroke include advanced age, premorbid cognitive impairment, and recurrent stroke. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

Survivors of spontaneous intracranial hemorrhage are also at increased risk for incident dementia. In a prospective study of 218 patients with spontaneous intracranial hemorrhage who were free of preexisting dementia and alive at six months posthemorrhage, the incidence of dementia was 14 percent at one year and 28 percent at four years [24]. A second prospective study estimated a 5.8 percent yearly incidence of dementia among those free of early dementia within the first six months after hemorrhage [25]. In the first study, the risk of dementia was more than twofold higher among patients with lobar hemorrhage compared with nonlobar hemorrhage (23 versus 9 percent at one year); additional risk factors included older age, disseminated superficial siderosis, cortical atrophy, and higher number of cerebral microbleeds [24]. (See "Cerebral amyloid angiopathy".)

Subclinical cerebral microbleeds, which may be a marker of brain damage caused by vascular and amyloid pathologic mechanisms, have also been associated with increased risk for incident dementia, including Alzheimer disease (AD) [26]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Cerebrovascular disease'.)

CARDIOMETABOLIC RISK FACTORS — Vascular risk factors have been linked to increased risk of cognitive decline and dementia as well as to Alzheimer disease (AD) and vascular dementia individually. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia" and "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Acquired risk factors'.)

The strongest degrees of association between these risk factors and late-life cognitive decline have been found in studies that identify the risk factor in midlife rather than late life [27-30]. In a prospective longitudinal study of more than 15,000 adults enrolled between 44 and 66 years of age and followed for 25 years, midlife diabetes (hazard ratio [HR] 1.8), smoking (HR 1.14), hypertension (HR 1.4), and prehypertension (HR 1.3) were each independently associated with increased risk of dementia [30].

The clustering of risk factors may also be important [31,32]. In one longitudinal cohort study, the risk of probable AD increased with the number of risk factors (diabetes, hypertension, heart disease, and smoking) [31]. HRs for one, two, and three or more risk factors were 1.8 (95% CI 1.1-3.0), 2.8 (95% CI 1.7-4.7), and 3.4 (95% CI 1.8-6.3) in a model adjusting for age, sex, apolipoprotein E epsilon 4 (APOE e4), and other confounders.

Diabetes mellitus — A large number of prospective population-based cohort studies have found that diabetes is associated with an approximately 1.5- to 2-fold increase in the relative risk of cognitive decline and dementia later in life [1,33-41]. The association is present for both vascular dementia and AD, although the magnitude of risk may be higher for vascular dementia. Higher glucose levels have also been associated with risk of cognitive impairment and dementia in nondiabetic individuals, implicating insulin resistance more broadly [42,43].

Among patients with diabetes, an inverse correlation has been noted between glycated hemoglobin (A1C) levels and some cognitive measures, suggesting that worse glycemic control may be associated with greater cognitive decline [44,45]. However, one study associated a history of severe hypoglycemic episodes with dementia risk among a cohort of patients with type 2 diabetes [46], suggesting some caution is appropriate in pursuing tight glycemic control in older adults.

It is not yet clear whether effective treatment of diabetes reduces dementia risk independent of other interventions. Cognitive outcomes, as measured by the Digit Symbol Substitution Test, were not different among patients randomized to intensive glycemic control versus usual care in a study subset of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial when assessed at 40 months into the trial [47].

The mechanism by which diabetes may increase dementia risk is uncertain; it does not appear to be mediated entirely through vascular disease [48,49]. While some clinicopathologic studies suggest that diabetes is associated with cerebrovascular but not Alzheimer pathology [35,50,51], one study linked elevated glucose levels with hippocampal atrophy, a finding more commonly associated with AD [52]. In addition, peripheral insulin anomalies are thought to cause a decrease in brain insulin production, which can impair amyloid clearance [1]. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Type 2 diabetes and obesity'.)

Hypercholesterolemia — Hypercholesterolemia may increase the risk of dementia [53-55], AD [56], and vascular dementia [57-59], but not all studies have confirmed this association [60-64]. Some have even shown a lower risk of dementia with high cholesterol levels measured later in life [65].

These discrepancies probably have their origin in study methodology, for example, whether all dementias or just a subset of dementias were included and, importantly, the timing of the hypercholesterolemia diagnosis (mid-life versus late-life). Some longitudinal studies indicate that, as with body mass index (BMI), serum cholesterol levels may decrease in the early stages of dementia, limiting the ability to see an effect of hypercholesterolemia on dementia risk when the measurements are made later in life [55,66]. (See 'Obesity and body mass index' below.)

A discussion of the possible, yet unproven role of cholesterol-lowering HMG-CoA reductase inhibitors (statins) for the prevention of dementia is found separately. (See "Prevention of dementia".)

Hypertension — Among cardiometabolic risk factors, hypertension may be the most important modifiable risk factor for dementia [1]. While the relationship between blood pressure and dementia risk is complex and nonlinear, the preponderance of evidence suggests that hypertension is associated with an approximately 1.5-fold increase in the relative risk of dementia, especially when present in midlife [30,53,54,67-75].

There are numerous mechanisms by which hypertension may increase the risk of dementia. It is likely that hypertension increases the risk of dementia in part by increasing the risk of stroke and multi-infarct dementia [76,77]. Changes in regional cerebral blood flow, vessel thickening and rigidity, and changes in vessel pliability induced by chronic hypertension also likely play a role [78]. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

Metabolic syndrome — The metabolic syndrome is a cluster of cardiovascular risk factors, which include obesity, hypertension, insulin resistance, and dyslipidemia. The metabolic syndrome has been linked to cardiovascular disease and overall mortality. (See "Metabolic syndrome (insulin resistance syndrome or syndrome X)".)

While there is some evidence linking the metabolic syndrome and dementia, longitudinal cohort studies have had mixed results [79-85]. In the French Three-City Study, the metabolic syndrome was associated with a modest increase in the risk of cognitive decline [84]. In the Honolulu-Asia Aging Study, the metabolic syndrome was weakly associated with incident vascular dementia but not AD [80]. Other longitudinal studies in older subjects have found either no association or increased cognitive decline only in people who also had increased markers of inflammation such as serum C-reactive protein and interleukin-6 [86,87]. In a study of 6401 individuals, both obesity and metabolic abnormalities were risk factors for cognitive decline, which was most pronounced in those with both [85].

Obesity and body mass index — Studies finding an association between obesity and incident dementia have usually measured BMI or adiposity in mid- rather than late life. Most of these studies [85,88-96], but not all [97], have found that midlife obesity increases the relative risk of dementia later in life by approximately 50 percent.

By contrast, weight loss in late life appears to more closely precede the diagnosis of either mild cognitive impairment (MCI) [98] or dementia [88,94,99-106].

Smoking — Data regarding the impact of smoking on the risk of dementia are conflicting [107]. While many prospective studies have found that smoking in middle-aged and older people is associated with an increased risk of dementia, the association does not always remain significant after adjusting for other cardiovascular risk factors [53,54,107-111]. An association between environmental tobacco smoke exposure and dementia has also been observed in some [112,113] but not all [114] studies.

A meta-analysis of 19 studies with at least 12 months of follow-up concluded that older adult smokers have increased risk of AD, vascular dementia, and any dementia, with relative risks of 1.27 (95% CI 1.02-1.60) to 1.79 (95% CI 1.43-2.23) [115]. Current smoking was also associated with greater yearly declines in Mini-Mental State Examination scores.

Effect modification by APOE e4 genotype may explain, at least in part, the conflicting results. In two population-based cohorts, smoking was associated with either memory decline or AD in patients without, but not with, the APOE e4 allele [116-118]. One possible explanation may be that because APOE e4 is such a strong risk factor for AD, an association between AD and smoking cannot be seen in its presence. Also, APOE e4 carriers with AD have fewer nicotinic receptor-binding sites than noncarriers, suggesting that there may be a direct biologic modification of the effect of smoking associated with APOE genotype [119].

Vascular disease — Clinically manifest cardiovascular disease as well as markers of atherosclerotic disease burden may also identify individuals at risk for cognitive decline and dementia. The association has been demonstrated for a wide range of markers of cardiovascular risk or disease burden, including:

●History of myocardial infarction or other vascular disease [120]

●Carotid atherosclerosis (visualized plaque and intimal medial thickness) [121-123]

●Extent of coronary artery calcium (CAC) [124-127]

●Retinal microvascular signs and retinopathy [128-132]

●Intracranial atherosclerosis [133]

LIFESTYLE AND ACTIVITY — Three components of lifestyle and activity (mental, physical, and social) have been inversely associated with the risk for dementia and Alzheimer disease (AD) in observational studies [134-156]. Establishing a causal link is difficult, however, and there are multiple potential confounders and reasons to suspect that reverse causality may explain some of the relationships.

The possible mechanisms by which lifestyle might affect the risk of dementia are speculative, but three biologically plausible hypotheses have emerged [157].

●The cognitive reserve hypothesis suggests that mental activity, learning, and social interaction prevent or reduce cognitive deficits by activating brain plasticity and enhancing synaptogenesis and perhaps neurogenesis. Physical activity may enhance vascular and non-neuronal brain components that support neurons. The cognitive reserve hypothesis is supported by the apparent effect of education (see 'Low educational attainment' below) on the risk of dementia.

●The vascular hypothesis suggests that social, mental, and physical activity prevents or reduces dementia and AD through reduction of cardiovascular disease and stroke. (See "Etiology, clinical manifestations, and diagnosis of vascular dementia".)

●The stress hypothesis suggests that active individuals have more positive emotional states and reduced stress, leading to a lower susceptibility to AD. Increased stress may result in dampening of negative feedback control of the adrenocortical axis via downregulation of hippocampal corticosteroid receptors, resulting in high cortisol levels, hippocampal atrophy, and impaired cognition.

Lifestyle and activity levels are clearly modifiable and may present options for decreasing the risk of cognitive decline and dementia. (See "Prevention of dementia", section on 'Lifestyle and activity' and "Mild cognitive impairment: Prognosis and treatment", section on 'Exercise'.)

Low educational attainment — Lower levels of education have been associated with an increased risk of dementia [158-160]. In a systematic review and meta-analysis of observational studies, less education (defined as no secondary school education) was associated with a 1.6-fold increase in the relative risk of dementia compared with higher levels of education [1].

It is thought that low educational attainment increases vulnerability to cognitive decline through lack of cognitive reserve [160-162]. In other words, for a given burden of amyloid neuropathologic change in the brain, individuals with higher levels of education may show less cognitive decline or delayed development of clinical dementia compared with those with lower levels of education [163-170]. Several observations suggest that a capacity for neuronal plasticity (perhaps through synaptic reorganization) may underlie the apparent protective mechanism that higher education and baseline cognition may play in the prevention of clinically apparent AD [171,172].

However, once AD develops, patients with higher education or occupational levels appear to experience a somewhat more rapid cognitive decline, at least in part because they are assumed to have accumulated a greater degree of AD pathology by the time dementia is apparent, compared with those with less education [173-175].

Physical inactivity — In a systematic review of 15 prospective studies in more than 30,000 individuals without dementia, engagement in at least a low to moderate level of physical activity was associated with a 35 percent reduction in the relative risk of cognitive decline over 1 to 12 years of follow-up [176]. Whether exercise during midlife or late life prevents dementia remains unproven, however, and clinical trials have thus far failed to show a benefit. (See "Prevention of dementia", section on 'Physical exercise'.)

Social isolation — Social isolation may be a prodromal symptom of dementia, but growing evidence suggests that it may also be a risk factor for dementia, possibly through an increase in the risk of hypertension, coronary heart disease, and depression [1].

OTHERS

Atrial fibrillation — Atrial fibrillation has been associated with an increased risk of incident dementia, independent of clinical stroke [120,177-181]. Meta-analyses of prospective observational studies have yielded a hazard ratio (HR) of 1.4 [177,182].

Alcohol — Data on alcohol use and risk of dementia are mixed. Alcohol abuse is associated with cognitive dysfunction and dementia. (See "Overview of the chronic neurologic complications of alcohol".)

While there is some evidence that light to moderate drinking may be protective, this is largely based on observational studies and the findings have been inconsistent. (See "Overview of the risks and benefits of alcohol consumption", section on 'Dementia'.)

Chronic kidney disease — Renal dysfunction is associated with a modest increase in the rate of cognitive decline and incidence of dementia in older adults, possibly due to shared risk factors such as coronary heart disease, diabetes, and hypertension. (See "Chronic kidney disease and coronary heart disease".)

In a systematic review and meta-analysis of prospective, population-based studies, albuminuria as a marker of chronic kidney disease was the most consistently associated with increased risk of cognitive impairment and dementia (odds ratio [OR] 1.35, 95% CI 1.06-1.73) [183]. Associations were weaker or less consistent for other markers of renal dysfunction, including glomerular filtration rate (GFR) <60 (OR 1.28, 95% CI 0.99-1.65), serum creatinine, and cystatin C.

Depression — Multiple studies suggest that a history of depression is associated with an increased risk for dementia [38,184-190]. In a meta-analysis that included 23 prospective cohort studies, late-life depression was associated with increased odds of all-cause dementia (OR 1.96, 95% CI 1.64-2.34), Alzheimer disease (AD; OR 1.85, 95% CI 1.45-2.37), and vascular dementia (OR 2.53, 95% CI 1.42-4.50) [190]. Depressive symptoms can be an early or preclinical manifestation of dementia, however, raising the possibility that reverse causality explains the association. (See "Mild cognitive impairment: Epidemiology, pathology, and clinical assessment", section on 'Neuropsychiatric symptoms'.)

Evidence to determine whether depression is an independent risk factor for dementia has been mixed. In one cohort study of adults followed over 25 years, the risk of dementia increased as a function of the number of depressive episodes, suggesting that recurrent depression might contribute to incident dementia risk [189]. In a separate cohort of adults followed longitudinally over 28 years, however, it was only in the 11 years before a dementia diagnosis that depressive symptoms increased compared with patients who were free of dementia [191]. This suggests that depressive symptoms are a prodromal feature of dementia or that the two disorders share common causes.

Estrogens — The role of estrogens and hormonal replacement therapy in cognition remains unsettled. Estrogen was felt previously to be a protective factor, based upon descriptive epidemiologic studies and possible protective effects in laboratory models of aging. However, the Women's Health Initiative Memory Study (WHIMS) found that estrogens provided no benefit, but rather were associated with an increased risk of dementia in a low-risk group. Thus, estrogens cannot be recommended as preventive therapy based on current evidence. This topic is discussed separately. (See "Estrogen and cognitive function".)

Gait impairment — Gait impairment has been identified as a risk factor for dementia, particularly non-Alzheimer dementia. This was illustrated in a prospective study of 422 community-dwelling patients older than age 75 years who did not have dementia at baseline [192]. Neurologic gait abnormalities were present in 85 patients at study entry. During a median 6.6 years of follow-up, there were 125 newly diagnosed cases of dementia. Patients with gait abnormalities (eg, unsteady gait, frontal gait, hemiparetic gait) had a greater risk of developing any dementia compared with patients without gait abnormalities (HR 1.96, 95% CI 1.30-2.96). The risk was increased for non-Alzheimer (HR 3.51, 95% CI 1.98-6.24) but not Alzheimer dementia.

Combined with cognitive complaints, gait slowing may be a precursor state to dementia, similar to mild cognitive impairment (MCI). Some have proposed calling this state the motoric cognitive risk (MCR) syndrome, defined as the presence of cognitive complaints and slow gait in older individuals without dementia or mobility disability [193]. MCR is discussed in more detail separately. (See "Mild cognitive impairment: Prognosis and treatment".)

Head trauma — Repeated mild head trauma sustained in American football, boxing, or other high-risk activities can result in chronic traumatic encephalopathy, as manifested by behavioral and mood problems, cognitive impairment, parkinsonism, and other speech and gait abnormalities [194]. Risk factors for chronic impairment after head injury are not well established but may include the severity of subjective complaints after concussion, prior concussion and a previous history of headaches, apolipoprotein E epsilon 4 (APOE e4) genotype, and preexisting learning disability [195]. (See "Sequelae of mild traumatic brain injury", section on 'Chronic traumatic encephalopathy'.)

Whether less intensive or more time-limited exposure to high-risk sports confers risk of cognitive impairment or dementia more broadly is not well studied [196]. One case-control study of nearly 3000 male participants of a longitudinal population-based cohort found no association between participation in high school American football and measures of cognition, mood, and other emotional symptoms at age 65 years [197]. Information on concussion history was not available.

Data are also inconclusive with regard to severe brain trauma, including nonrepetitive traumatic brain injury (TBI) with loss of consciousness, as a risk factor for AD or other forms of dementia. Several small studies have reported a link between TBI and AD [198], and an Institute of Medicine report concluded that moderate or severe TBI was a risk factor for AD [199]. However, an observational study that included over 7000 participants enrolled in three prospective cohort studies found no association between self-reported TBI with loss of consciousness and MCI, dementia, clinical AD, or AD pathologic changes at the time of autopsy [200]. Rather, TBI was associated with an increased risk of Lewy body pathologic change as well as incident Parkinson disease (PD) in one of the cohorts.

Hearing loss — A growing number of studies suggest that peripheral hearing loss may be a risk factor for the development of dementia, independent of age and other potential confounding factors [201-206]. As an example, one prospective study enrolled 1984 older adults with no evidence of baseline cognitive impairment and followed them for up to 11 years after complete audiometric assessment [202]. Individuals with baseline hearing loss had an increased risk for incident cognitive impairment (HR 1.24, 95% CI 1.05-1.48) and greater annual rates of cognitive decline than those without baseline hearing loss. It is not yet known whether hearing aids or other interventions can alter the trajectory of cognitive decline.

Central auditory dysfunction (CAD) has also been associated with incident dementia [207-209]. In a study of 274 volunteers enrolled in a dementia surveillance cohort, patients with severe CAD (based on a test of dichotic sentence identification) were at increased risk for incident AD over a four-year follow-up period (HR 9.9) [207]. The majority of patients diagnosed with AD during the follow-up period had abnormal memory testing at baseline, however, suggesting that CAD may be an early sign of AD rather than a risk factor.

Homocysteine — The amino acid homocysteine may be an independent risk factor for cognitive decline and dementia, but the evidence is conflicting [210-219]. The potential mechanisms whereby homocysteine might mediate cognitive decline and dementia include [213]:

●Neurotoxicity induced by activation of N-methyl-D-aspartate (NMDA) receptors

●Promotion of apoptosis

●Vascular injury from promotion of atherogenesis and proliferation of smooth muscle cells

●Platelet activation

●Increased burden of ischemic strokes and white matter lesions

Homocysteine is recognized as a risk factor for stroke and heart disease, and it could potentially play a role in vascular dementia through its association with large [220] and small vessel disease [221]. (See "Overview of homocysteine".)

However, some studies suggest that the association between abnormal homocysteine levels and other changes in serum vitamin concentrations reflects early weight loss as a manifestation of early dementia rather than its cause [222]. (See 'Obesity and body mass index' above.)

Moreover, homocysteine-lowering therapy using supplementation with vitamins B12 and B6 has not been shown to improve cognitive function or prevent cognitive decline. (See "Prevention of dementia", section on 'Vitamins B6, B12, and folate'.)

Medical illness — A higher risk of cognitive decline and dementia has been postulated to occur in survivors of acute medical illness, particularly in older adults. Specific settings in which this has been studied include cardiac surgery (see "Neurologic complications of cardiac surgery", section on 'Encephalopathy') and hospitalizations complicated by delirium. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Outcomes'.)

Survivors of severe sepsis had a substantial increase (OR 3.3) in the prevalence of dementia compared with survivors of a nonsepsis-related hospitalization in one large prospective cohort study of older hospitalized adults [223]. There was also an associated increase in new functional limitations in these patients.

Other studies suggest that this may be of concern in a broader range of acute and chronic medical illness [224-227]. Whether acute medical illness is a risk factor for incident dementia or hastens its presentation is not certain.

Medications — Multiple studies have found an association between short-term use of certain medication classes (eg, benzodiazepines, anticholinergics, antihistamines, opioids) and cognitive impairment in older adults, but the effects have been presumed to be transient and reversible [228]. Several studies have observed a dose-response relationship between medication use and incident dementia and AD that persists despite adjustment for confounders, however, raising the possibility that adverse cognitive effects may not be reversible in some patients [229,230]. Potentially implicated classes of medications include benzodiazepines, anticholinergics, and proton pump inhibitors. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Medications'.)

It remains uncertain whether long-term use of medications such as benzodiazepines is associated with an increased risk of cognitive decline, however, and the data are conflicting. Interpretation of observational data is difficult in large part because benzodiazepines are prescribed to treat insomnia and anxiety, which can be prodromal symptoms of dementia. In studies that attempted to control for the prodromal phase and the potential for reverse causation, two found an increased risk of dementia with benzodiazepine use [229,231], while two others did not [232,233].

The case for anticholinergics increasing risk of irreversible effects is probably stronger [230,234] and makes more sense physiologically given the prominence of cholinergic deficits in AD.

Obstructive sleep apnea — Obstructive sleep apnea (OSA) has been associated with an increased risk for MCI and dementia in both cross-sectional and prospective observational studies [235-244]. In a pooled analysis of six prospective studies in over 200,000 adults, those with sleep-disordered breathing were 26 percent more likely to develop clinically relevant cognitive decline or dementia (OR 1.26, 95% CI 1.05-1.50) [243].

Most studies have observed higher risk among those with more severe OSA (ie, higher apnea-hypopnea index [AHI], more severe nocturnal oxygen desaturations), leading to the hypothesis that hypoxia may be a potential mechanism. Other studies suggest that OSA may accelerate cerebral amyloid deposition [245,246].

In one prospective study, a self-reported history of sleep apnea was associated with an earlier age of onset for both MCI (77 versus 90 years of age) and Alzheimer dementia (83 versus 88 years of age) [239]. Use of continuous positive airway pressure (CPAP) was associated with a delayed onset of MCI, although this observation might be explained by other factors related to an individual's likelihood to use CPAP. Further studies are needed to determine whether effective treatment of OSA can reduce the risk of dementia.

Sleep disturbances — Sleep disturbances, including fragmentation of sleep and decreased sleep duration, are common in patients with dementia and may be a risk factor for cognitive decline and dementia in older adults, although it is difficult to rule out reverse causality. A decreased percentage of rapid eye movement (REM) sleep and other changes in sleep architecture have also been documented in older adults and have been associated with an increased risk of dementia over time [247]. These associations are reviewed in more detail separately. (See "Sleep-wake disturbances and sleep disorders in patients with dementia", section on 'Sleep changes in aging and dementia'.)

Toxins and air pollution — Systematic reviews of observational studies have identified low- to moderate-quality evidence supporting a positive association between certain environmental or occupational toxin exposures and dementia [248,249].

In particular, air pollution has received increasing attention as a potential contributor to cognitive decline and dementia [250,251]. The overall quality of the evidence is limited in that most studies have used recent air pollution exposure as a surrogate for long-term exposure, and few studies have looked at within-person cognitive or pathologic change. Examples of studies implicating air pollution as a risk factor for dementia include the following:

●A population-based study of 2.2 million adults aged 55 to 85 years living in Ontario, Canada identified nearly 250,000 cases of incident dementia from a large claims database from 2001 to 2012 [252]. Residential address in 2001 was used as a proxy for exposure to air pollution, and dementia diagnoses were based on administrative database extraction and not individually verified. Individuals living in close proximity to high-traffic roads (<50 meters) had an increased risk of dementia (adjusted OR 1.07), and the effect size was largest for those living in major cities (OR 1.12). No such associations were found for incident PD or multiple sclerosis. The study did not measure lead exposure, which might confound or contribute to the effects of air pollution in the decades before lead was removed from gasoline [253,254].

●In a United States-wide cohort of older women enrolled in the prospective WHIMS, daily exposure to particulate matter with aerodynamic diameters <2.5 microns (PM2.5) was assessed via the Environmental Protection Agency (EPA) air quality monitoring system and assigned based on residential address [255]. After adjusting for a wide range of potential confounders, including age, education, household income, lifestyle factors, and medical comorbidities, exposure to PM2.5 levels exceeding EPA standards was associated with a nearly twofold higher risk of all-cause dementia (HR 1.92). The effect size was largest among women who were homozygous for APOE e4, although numbers were small (n = 81; HR 3.95, 95% CI 1.2-13.2). This study and others have focused on inflammation and increased amyloid deposition as potential mechanistic links between air pollution and AD, specifically. (See "Epidemiology, pathology, and pathogenesis of Alzheimer disease", section on 'Environmental risk factors'.)

Vitamin D deficiency — There is some evidence that vitamin D deficiency is associated with cognitive impairment and AD in older adults [256]. The effect appears to be small and of uncertain clinical significance.

A population-based cross-sectional study of older women found that those with vitamin D deficiency had lower cognitive scores compared with those without deficiency [257], while another found that women with vitamin D intake at the recommended level had higher cognitive scores compared with those with inadequate intake [258]. Other cross-sectional and case-control studies have found that patients with low vitamin D levels have higher volumes of white matter hyperintensities and infarctions as well as higher odds (2.0) of all-cause dementia [259] or AD specifically [260].

Prospective cohort series have been less consistent. One prospective study that followed 1604 older men for a mean 4.6 years found no significant relationship between vitamin D status and either concurrent or incident dementia [261]. By contrast, low levels of vitamin D were associated with cognitive decline over a six-year observation period in a cohort of 858 adults over 65 years [262]. In another study involving 1658 older adults followed for a mean of 5.6 years, severe vitamin D deficiency (<25 nmol/L) was associated with an approximately twofold higher relative risk of both all-cause dementia and Alzheimer dementia compared with a vitamin D replete state [263].

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topic (see "Patient education: Dementia (including Alzheimer disease) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Age remains the strongest risk factor for dementia, particularly for Alzheimer disease (AD), in which the incidence increases exponentially with each decade. (See 'Age' above.)

●The genetic risk factors for dementia are studied best in AD. Genetic risk plays an important role in both early-onset and late-onset forms of AD along with other neurodegenerative diseases, such as frontotemporal dementia (FTD). (See 'Genetic factors' above.)

●Vascular risk factors (diabetes, hypertension, hypercholesterolemia, obesity, tobacco) have been linked to cognitive decline and all-cause dementia as well as to AD and vascular dementia individually. The associations are strongest when vascular risk factors are measured in midlife, rather than late life, and when multiple factors are present. (See 'Cardiometabolic risk factors' above.)

●Evidence from observational studies suggests that low educational attainment, physical inactivity, and social isolation are associated with increased risk for cognitive decline and dementia. One theory holds that higher levels of education along with cognitive and social activity produce a cognitive reserve that decreases the impact of neurodegeneration on cognitive function. (See 'Lifestyle and activity' above.)

●Other factors that might increase the risk of dementia include atrial fibrillation, excessive alcohol, chronic kidney disease and other medical illnesses, depression, head trauma, hearing loss, exposure to certain medications and toxins, and obstructive sleep apnea (OSA). (See 'Others' above.)

ACKNOWLEDGMENT — The editorial staff at UpToDate would like to acknowledge Marie-Florence Shadlen, MD, who contributed to an earlier version of this topic review.

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Topic 5079 Version 51.0

References

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73 : High blood pressure, hypertension, and high pulse pressure are associated with poorer cognitive function in persons aged 60 and older: the Third National Health and Nutrition Examination Survey.

74 : Association of higher diastolic blood pressure levels with cognitive impairment.

75 : Blood pressure from mid- to late life and risk of incident dementia.

76 : Pre-existing hypertension and the impact of stroke on cognitive function.

77 : Blood pressure and brain injury in older adults: findings from a community-based autopsy study.

78 : Longitudinal changes in cerebral blood flow in the older hypertensive brain.

79 : The metabolic syndrome and Alzheimer disease.

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81 : The metabolic syndrome and development of cognitive impairment among older women.

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88 : Measures of adiposity and dementia risk in elderly persons.

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90 : Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease.

91 : Body mass index, other cardiovascular risk factors, and hospitalization for dementia.

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120 : Cardiovascular disease and cognitive decline in postmenopausal women: results from the Women's Health Initiative Memory Study.

121 : Atherosclerosis and risk for dementia.

122 : Carotid intimal medial thickness predicts cognitive decline among adults without clinical vascular disease.

123 : Carotid atherosclerosis and prospective risk of dementia.

124 : Calcification in major vessel beds relates to vascular brain disease.

125 : Coronary artery calcium, brain function and structure: the AGES-Reykjavik Study.

126 : Subclinical atherosclerotic calcification and cognitive functioning in middle-aged adults: the CARDIA study.

127 : Subclinical Cardiovascular Disease and Death, Dementia, and Coronary Heart Disease in Patients 80+ Years.

128 : Retinal microvascular signs, cognitive function, and dementia in older persons: the Cardiovascular Health Study.

129 : Retinal microvascular abnormalities and cognitive decline: the ARIC 14-year follow-up study.

130 : Retinal vascular caliber and risk of dementia: the Rotterdam study.

131 : Cognitive function and retinal and ischemic brain changes: the Women's Health Initiative.

132 : Retinopathy and risk of dementia: the Rotterdam Study.

133 : Atherosclerosis, dementia, and Alzheimer disease in the Baltimore Longitudinal Study of Aging cohort.

134 : Walking and dementia in physically capable elderly men.

135 : Physical activity, including walking, and cognitive function in older women.

136 : Social resources and cognitive decline in a population of older African Americans and whites.

137 : A longitudinal study of cardiorespiratory fitness and cognitive function in healthy older adults.

138 : Leisure-time physical activity at midlife and the risk of dementia and Alzheimer's disease.

139 : Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older.

140 : Leisure activities and the risk of amnestic mild cognitive impairment in the elderly.

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142 : Physical fitness and lifetime cognitive change.

143 : Relation of cognitive activity to risk of developing Alzheimer disease.

144 : Physical activity and dementia risk in the elderly: findings from a prospective Italian study.

145 : Cardiorespiratory fitness and brain atrophy in early Alzheimer disease.

146 : Physical activity, diet, and risk of Alzheimer disease.

147 : Leisure activities and the risk of dementia in the elderly: results from the Three-City Study.

148 : Physical activity and cognition in women with vascular conditions.

149 : Activity energy expenditure and incident cognitive impairment in older adults.

150 : Total daily physical activity and the risk of AD and cognitive decline in older adults.

151 : Influence of late-life cognitive activity on cognitive health.

152 : Physical activity prevents progression for cognitive impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study.

153 : Exercise and Alzheimer's disease biomarkers in cognitively normal older adults.

154 : Cardiovascular and cognitive fitness at age 18 and risk of early-onset dementia.

155 : Association Between Mentally Stimulating Activities in Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOEε4 Genotype.

156 : The association between midlife cardiorespiratory fitness levels and later-life dementia: a cohort study.

157 : An active and socially integrated lifestyle in late life might protect against dementia.

158 : Influence of education and occupation on the incidence of Alzheimer's disease.

159 : Education and other measures of socioeconomic status and risk of incident Alzheimer disease in a defined population of older persons.

160 : Dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 Dementia Research Group population-based cohort study.

161 : Education and dementia: what lies behind the association?

162 : Brain volume decline in aging: evidence for a relation between socioeconomic status, preclinical Alzheimer disease, and reserve.

163 : Association of plasma beta-amyloid level and cognitive reserve with subsequent cognitive decline.

164 : Education modifies the relation of AD pathology to level of cognitive function in older persons.

165 : Processing resources reduce the effect of Alzheimer pathology on other cognitive systems.

166 : Education and Alzheimer disease without dementia: support for the cognitive reserve hypothesis.

167 : Schooling mediates brain reserve in Alzheimer's disease: findings of fluoro-deoxy-glucose-positron emission tomography.

168 : Education and occupation as proxies for reserve in aMCI converters and AD: FDG-PET evidence.

169 : Alzheimer disease and cognitive reserve: variation of education effect with carbon 11-labeled Pittsburgh Compound B uptake.

170 : Cognition, reserve, and amyloid deposition in normal aging.

171 : The Nun study: clinically silent AD, neuronal hypertrophy, and linguistic skills in early life.

172 : Neuronal hypertrophy in asymptomatic Alzheimer disease.

173 : Education and the course of cognitive decline in Alzheimer disease.

174 : Education delays accelerated decline on a memory test in persons who develop dementia.

175 : Does cognitive reserve shape cognitive decline?

176 : Physical activity and risk of cognitive decline: a meta-analysis of prospective studies.

177 : Atrial fibrillation and the risk of incident dementia: a meta-analysis.

178 : Atrial fibrillation and risk of dementia: a prospective cohort study.

179 : Atrial fibrillation and cognitive decline: a longitudinal cohort study.

180 : Increased risk of cognitive and functional decline in patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies.

181 : Association Between Atrial Fibrillation and Dementia in the General Population.

182 : Cognitive impairment associated with atrial fibrillation: a meta-analysis.

183 : Dementia risk in renal dysfunction: A systematic review and meta-analysis of prospective studies.

184 : Depression as a risk factor for Alzheimer disease: the MIRAGE Study.

185 : Depression and risk for Alzheimer disease: systematic review, meta-analysis, and metaregression analysis.

186 : History of depression, depressive symptoms, and medial temporal lobe atrophy and the risk of Alzheimer disease.

187 : Depressive symptoms and cognitive decline in community-dwelling older adults.

188 : Depressive symptoms and risk of dementia: the Framingham Heart Study.

189 : Recurrent depressive symptoms and the incidence of dementia and mild cognitive impairment.

190 : Late-life depression and risk of vascular dementia and Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies.

191 : Trajectories of Depressive Symptoms Before Diagnosis of Dementia: A 28-Year Follow-up Study.

192 : Abnormality of gait as a predictor of non-Alzheimer's dementia.

193 : Motoric cognitive risk syndrome and the risk of dementia.

194 : Clinicopathological Evaluation of Chronic Traumatic Encephalopathy in Players of American Football.

195 : Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology.

196 : Reassuring News About Football and Cognitive Decline?: Not So Fast.

197 : Association of Playing High School Football With Cognition and Mental Health Later in Life.

198 : Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

199 : Polypathology and dementia after brain trauma: Does brain injury trigger distinct neurodegenerative diseases, or should they be classified together as traumatic encephalopathy?

200 : Association of Traumatic Brain Injury With Late-Life Neurodegenerative Conditions and Neuropathologic Findings.

201 : Hearing loss and incident dementia.

202 : Hearing loss and cognitive decline in older adults.

203 : Hearing Impairment Affects Dementia Incidence. An Analysis Based on Longitudinal Health Claims Data in Germany.

204 : Relationship of hearing loss and dementia: a prospective, population-based study.

205 : Self-Reported Hearing Loss, Hearing Aids, and Cognitive Decline in Elderly Adults: A 25-Year Study.

206 : Observed Hearing Loss and Incident Dementia in a Multiethnic Cohort.

207 : Central auditory dysfunction as a harbinger of Alzheimer dementia.

208 : Executive dysfunction and presbycusis in older persons with and without memory loss and dementia.

209 : Central auditory dysfunction in older persons with memory impairment or Alzheimer dementia.

210 : Plasma homocysteine as a risk factor for dementia and Alzheimer's disease.

211 : Total homocysteine and cognitive decline in a community-based sample of elderly subjects: the Rotterdam Study.

212 : Total homocysteine and cognition in a tri-ethnic cohort: the Northern Manhattan Study.

213 : Homocysteine and cognitive function in elderly people.

214 : Homocysteine versus the vitamins folate, B6, and B12 as predictors of cognitive function and decline in older high-functioning adults: MacArthur Studies of Successful Aging.

215 : Association of homocysteine with plasma amyloid beta protein in aging and neurodegenerative disease.

216 : Plasma total homocysteine and memory in the elderly: the Hordaland Homocysteine Study.

217 : Methylenetetrahydrofolate reductase C677T polymorphism and cognitive function in older women.

218 : Homocysteine and holotranscobalamin and the risk of Alzheimer disease: a longitudinal study.

219 : Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia.

220 : Relationship between plasma homocysteine, vitamin status and extracranial carotid-artery stenosis in the Framingham Study population.

221 : Homocysteine is a risk factor for cerebral small vessel disease, acting via endothelial dysfunction.

222 : Changes in folate, vitamin B12 and homocysteine associated with incident dementia.

223 : Long-term cognitive impairment and functional disability among survivors of severe sepsis.

224 : Association between acute care and critical illness hospitalization and cognitive function in older adults.

225 : Cognitive decline after hospitalization in a community population of older persons.

226 : Nontraditional risk factors combine to predict Alzheimer disease and dementia.

227 : Self-rated health and risk of incident dementia: a community-based elderly cohort, the 3C study.

228 : A systematic review of amnestic and non-amnestic mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid drugs.

229 : Benzodiazepine use and risk of Alzheimer's disease: case-control study.

230 : Cumulative use of strong anticholinergics and incident dementia: a prospective cohort study.

231 : Benzodiazepine use and risk of dementia: prospective population based study.

232 : Benzodiazepine Use and Risk of Developing Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis.

233 : Benzodiazepine use and risk of incident dementia or cognitive decline: prospective population based study.

234 : Association Between Anticholinergic Medication Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults.

235 : Sleep-disordered breathing, hypoxia, and risk of mild cognitive impairment and dementia in older women.

236 : Sleep-disordered breathing and cognition in older women.

237 : Associations between sleep-disordered breathing, nocturnal hypoxemia, and subsequent cognitive decline in older community-dwelling men: the Osteoporotic Fractures in Men Sleep Study.

238 : Obstructive sleep apnea increases risk of incident dementia in community-dwelling older adults

239 : Sleep-disordered breathing advances cognitive decline in the elderly.

240 : Sleep characteristics and cognitive impairment in the general population: The HypnoLaus study.

241 : Obstructive sleep apnea and neurocognitive function in a Hispanic/Latino population.

242 : Sleep disturbances and cognitive decline in the Northern Manhattan Study.

243 : Association of Sleep-Disordered Breathing With Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis.

244 : Sleep Quality and Risk of Dementia Among Older Male Veterans.

245 : Amyloid Burden in Obstructive Sleep Apnea.

246 : Obstructive Sleep Apnea is Associated With Early but Possibly Modifiable Alzheimer's Disease Biomarkers Changes.

247 : Sleep architecture and the risk of incident dementia in the community.

248 : Environmental risk factors for dementia: a systematic review.

249 : Parkinson disease and Alzheimer disease: environmental risk factors.

250 : Exposure to air pollution as a potential contributor to cognitive function, cognitive decline, brain imaging, and dementia: A systematic review of epidemiologic research.

251 : Is air pollution associated with increased risk of cognitive decline? A systematic review.

252 : Living near major roads and the incidence of dementia, Parkinson's disease, and multiple sclerosis: a population-based cohort study.

253 : Exposure to lead in petrol and increased incidence of dementia.

254 : Exposure to lead in petrol and increased incidence of dementia.

255 : Particulate air pollutants, APOE alleles and their contributions to cognitive impairment in older women and to amyloidogenesis in experimental models.

256 : Vitamin D, cognition, and dementia: a systematic review and meta-analysis.

257 : 25-Hydroxyvitamin D, dementia, and cerebrovascular pathology in elders receiving home services.

258 : Dietary intake of vitamin D and cognition in older women: a large population-based study.

259 : Association of vitamin D deficiency with cognitive impairment in older women: cross-sectional study.

260 : Genetically decreased vitamin D and risk of Alzheimer disease.

261 : 25-Hydroxyvitamin D levels and cognitive performance and decline in elderly men.

262 : Vitamin D and risk of cognitive decline in elderly persons.

263 : Vitamin D and the risk of dementia and Alzheimer disease.