Risk Factors For Cognitive Decline and Dementia

23-07-2019 Risk factors for cognitive decline and dementia - UpToDate
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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
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Jun 2019. | This topic last updated: Dec 15, 2017.
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
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● 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 dementia" and "Treatment and prevention of vascular 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, care needs, and
clinical course'.)
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", section on 'Risk factors for
poststroke 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", section on
'Cognitive impairment'.)
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 "Epidemiology, pathology, and pathogenesis of
Alzheimer disease", section on 'Cerebrovascular disease' and "Etiology, clinical manifestations, and
diagnosis of vascular dementia", section on 'Etiology and pathophysiology'.)
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 "The 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", section on 'Slow gait'.)
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
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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].
INFORMATION FOR PATIENTS
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The
Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and
they answer the four or five key questions a patient might have about a given condition. These
articles are best for patients who want a general overview and who prefer short, easy-to-read
materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more
detailed. These articles are written at the 10th to 12th grade reading level and are best for patients
who want in-depth information and are comfortable with some medical jargon.
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.
Use of UpToDate is subject to the Subscription and License Agreement.
REFERENCES
1. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care.

Lancet 2017; 390:2673.
2. Kane RL, Bulter M, Fink HA, et al. Interventions to prevent age-related cognitive decline, mild co
gnitive impairment, and clinical Alzheimer's-type dementia: Comparative effectiveness review N
o. 188. AHRQ Pub. No. 17-EHC008-EF, Agency for Healthcare Research and Quality, Rockville,
MD 2017.
3. Preventing Cognitive Decline and Dementia: A Way Forward. National Academies Press; Nation
al Academies of Sciences, Engineering, and Medicine, Washington, DC, 2017.
4. Satizabal CL, Beiser AS, Chouraki V, et al. Incidence of Dementia over Three Decades in the
Framingham Heart Study. N Engl J Med 2016; 374:523.
5. Schrijvers EM, Verhaaren BF, Koudstaal PJ, et al. Is dementia incidence declining?: Trends in
dementia incidence since 1990 in the Rotterdam Study. Neurology 2012; 78:1456.
6. Rocca WA, Petersen RC, Knopman DS, et al. Trends in the incidence and prevalence of
Alzheimer's disease, dementia, and cognitive impairment in the United States. Alzheimers
Dement 2011; 7:80.

7. Matthews FE, Arthur A, Barnes LE, et al. A two-decade comparison of prevalence of dementia
in individuals aged 65 years and older from three geographical areas of England: results of the
Cognitive Function and Ageing Study I and II. Lancet 2013; 382:1405.
8. Qiu C, von Strauss E, Bäckman L, et al. Twenty-year changes in dementia occurrence suggest
decreasing incidence in central Stockholm, Sweden. Neurology 2013; 80:1888.
9. Langa KM, Larson EB, Crimmins EM, et al. A Comparison of the Prevalence of Dementia in the
United States in 2000 and 2012. JAMA Intern Med 2017; 177:51.
10. Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of

Alzheimer's disease in Europe: A meta-analysis. Neurologia 2017; 32:523.
11. Carone M, Asgharian M, Jewell NP. Estimating the lifetime risk of dementia in the Canadian
elderly population using cross-sectional cohort survival data. J Am Stat Assoc 2014; 109:24.
12. Corrada MM, Brookmeyer R, Berlau D, et al. Prevalence of dementia after age 90: results from
the 90+ study. Neurology 2008; 71:337.
13. Corrada MM, Brookmeyer R, Paganini-Hill A, et al. Dementia incidence continues to increase
with age in the oldest old: the 90+ study. Ann Neurol 2010; 67:114.
14. Larson EB, Langa KM. The rising tide of dementia worldwide. Lancet 2008; 372:430.
15. Chan KY, Wang W, Wu JJ, et al. Epidemiology of Alzheimer's disease and other forms of
dementia in China, 1990-2010: a systematic review and analysis. Lancet 2013; 381:2016.
16. Mercy L, Hodges JR, Dawson K, et al. Incidence of early-onset dementias in Cambridgeshire,
United Kingdom. Neurology 2008; 71:1496.
17. Garre-Olmo J, Genís Batlle D, del Mar Fernández M, et al. Incidence and subtypes of early-
onset dementia in a geographically defined general population. Neurology 2010; 75:1249.
18. Kelley BJ, Boeve BF, Josephs KA. Young-onset dementia: demographic and etiologic
characteristics of 235 patients. Arch Neurol 2008; 65:1502.
19. Green RC, Cupples LA, Go R, et al. Risk of dementia among white and African American
relatives of patients with Alzheimer disease. JAMA 2002; 287:329.
20. Wolters FJ, van der Lee SJ, Koudstaal PJ, et al. Parental family history of dementia in relation
to subclinical brain disease and dementia risk. Neurology 2017.

21. Pendlebury ST, Rothwell PM. Prevalence, incidence, and factors associated with pre-stroke and
post-stroke dementia: a systematic review and meta-analysis. Lancet Neurol 2009; 8:1006.
22. Gottesman RF, Hillis AE. Predictors and assessment of cognitive dysfunction resulting from
ischaemic stroke. Lancet Neurol 2010; 9:895.
23. Levine DA, Galecki AT, Langa KM, et al. Trajectory of Cognitive Decline After Incident Stroke.
JAMA 2015; 314:41.
24. Moulin S, Labreuche J, Bombois S, et al. Dementia risk after spontaneous intracerebral
haemorrhage: a prospective cohort study. Lancet Neurol 2016; 15:820.
25. Biffi A, Bailey D, Anderson CD, et al. Risk Factors Associated With Early vs Delayed Dementia
After Intracerebral Hemorrhage. JAMA Neurol 2016; 73:969.
26. Akoudad S, Wolters FJ, Viswanathan A, et al. Association of Cerebral Microbleeds With
Cognitive Decline and Dementia. JAMA Neurol 2016; 73:934.
27. Debette S, Seshadri S, Beiser A, et al. Midlife vascular risk factor exposure accelerates
structural brain aging and cognitive decline. Neurology 2011; 77:461.
28. Yaffe K, Vittinghoff E, Pletcher MJ, et al. Early adult to midlife cardiovascular risk factors and
cognitive function. Circulation 2014; 129:1560.
29. Gottesman RF, Schneider AL, Albert M, et al. Midlife hypertension and 20-year cognitive
change: the atherosclerosis risk in communities neurocognitive study. JAMA Neurol 2014;
71:1218.
30. Gottesman RF, Albert MS, Alonso A, et al. Associations Between Midlife Vascular Risk Factors
and 25-Year Incident Dementia in the Atherosclerosis Risk in Communities (ARIC) Cohort.
JAMA Neurol 2017; 74:1246.
31. Luchsinger JA, Reitz C, Honig LS, et al. Aggregation of vascular risk factors and risk of incident
Alzheimer disease. Neurology 2005; 65:545.
32. Unverzagt FW, McClure LA, Wadley VG, et al. Vascular risk factors and cognitive impairment in
a stroke-free cohort. Neurology 2011; 77:1729.
33. Irie F, Fitzpatrick AL, Lopez OL, et al. Enhanced risk for Alzheimer disease in persons with type
2 diabetes and APOE epsilon4: the Cardiovascular Health Study Cognition Study. Arch Neurol
2008; 65:89.

34. Verdelho A, Madureira S, Moleiro C, et al. White matter changes and diabetes predict cognitive
decline in the elderly: the LADIS study. Neurology 2010; 75:160.
35. Ahtiluoto S, Polvikoski T, Peltonen M, et al. Diabetes, Alzheimer disease, and vascular
dementia: a population-based neuropathologic study. Neurology 2010; 75:1195.
36. Ohara T, Doi Y, Ninomiya T, et al. Glucose tolerance status and risk of dementia in the
community: the Hisayama study. Neurology 2011; 77:1126.
37. Rawlings AM, Sharrett AR, Schneider AL, et al. Diabetes in midlife and cognitive change over
20 years: a cohort study. Ann Intern Med 2014; 161:785.
38. Katon W, Pedersen HS, Ribe AR, et al. Effect of depression and diabetes mellitus on the risk for
dementia: a national population-based cohort study. JAMA Psychiatry 2015; 72:612.
39. Ng TP, Feng L, Nyunt MS, et al. Metabolic Syndrome and the Risk of Mild Cognitive Impairment
and Progression to Dementia: Follow-up of the Singapore Longitudinal Ageing Study Cohort.
JAMA Neurol 2016; 73:456.
40. Li W, Risacher SL, Huang E, et al. Type 2 diabetes mellitus is associated with brain atrophy and
hypometabolism in the ADNI cohort. Neurology 2016; 87:595.
41. Biessels GJ, Staekenborg S, Brunner E, et al. Risk of dementia in diabetes mellitus: a
systematic review. Lancet Neurol 2006; 5:64.
42. Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med
2013; 369:540.
43. Kerti L, Witte AV, Winkler A, et al. Higher glucose levels associated with lower memory and
reduced hippocampal microstructure. Neurology 2013; 81:1746.
44. Avadhani R, Fowler K, Barbato C, et al. Glycemia and cognitive function in metabolic syndrome
and coronary heart disease. Am J Med 2015; 128:46.
45. Munshi M, Grande L, Hayes M, et al. Cognitive dysfunction is associated with poor diabetes
control in older adults. Diabetes Care 2006; 29:1794.
46. Whitmer RA, Karter AJ, Yaffe K, et al. Hypoglycemic episodes and risk of dementia in older
patients with type 2 diabetes mellitus. JAMA 2009; 301:1565.
47. Launer LJ, Miller ME, Williamson JD, et al. Effects of intensive glucose lowering on brain
structure and function in people with type 2 diabetes (ACCORD MIND): a randomised open-

label substudy. Lancet Neurol 2011; 10:969.
48. Lovestone S. Diabetes and dementia: is the brain another site of end-organ damage?
Neurology 1999; 53:1907.
49. Biessels GJ, De Leeuw FE, Lindeboom J, et al. Increased cortical atrophy in patients with
Alzheimer's disease and type 2 diabetes mellitus. J Neurol Neurosurg Psychiatry 2006; 77:304.
50. Arvanitakis Z, Schneider JA, Wilson RS, et al. Diabetes is related to cerebral infarction but not
to AD pathology in older persons. Neurology 2006; 67:1960.
51. Sonnen JA, Larson EB, Brickell K, et al. Different patterns of cerebral injury in dementia with or
without diabetes. Arch Neurol 2009; 66:315.
52. Cherbuin N, Sachdev P, Anstey KJ. Higher normal fasting plasma glucose is associated with
hippocampal atrophy: The PATH Study. Neurology 2012; 79:1019.
53. Whitmer RA, Sidney S, Selby J, et al. Midlife cardiovascular risk factors and risk of dementia in
late life. Neurology 2005; 64:277.
54. Alonso A, Mosley TH Jr, Gottesman RF, et al. Risk of dementia hospitalisation associated with
cardiovascular risk factors in midlife and older age: the Atherosclerosis Risk in Communities
(ARIC) study. J Neurol Neurosurg Psychiatry 2009; 80:1194.
55. Solomon A, Kåreholt I, Ngandu T, et al. Serum cholesterol changes after midlife and late-life
cognition: twenty-one-year follow-up study. Neurology 2007; 68:751.
56. Shepardson NE, Shankar GM, Selkoe DJ. Cholesterol level and statin use in Alzheimer
disease: I. Review of epidemiological and preclinical studies. Arch Neurol 2011; 68:1239.
57. Moroney JT, Tang MX, Berglund L, et al. Low-density lipoprotein cholesterol and the risk of
dementia with stroke. JAMA 1999; 282:254.
58. Reitz C, Tang MX, Luchsinger J, Mayeux R. Relation of plasma lipids to Alzheimer disease and
vascular dementia. Arch Neurol 2004; 61:705.
59. Dufouil C, Richard F, Fiévet N, et al. APOE genotype, cholesterol level, lipid-lowering treatment,
and dementia: the Three-City Study. Neurology 2005; 64:1531.
60. Tan ZS, Seshadri S, Beiser A, et al. Plasma total cholesterol level as a risk factor for Alzheimer
disease: the Framingham Study. Arch Intern Med 2003; 163:1053.

61. Reitz C, Luchsinger J, Tang MX, et al. Impact of plasma lipids and time on memory performance
in healthy elderly without dementia. Neurology 2005; 64:1378.
62. Li G, Shofer JB, Kukull WA, et al. Serum cholesterol and risk of Alzheimer disease: a
community-based cohort study. Neurology 2005; 65:1045.
63. Xiong GL, Plassman BL, Helms MJ, Steffens DC. Vascular risk factors and cognitive decline
among elderly male twins. Neurology 2006; 67:1586.
64. Mielke MM, Zandi PP, Shao H, et al. The 32-year relationship between cholesterol and
dementia from midlife to late life. Neurology 2010; 75:1888.
65. Mielke MM, Zandi PP, Sjögren M, et al. High total cholesterol levels in late life associated with a
reduced risk of dementia. Neurology 2005; 64:1689.
66. Stewart R, White LR, Xue QL, Launer LJ. Twenty-six-year change in total cholesterol levels and
incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2007; 64:103.
67. Verdelho A, Madureira S, Ferro JM, et al. Differential impact of cerebral white matter changes,
diabetes, hypertension and stroke on cognitive performance among non-disabled elderly. The
LADIS study. J Neurol Neurosurg Psychiatry 2007; 78:1325.
68. Elias MF, Wolf PA, D'Agostino RB, et al. Untreated blood pressure level is inversely related to
cognitive functioning: the Framingham Study. Am J Epidemiol 1993; 138:353.
69. Skoog I, Lernfelt B, Landahl S, et al. 15-year longitudinal study of blood pressure and dementia.
Lancet 1996; 347:1141.
70. Kilander L, Nyman H, Boberg M, et al. Hypertension is related to cognitive impairment: a 20-
year follow-up of 999 men. Hypertension 1998; 31:780.
71. Tzourio C, Dufouil C, Ducimetière P, Alpérovitch A. Cognitive decline in individuals with high
blood pressure: a longitudinal study in the elderly. EVA Study Group. Epidemiology of Vascular
Aging. Neurology 1999; 53:1948.
72. Freitag MH, Peila R, Masaki K, et al. Midlife pulse pressure and incidence of dementia: the
Honolulu-Asia Aging Study. Stroke 2006; 37:33.
73. Obisesan TO, Obisesan OA, Martins S, et al. 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. J Am Geriatr Soc 2008; 56:501.

74. Tsivgoulis G, Alexandrov AV, Wadley VG, et al. Association of higher diastolic blood pressure
levels with cognitive impairment. Neurology 2009; 73:589.
75. McGrath ER, Beiser AS, DeCarli C, et al. Blood pressure from mid- to late life and risk of
incident dementia. Neurology 2017; 89:2447.
76. Elkins JS, Yaffe K, Cauley JA, et al. Pre-existing hypertension and the impact of stroke on
cognitive function. Ann Neurol 2005; 58:68.
77. Wang LY, Larson EB, Sonnen JA, et al. Blood pressure and brain injury in older adults: findings
from a community-based autopsy study. J Am Geriatr Soc 2009; 57:1975.
78. Beason-Held LL, Moghekar A, Zonderman AB, et al. Longitudinal changes in cerebral blood
flow in the older hypertensive brain. Stroke 2007; 38:1766.
79. Razay G, Vreugdenhil A, Wilcock G. The metabolic syndrome and Alzheimer disease. Arch
Neurol 2007; 64:93.
80. Kalmijn S, Foley D, White L, et al. Metabolic cardiovascular syndrome and risk of dementia in
Japanese-American elderly men. The Honolulu-Asia aging study. Arterioscler Thromb Vasc Biol
2000; 20:2255.
81. Yaffe K, Weston AL, Blackwell T, Krueger KA. The metabolic syndrome and development of
cognitive impairment among older women. Arch Neurol 2009; 66:324.
82. Solfrizzi V, Scafato E, Capurso C, et al. Metabolic syndrome and the risk of vascular dementia:
the Italian Longitudinal Study on Ageing. J Neurol Neurosurg Psychiatry 2010; 81:433.
83. Vanhanen M, Koivisto K, Moilanen L, et al. Association of metabolic syndrome with Alzheimer
disease: a population-based study. Neurology 2006; 67:843.
84. Raffaitin C, Féart C, Le Goff M, et al. Metabolic syndrome and cognitive decline in French
elders: the Three-City Study. Neurology 2011; 76:518.
85. Singh-Manoux A, Czernichow S, Elbaz A, et al. Obesity phenotypes in midlife and cognition in
early old age: the Whitehall II cohort study. Neurology 2012; 79:755.
86. Yaffe K, Kanaya A, Lindquist K, et al. The metabolic syndrome, inflammation, and risk of
cognitive decline. JAMA 2004; 292:2237.
87. van den Berg E, Biessels GJ, de Craen AJ, et al. The metabolic syndrome is associated with
decelerated cognitive decline in the oldest old. Neurology 2007; 69:979.

88. Luchsinger JA, Patel B, Tang MX, et al. Measures of adiposity and dementia risk in elderly
persons. Arch Neurol 2007; 64:392.
89. Whitmer RA, Gunderson EP, Barrett-Connor E, et al. Obesity in middle age and future risk of
dementia: a 27 year longitudinal population based study. BMJ 2005; 330:1360.
90. Kivipelto M, Ngandu T, Fratiglioni L, et al. Obesity and vascular risk factors at midlife and the
risk of dementia and Alzheimer disease. Arch Neurol 2005; 62:1556.
91. Rosengren A, Skoog I, Gustafson D, Wilhelmsen L. Body mass index, other cardiovascular risk
factors, and hospitalization for dementia. Arch Intern Med 2005; 165:321.
92. Gustafson D, Rothenberg E, Blennow K, et al. An 18-year follow-up of overweight and risk of
Alzheimer disease. Arch Intern Med 2003; 163:1524.
93. Whitmer RA, Gustafson DR, Barrett-Connor E, et al. Central obesity and increased risk of
dementia more than three decades later. Neurology 2008; 71:1057.
94. Gustafson DR, Bäckman K, Waern M, et al. Adiposity indicators and dementia over 32 years in
Sweden. Neurology 2009; 73:1559.
95. Xu WL, Atti AR, Gatz M, et al. Midlife overweight and obesity increase late-life dementia risk: a
population-based twin study. Neurology 2011; 76:1568.
96. Cournot M, Marquié JC, Ansiau D, et al. Relation between body mass index and cognitive
function in healthy middle-aged men and women. Neurology 2006; 67:1208.
97. Albanese E, Davis B, Jonsson PV, et al. Overweight and Obesity in Midlife and Brain Structure
and Dementia 26 Years Later: The AGES-Reykjavik Study. Am J Epidemiol 2015; 181:672.
98. Alhurani RE, Vassilaki M, Aakre JA, et al. Decline in Weight and Incident Mild Cognitive
Impairment: Mayo Clinic Study of Aging. JAMA Neurol 2016; 73:439.
99. Stewart R, Masaki K, Xue QL, et al. A 32-year prospective study of change in body weight and
incident dementia: the Honolulu-Asia Aging Study. Arch Neurol 2005; 62:55.
100. Buchman AS, Wilson RS, Bienias JL, et al. Change in body mass index and risk of incident
101. Nourhashémi F, Deschamps V, Larrieu S, et al. Body mass index and incidence of dementia:
the PAQUID study. Neurology 2003; 60:117.

102. Johnson DK, Wilkins CH, Morris JC. Accelerated weight loss may precede diagnosis in
Alzheimer disease. Arch Neurol 2006; 63:1312.
103. Knopman DS, Edland SD, Cha RH, et al. Incident dementia in women is preceded by weight
loss by at least a decade. Neurology 2007; 69:739.
104. Hughes TF, Borenstein AR, Schofield E, et al. Association between late-life body mass index
and dementia: The Kame Project. Neurology 2009; 72:1741.
105. Vidoni ED, Townley RA, Honea RA, et al. Alzheimer disease biomarkers are associated with
body mass index. Neurology 2011; 77:1913.
106. Burns JM, Johnson DK, Watts A, et al. Reduced lean mass in early Alzheimer disease and its
association with brain atrophy. Arch Neurol 2010; 67:428.
107. Almeida OP, Hulse GK, Lawrence D, Flicker L. Smoking as a risk factor for Alzheimer's disease:
contrasting evidence from a systematic review of case-control and cohort studies. Addiction
2002; 97:15.
108. Tyas SL, White LR, Petrovitch H, et al. Mid-life smoking and late-life dementia: the Honolulu-
Asia Aging Study. Neurobiol Aging 2003; 24:589.
109. Sabia S, Marmot M, Dufouil C, Singh-Manoux A. Smoking history and cognitive function in
middle age from the Whitehall II study. Arch Intern Med 2008; 168:1165.
110. Rusanen M, Kivipelto M, Quesenberry CP Jr, et al. Heavy smoking in midlife and long-term risk
of Alzheimer disease and vascular dementia. Arch Intern Med 2011; 171:333.
111. Yamada M, Kasagi F, Sasaki H, et al. Association between dementia and midlife risk factors: the
Radiation Effects Research Foundation Adult Health Study. J Am Geriatr Soc 2003; 51:410.
112. Chen R, Wilson K, Chen Y, et al. Association between environmental tobacco smoke exposure
and dementia syndromes. Occup Environ Med 2013; 70:63.
113. Llewellyn DJ, Lang IA, Langa KM, et al. Exposure to secondhand smoke and cognitive
impairment in non-smokers: national cross sectional study with cotinine measurement. BMJ
2009; 338:b462.
114. Barnes DE, Haight TJ, Mehta KM, et al. Secondhand smoke, vascular disease, and dementia
incidence: findings from the cardiovascular health cognition study. Am J Epidemiol 2010;
171:292.

115. Anstey KJ, von Sanden C, Salim A, O'Kearney R. Smoking as a risk factor for dementia and
cognitive decline: a meta-analysis of prospective studies. Am J Epidemiol 2007; 166:367.
116. Reitz C, Luchsinger J, Tang MX, Mayeux R. Effect of smoking and time on cognitive function in
the elderly without dementia. Neurology 2005; 65:870.
117. Ott A, Slooter AJ, Hofman A, et al. Smoking and risk of dementia and Alzheimer's disease in a
population-based cohort study: the Rotterdam Study. Lancet 1998; 351:1840.
118. Reitz C, den Heijer T, van Duijn C, et al. Relation between smoking and risk of dementia and
Alzheimer disease: the Rotterdam Study. Neurology 2007; 69:998.
119. Poirier J, Delisle MC, Quirion R, et al. Apolipoprotein E4 allele as a predictor of cholinergic
deficits and treatment outcome in Alzheimer disease. Proc Natl Acad Sci U S A 1995; 92:12260.
120. Haring B, Leng X, Robinson J, et al. Cardiovascular disease and cognitive decline in
postmenopausal women: results from the Women's Health Initiative Memory Study. J Am Heart
Assoc 2013; 2:e000369.
121. van Oijen M, de Jong FJ, Witteman JC, et al. Atherosclerosis and risk for dementia. Ann Neurol
2007; 61:403.
122. Wendell CR, Zonderman AB, Metter EJ, et al. Carotid intimal medial thickness predicts cognitive
decline among adults without clinical vascular disease. Stroke 2009; 40:3180.
123. Wendell CR, Waldstein SR, Ferrucci L, et al. Carotid atherosclerosis and prospective risk of
dementia. Stroke 2012; 43:3319.
124. Bos D, Ikram MA, Elias-Smale SE, et al. Calcification in major vessel beds relates to vascular
brain disease. Arterioscler Thromb Vasc Biol 2011; 31:2331.
125. Vidal JS, Sigurdsson S, Jonsdottir MK, et al. Coronary artery calcium, brain function and
structure: the AGES-Reykjavik Study. Stroke 2010; 41:891.
126. Reis JP, Launer LJ, Terry JG, et al. Subclinical atherosclerotic calcification and cognitive
functioning in middle-aged adults: the CARDIA study. Atherosclerosis 2013; 231:72.
127. Kuller LH, Lopez OL, Mackey RH, et al. Subclinical Cardiovascular Disease and Death,
Dementia, and Coronary Heart Disease in Patients 80+ Years. J Am Coll Cardiol 2016; 67:1013.
128. Baker ML, Marino Larsen EK, Kuller LH, et al. Retinal microvascular signs, cognitive function,
and dementia in older persons: the Cardiovascular Health Study. Stroke 2007; 38:2041.

129. Lesage SR, Mosley TH, Wong TY, et al. Retinal microvascular abnormalities and cognitive
decline: the ARIC 14-year follow-up study. Neurology 2009; 73:862.
130. de Jong FJ, Schrijvers EM, Ikram MK, et al. Retinal vascular caliber and risk of dementia: the
Rotterdam study. Neurology 2011; 76:816.
131. Haan M, Espeland MA, Klein BE, et al. Cognitive function and retinal and ischemic brain
changes: the Women's Health Initiative. Neurology 2012; 78:942.
132. Schrijvers EM, Buitendijk GH, Ikram MK, et al. Retinopathy and risk of dementia: the Rotterdam
Study. Neurology 2012; 79:365.
133. Dolan H, Crain B, Troncoso J, et al. Atherosclerosis, dementia, and Alzheimer disease in the
Baltimore Longitudinal Study of Aging cohort. Ann Neurol 2010; 68:231.
134. Abbott RD, White LR, Ross GW, et al. Walking and dementia in physically capable elderly men.
JAMA 2004; 292:1447.
135. Weuve J, Kang JH, Manson JE, et al. Physical activity, including walking, and cognitive function
in older women. JAMA 2004; 292:1454.
136. Barnes LL, Mendes de Leon CF, Wilson RS, et al. Social resources and cognitive decline in a
population of older African Americans and whites. Neurology 2004; 63:2322.
137. Barnes DE, Yaffe K, Satariano WA, Tager IB. A longitudinal study of cardiorespiratory fitness
and cognitive function in healthy older adults. J Am Geriatr Soc 2003; 51:459.
138. Rovio S, Kåreholt I, Helkala EL, et al. Leisure-time physical activity at midlife and the risk of
dementia and Alzheimer's disease. Lancet Neurol 2005; 4:705.
139. Larson EB, Wang L, Bowen JD, et al. Exercise is associated with reduced risk for incident
dementia among persons 65 years of age and older. Ann Intern Med 2006; 144:73.
140. Verghese J, LeValley A, Derby C, et al. Leisure activities and the risk of amnestic mild cognitive
impairment in the elderly. Neurology 2006; 66:821.
141. Bennett DA, Schneider JA, Tang Y, et al. The effect of social networks on the relation between
Alzheimer's disease pathology and level of cognitive function in old people: a longitudinal cohort
study. Lancet Neurol 2006; 5:406.
142. Deary IJ, Whalley LJ, Batty GD, Starr JM. Physical fitness and lifetime cognitive change.
Neurology 2006; 67:1195.

143. Wilson RS, Scherr PA, Schneider JA, et al. Relation of cognitive activity to risk of developing
144. Ravaglia G, Forti P, Lucicesare A, et al. Physical activity and dementia risk in the elderly:
findings from a prospective Italian study. Neurology 2008; 70:1786.
145. Burns JM, Cronk BB, Anderson HS, et al. Cardiorespiratory fitness and brain atrophy in early
146. Scarmeas N, Luchsinger JA, Schupf N, et al. Physical activity, diet, and risk of Alzheimer
disease. JAMA 2009; 302:627.
147. Akbaraly TN, Portet F, Fustinoni S, et al. Leisure activities and the risk of dementia in the
elderly: results from the Three-City Study. Neurology 2009; 73:854.
148. Vercambre MN, Grodstein F, Manson JE, et al. Physical activity and cognition in women with
vascular conditions. Arch Intern Med 2011; 171:1244.
149. Middleton LE, Manini TM, Simonsick EM, et al. Activity energy expenditure and incident
cognitive impairment in older adults. Arch Intern Med 2011; 171:1251.
150. Buchman AS, Boyle PA, Yu L, et al. Total daily physical activity and the risk of AD and cognitive
decline in older adults. Neurology 2012; 78:1323.
151. Wilson RS, Segawa E, Boyle PA, Bennett DA. Influence of late-life cognitive activity on cognitive
health. Neurology 2012; 78:1123.
152. Verdelho A, Madureira S, Ferro JM, et al. Physical activity prevents progression for cognitive
impairment and vascular dementia: results from the LADIS (Leukoaraiosis and Disability) study.
Stroke 2012; 43:3331.
153. Liang KY, Mintun MA, Fagan AM, et al. Exercise and Alzheimer's disease biomarkers in
cognitively normal older adults. Ann Neurol 2010; 68:311.
154. Nyberg J, Åberg MA, Schiöler L, et al. Cardiovascular and cognitive fitness at age 18 and risk of
early-onset dementia. Brain 2014; 137:1514.
155. Krell-Roesch J, Vemuri P, Pink A, et al. Association Between Mentally Stimulating Activities in
Late Life and the Outcome of Incident Mild Cognitive Impairment, With an Analysis of the APOE
ε4 Genotype. JAMA Neurol 2017; 74:332.

156. Defina LF, Willis BL, Radford NB, et al. The association between midlife cardiorespiratory
fitness levels and later-life dementia: a cohort study. Ann Intern Med 2013; 158:162.
157. Fratiglioni L, Paillard-Borg S, Winblad B. An active and socially integrated lifestyle in late life
might protect against dementia. Lancet Neurol 2004; 3:343.
158. Stern Y, Gurland B, Tatemichi TK, et al. Influence of education and occupation on the incidence
of Alzheimer's disease. JAMA 1994; 271:1004.
159. Evans DA, Hebert LE, Beckett LA, et al. Education and other measures of socioeconomic status
and risk of incident Alzheimer disease in a defined population of older persons. Arch Neurol
1997; 54:1399.
160. Prince M, Acosta D, Ferri CP, et al. 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. Lancet 2012; 380:50.
161. Ngandu T, von Strauss E, Helkala EL, et al. Education and dementia: what lies behind the
association? Neurology 2007; 69:1442.
162. Fotenos AF, Mintun MA, Snyder AZ, et al. Brain volume decline in aging: evidence for a relation
between socioeconomic status, preclinical Alzheimer disease, and reserve. Arch Neurol 2008;
65:113.
163. Yaffe K, Weston A, Graff-Radford NR, et al. Association of plasma beta-amyloid level and
cognitive reserve with subsequent cognitive decline. JAMA 2011; 305:261.
164. Bennett DA, Wilson RS, Schneider JA, et al. Education modifies the relation of AD pathology to
level of cognitive function in older persons. Neurology 2003; 60:1909.
165. Boyle PA, Wilson RS, Schneider JA, et al. Processing resources reduce the effect of Alzheimer
pathology on other cognitive systems. Neurology 2008; 70:1534.
166. Roe CM, Xiong C, Miller JP, Morris JC. Education and Alzheimer disease without dementia:
support for the cognitive reserve hypothesis. Neurology 2007; 68:223.
167. Perneczky R, Drzezga A, Diehl-Schmid J, et al. Schooling mediates brain reserve in Alzheimer's
disease: findings of fluoro-deoxy-glucose-positron emission tomography. J Neurol Neurosurg
Psychiatry 2006; 77:1060.
168. Garibotto V, Borroni B, Kalbe E, et al. Education and occupation as proxies for reserve in aMCI
converters and AD: FDG-PET evidence. Neurology 2008; 71:1342.
169. Roe CM, Mintun MA, D'Angelo G, et al. Alzheimer disease and cognitive reserve: variation of
education effect with carbon 11-labeled Pittsburgh Compound B uptake. Arch Neurol 2008;
65:1467.
170. Rentz DM, Locascio JJ, Becker JA, et al. Cognition, reserve, and amyloid deposition in normal
aging. Ann Neurol 2010; 67:353.
171. Iacono D, Markesbery WR, Gross M, et al. The Nun study: clinically silent AD, neuronal
hypertrophy, and linguistic skills in early life. Neurology 2009; 73:665.
172. Iacono D, O'Brien R, Resnick SM, et al. Neuronal hypertrophy in asymptomatic Alzheimer
disease. J Neuropathol Exp Neurol 2008; 67:578.
173. Wilson RS, Li Y, Aggarwal NT, et al. Education and the course of cognitive decline in Alzheimer
disease. Neurology 2004; 63:1198.
174. Hall CB, Derby C, LeValley A, et al. Education delays accelerated decline on a memory test in
persons who develop dementia. Neurology 2007; 69:1657.
175. Singh-Manoux A, Marmot MG, Glymour M, et al. Does cognitive reserve shape cognitive
decline? Ann Neurol 2011; 70:296.
176. Sofi F, Valecchi D, Bacci D, et al. Physical activity and risk of cognitive decline: a meta-analysis
of prospective studies. J Intern Med 2011; 269:107.
177. Santangeli P, Di Biase L, Bai R, et al. Atrial fibrillation and the risk of incident dementia: a meta-
analysis. Heart Rhythm 2012; 9:1761.
178. Dublin S, Anderson ML, Haneuse SJ, et al. Atrial fibrillation and risk of dementia: a prospective
cohort study. J Am Geriatr Soc 2011; 59:1369.
179. Thacker EL, McKnight B, Psaty BM, et al. Atrial fibrillation and cognitive decline: a longitudinal
cohort study. Neurology 2013; 81:119.
180. Marzona I, O'Donnell M, Teo K, et al. Increased risk of cognitive and functional decline in
patients with atrial fibrillation: results of the ONTARGET and TRANSCEND studies. CMAJ 2012;
184:E329.
181. de Bruijn RF, Heeringa J, Wolters FJ, et al. Association Between Atrial Fibrillation and Dementia
in the General Population. JAMA Neurol 2015; 72:1288.

182. Kalantarian S, Stern TA, Mansour M, Ruskin JN. Cognitive impairment associated with atrial
fibrillation: a meta-analysis. Ann Intern Med 2013; 158:338.
183. Deckers K, Camerino I, van Boxtel MP, et al. Dementia risk in renal dysfunction: A systematic
review and meta-analysis of prospective studies. Neurology 2017; 88:198.
184. Green RC, Cupples LA, Kurz A, et al. Depression as a risk factor for Alzheimer disease: the
MIRAGE Study. Arch Neurol 2003; 60:753.
185. Ownby RL, Crocco E, Acevedo A, et al. Depression and risk for Alzheimer disease: systematic
review, meta-analysis, and metaregression analysis. Arch Gen Psychiatry 2006; 63:530.
186. Geerlings MI, den Heijer T, Koudstaal PJ, et al. History of depression, depressive symptoms,
and medial temporal lobe atrophy and the risk of Alzheimer disease. Neurology 2008; 70:1258.
187. Köhler S, van Boxtel MP, van Os J, et al. Depressive symptoms and cognitive decline in
community-dwelling older adults. J Am Geriatr Soc 2010; 58:873.
188. Saczynski JS, Beiser A, Seshadri S, et al. Depressive symptoms and risk of dementia: the
Framingham Heart Study. Neurology 2010; 75:35.
189. Dotson VM, Beydoun MA, Zonderman AB. Recurrent depressive symptoms and the incidence
of dementia and mild cognitive impairment. Neurology 2010; 75:27.
190. Diniz BS, Butters MA, Albert SM, et al. Late-life depression and risk of vascular dementia and
Alzheimer's disease: systematic review and meta-analysis of community-based cohort studies.
Br J Psychiatry 2013; 202:329.
191. Singh-Manoux A, Dugravot A, Fournier A, et al. Trajectories of Depressive Symptoms Before

Diagnosis of Dementia: A 28-Year Follow-up Study. JAMA Psychiatry 2017; 74:712.
192. Verghese J, Lipton RB, Hall CB, et al. Abnormality of gait as a predictor of non-Alzheimer's
dementia. N Engl J Med 2002; 347:1761.
193. Verghese J, Wang C, Lipton RB, Holtzer R. Motoric cognitive risk syndrome and the risk of
dementia. J Gerontol A Biol Sci Med Sci 2013; 68:412.
194. Mez J, Daneshvar DH, Kiernan PT, et al. Clinicopathological Evaluation of Chronic Traumatic
Encephalopathy in Players of American Football. JAMA 2017; 318:360.
195. Giza CC, Kutcher JS, Ashwal S, et al. 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. Neurology 2013; 80:2250.
196. Kaup AR, Yaffe K. Reassuring News About Football and Cognitive Decline?: Not So Fast. JAMA
Neurol 2017; 74:898.
197. Deshpande SK, Hasegawa RB, Rabinowitz AR, et al. Association of Playing High School
Football With Cognition and Mental Health Later in Life. JAMA Neurol 2017; 74:909.
198. Washington PM, Villapol S, Burns MP. Polypathology and dementia after brain trauma: Does
brain injury trigger distinct neurodegenerative diseases, or should they be classified together as
traumatic encephalopathy? Exp Neurol 2016; 275 Pt 3:381.
199. Institute of Medicine. Long-term consequences of traumatic brain injury, Volume 7. National Aca
demies Press; Gulf War and Health, Washington, DC, 2009.
200. Crane PK, Gibbons LE, Dams-O'Connor K, et al. Association of Traumatic Brain Injury With
Late-Life Neurodegenerative Conditions and Neuropathologic Findings. JAMA Neurol 2016;
73:1062.
201. Lin FR, Metter EJ, O'Brien RJ, et al. Hearing loss and incident dementia. Arch Neurol 2011;
68:214.
202. Lin FR, Yaffe K, Xia J, et al. Hearing loss and cognitive decline in older adults. JAMA Intern Med
2013; 173:293.
203. Fritze T, Teipel S, Óvári A, et al. Hearing Impairment Affects Dementia Incidence. An Analysis
Based on Longitudinal Health Claims Data in Germany. PLoS One 2016; 11:e0156876.
204. Gurgel RK, Ward PD, Schwartz S, et al. Relationship of hearing loss and dementia: a
prospective, population-based study. Otol Neurotol 2014; 35:775.
205. Amieva H, Ouvrard C, Giulioli C, et al. Self-Reported Hearing Loss, Hearing Aids, and Cognitive
Decline in Elderly Adults: A 25-Year Study. J Am Geriatr Soc 2015; 63:2099.
206. Golub JS, Luchsinger JA, Manly JJ, et al. Observed Hearing Loss and Incident Dementia in a
Multiethnic Cohort. J Am Geriatr Soc 2017; 65:1691.
207. Gates GA, Anderson ML, McCurry SM, et al. Central auditory dysfunction as a harbinger of
Alzheimer dementia. Arch Otolaryngol Head Neck Surg 2011; 137:390.
208. Gates GA, Gibbons LE, McCurry SM, et al. Executive dysfunction and presbycusis in older
persons with and without memory loss and dementia. Cogn Behav Neurol 2010; 23:218.

209. Gates GA, Anderson ML, Feeney MP, et al. Central auditory dysfunction in older persons with
memory impairment or Alzheimer dementia. Arch Otolaryngol Head Neck Surg 2008; 134:771.
210. 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; 346:476.
211. Kalmijn S, Launer LJ, Lindemans J, et al. Total homocysteine and cognitive decline in a
community-based sample of elderly subjects: the Rotterdam Study. Am J Epidemiol 1999;
150:283.
212. Wright CB, Lee HS, Paik MC, et al. Total homocysteine and cognition in a tri-ethnic cohort: the
Northern Manhattan Study. Neurology 2004; 63:254.
213. Garcia A, Zanibbi K. Homocysteine and cognitive function in elderly people. CMAJ 2004;
171:897.
214. Kado DM, Karlamangla AS, Huang MH, et al. 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. Am J Med 2005; 118:161.
215. Irizarry MC, Gurol ME, Raju S, et al. Association of homocysteine with plasma amyloid beta
protein in aging and neurodegenerative disease. Neurology 2005; 65:1402.
216. Nurk E, Refsum H, Tell GS, et al. Plasma total homocysteine and memory in the elderly: the
Hordaland Homocysteine Study. Ann Neurol 2005; 58:847.
217. Elkins JS, Johnston SC, Ziv E, et al. Methylenetetrahydrofolate reductase C677T polymorphism
and cognitive function in older women. Am J Epidemiol 2007; 166:672.
218. Hooshmand B, Solomon A, Kåreholt I, et al. Homocysteine and holotranscobalamin and the risk
of Alzheimer disease: a longitudinal study. Neurology 2010; 75:1408.
219. Ford AH, Flicker L, Alfonso H, et al. Plasma homocysteine and MTHFRC677T polymorphism as
risk factors for incident dementia. J Neurol Neurosurg Psychiatry 2012; 83:70.
220. Selhub J, Jacques PF, Bostom AG, et al. Relationship between plasma homocysteine, vitamin
status and extracranial carotid-artery stenosis in the Framingham Study population. J Nutr
1996; 126:1258S.
221. Hassan A, Hunt BJ, O'Sullivan M, et al. Homocysteine is a risk factor for cerebral small vessel
disease, acting via endothelial dysfunction. Brain 2004; 127:212.

222. Kim JM, Stewart R, Kim SW, et al. Changes in folate, vitamin B12 and homocysteine associated
with incident dementia. J Neurol Neurosurg Psychiatry 2008; 79:864.
223. Iwashyna TJ, Ely EW, Smith DM, Langa KM. Long-term cognitive impairment and functional
disability among survivors of severe sepsis. JAMA 2010; 304:1787.
224. Ehlenbach WJ, Hough CL, Crane PK, et al. Association between acute care and critical illness
hospitalization and cognitive function in older adults. JAMA 2010; 303:763.
225. Wilson RS, Hebert LE, Scherr PA, et al. Cognitive decline after hospitalization in a community
population of older persons. Neurology 2012; 78:950.
226. Song X, Mitnitski A, Rockwood K. Nontraditional risk factors combine to predict Alzheimer
disease and dementia. Neurology 2011; 77:227.
227. Montlahuc C, Soumaré A, Dufouil C, et al. Self-rated health and risk of incident dementia: a
community-based elderly cohort, the 3C study. Neurology 2011; 77:1457.
228. Tannenbaum C, Paquette A, Hilmer S, et al. A systematic review of amnestic and non-amnestic
mild cognitive impairment induced by anticholinergic, antihistamine, GABAergic and opioid
drugs. Drugs Aging 2012; 29:639.
229. Billioti de Gage S, Moride Y, Ducruet T, et al. Benzodiazepine use and risk of Alzheimer's
disease: case-control study. BMJ 2014; 349:g5205.
230. Gray SL, Anderson ML, Dublin S, et al. Cumulative use of strong anticholinergics and incident
dementia: a prospective cohort study. JAMA Intern Med 2015; 175:401.
231. Billioti de Gage S, Bégaud B, Bazin F, et al. Benzodiazepine use and risk of dementia:
prospective population based study. BMJ 2012; 345:e6231.
232. Imfeld P, Bodmer M, Jick SS, Meier CR. Benzodiazepine Use and Risk of Developing
Alzheimer's Disease or Vascular Dementia: A Case-Control Analysis. Drug Saf 2015; 38:909.
233. Gray SL, Dublin S, Yu O, et al. Benzodiazepine use and risk of incident dementia or cognitive
decline: prospective population based study. BMJ 2016; 352:i90.
234. Risacher SL, McDonald BC, Tallman EF, et al. Association Between Anticholinergic Medication
Use and Cognition, Brain Metabolism, and Brain Atrophy in Cognitively Normal Older Adults.
JAMA Neurol 2016; 73:721.

235. Yaffe K, Laffan AM, Harrison SL, et al. Sleep-disordered breathing, hypoxia, and risk of mild
cognitive impairment and dementia in older women. JAMA 2011; 306:613.
236. Spira AP, Blackwell T, Stone KL, et al. Sleep-disordered breathing and cognition in older
women. J Am Geriatr Soc 2008; 56:45.
237. Blackwell T, Yaffe K, Laffan A, et al. Associations between sleep-disordered breathing, nocturnal
hypoxemia, and subsequent cognitive decline in older community-dwelling men: the
Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2015; 63:453.
238. Ju Y, Lopez O, Redline S, Stein P. Obstructive sleep apnea increases risk of incident dementia
in community-dwelling older adults. Neurology 2013; 80:P03.098.
239. Osorio RS, Gumb T, Pirraglia E, et al. Sleep-disordered breathing advances cognitive decline in
the elderly. Neurology 2015; 84:1964.
240. Haba-Rubio J, Marti-Soler H, Tobback N, et al. Sleep characteristics and cognitive impairment
in the general population: The HypnoLaus study. Neurology 2017; 88:463.
241. Ramos AR, Tarraf W, Rundek T, et al. Obstructive sleep apnea and neurocognitive function in a
Hispanic/Latino population. Neurology 2015; 84:391.
242. Ramos AR, Gardener H, Rundek T, et al. Sleep disturbances and cognitive decline in the
Northern Manhattan Study. Neurology 2016; 87:1511.
243. Leng Y, McEvoy CT, Allen IE, Yaffe K. Association of Sleep-Disordered Breathing With
Cognitive Function and Risk of Cognitive Impairment: A Systematic Review and Meta-analysis.
JAMA Neurol 2017; 74:1237.
244. Yaffe K, Nettiksimmons J, Yesavage J, Byers A. Sleep Quality and Risk of Dementia Among
Older Male Veterans. Am J Geriatr Psychiatry 2015; 23:651.
245. Yun CH, Lee HY, Lee SK, et al. Amyloid Burden in Obstructive Sleep Apnea. J Alzheimers Dis
2017; 59:21.
246. Liguori C, Mercuri NB, Izzi F, et al. Obstructive Sleep Apnea is Associated With Early but
Possibly Modifiable Alzheimer's Disease Biomarkers Changes. Sleep 2017; 40.
247. Pase MP, Himali JJ, Grima NA, et al. Sleep architecture and the risk of incident dementia in the
community. Neurology 2017; 89:1244.

248. Killin LO, Starr JM, Shiue IJ, Russ TC. Environmental risk factors for dementia: a systematic
review. BMC Geriatr 2016; 16:175.
249. Campdelacreu J. Parkinson disease and Alzheimer disease: environmental risk factors.
Neurologia 2014; 29:541.
250. Power MC, Adar SD, Yanosky JD, Weuve J. Exposure to air pollution as a potential contributor
to cognitive function, cognitive decline, brain imaging, and dementia: A systematic review of
epidemiologic research. Neurotoxicology 2016; 56:235.
251. Peters R, Peters J, Booth A, Mudway I. Is air pollution associated with increased risk of
cognitive decline? A systematic review. Age Ageing 2015; 44:755.
252. Chen H, Kwong JC, Copes R, et al. Living near major roads and the incidence of dementia,
Parkinson's disease, and multiple sclerosis: a population-based cohort study. Lancet 2017;
389:718.
253. Fuller-Thomson E, Jopling SA. Exposure to lead in petrol and increased incidence of dementia.
Lancet 2017; 389:2371.
254. Laidlaw MAS, Poropat AE, Ball A, Mielke HW. Exposure to lead in petrol and increased
incidence of dementia. Lancet 2017; 389:2371.
255. Cacciottolo M, Wang X, Driscoll I, et al. Particulate air pollutants, APOE alleles and their
contributions to cognitive impairment in older women and to amyloidogenesis in experimental
models. Transl Psychiatry 2017; 7:e1022.
256. Balion C, Griffith LE, Strifler L, et al. Vitamin D, cognition, and dementia: a systematic review
and meta-analysis. Neurology 2012; 79:1397.
257. Buell JS, Dawson-Hughes B, Scott TM, et al. 25-Hydroxyvitamin D, dementia, and
cerebrovascular pathology in elders receiving home services. Neurology 2010; 74:18.
258. Annweiler C, Schott AM, Rolland Y, et al. Dietary intake of vitamin D and cognition in older
women: a large population-based study. Neurology 2010; 75:1810.
259. Annweiler C, Schott AM, Allali G, et al. Association of vitamin D deficiency with cognitive
impairment in older women: cross-sectional study. Neurology 2010; 74:27.
260. Mokry LE, Ross S, Morris JA, et al. Genetically decreased vitamin D and risk of Alzheimer

261. Slinin Y, Paudel ML, Taylor BC, et al. 25-Hydroxyvitamin D levels and cognitive performance
and decline in elderly men. Neurology 2010; 74:33.
262. Llewellyn DJ, Lang IA, Langa KM, et al. Vitamin D and risk of cognitive decline in elderly
persons. Arch Intern Med 2010; 170:1135.
263. Littlejohns TJ, Henley WE, Lang IA, et al. Vitamin D and the risk of dementia and Alzheimer
Topic 5079 Version 50.0
Contributor Disclosures
Eric B Larson, MD, MPH Nothing to disclose Steven T DeKosky, MD, FAAN, FACP,
FANA Consultant/Advisory Boards: Biogen [Alzheimer disease (Aducanumab)]; Cognition Therapeutics
[Alzheimer disease]; Amgen [Neuroscience]. Janet L Wilterdink, MD Nothing to disclose
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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Risk Factors For Cognitive Decline and Dementia

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Risk factors for cognitive decline and dementia

Dementia is a disorder that is characterized by impairment of cognition, typically involving memory

● Low educational attainment

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MILD COGNITIVE IMPAIRMENT

ISCHEMIC OR HEMORRHAGIC STROKE

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CARDIOMETABOLIC RISK FACTORS

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Hypercholesterolemia — Hypercholesterolemia may increase the risk of dementia [53-55], AD [56],

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Vascular disease — Clinically manifest cardiovascular disease as well as markers of atherosclerotic

● 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

Physical inactivity — In a systematic review of 15 prospective studies in more than 30,000

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In a systematic review and meta-analysis of prospective, population-based studies, albuminuria as a

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

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(See "Overview of homocysteine".)

It remains uncertain whether long-term use of medications such as benzodiazepines is associated

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INFORMATION FOR PATIENTS

SUMMARY AND RECOMMENDATIONS

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1. Livingston G, Sommerlad A, Orgeta V, et al. Dementia prevention, intervention, and care.

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10. Niu H, Álvarez-Álvarez I, Guillén-Grima F, Aguinaga-Ontoso I. Prevalence and incidence of

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label substudy. Lancet Neurol 2011; 10:969.

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191. Singh-Manoux A, Dugravot A, Fournier A, et al. Trajectories of Depressive Symptoms Before

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of the American Academy of Neurology. Neurology 2013; 80:2250.

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