In the past decade, studies of Alzheimer disease risk and medication exposures, supplement intake, and dietary factors have grown in number. Typically identified in case-control and cross-sectional studies, many of these exposures have also been replicated in prospective studies. These observational studies have provided the foundation for the development of several prevention trials. This brief review focuses on exposures that have been identified in multiple studies. Observational studies of medications suggesting protection for Alzheimer disease include estrogen hormonal therapy, nonsteroidal anti-inflammatory drugs, and cholesterol-lowering statins. Evidence regarding dietary and supplemental intake of vitamins E, C, and folate, and studies of alcohol and wine intake are also reviewed. At present, there is insufficient evidence to make public health recommendations, but these studies can provide potentially important clues and new avenues for clinical and laboratory research.
risk factor; medications; diet; Alzheimer disease
To determine the prevalence and types of cognitive impairment in a sample of non-demented aged 90 and older (the oldest-old) and to examine the relationships between cognitive impairment and cardiovascular risk factors.
420 non-demented participants from The 90+ Study, a study of aging and dementia in the oldest-old. Participants were categorized into four non-overlapping groups: normal cognition, amnestic mild cognitive impairment (aMCI), non-amnestic MCI (naMCI), and other cognitive impairment (OCI). History of cardiovascular risk factors was assessed through self-report.
The overall prevalence of cognitive impairment in non-demented was 34.0% (95%CI: 29.5–38.5). The prevalence of OCI was highest (17.4%; 95%CI: 13.9–21.4) followed by aMCI (8.3%; 95%CI: 5.9–11.4) and naMCI (8.3%; 95%CI: 5.9–11.4). Normal cognition was present in 66.0% (95%CI: 61.2–70.5) of participants. History of hypertension and stroke were the only risk factors that varied between the groups, occurring more frequently in participants with naMCI (χ2=3.82; p<0.05) and OCI (χ2=5.51; p<0.05).
This study found a high prevalence of cognitive impairment in a sample of non-demented oldest-old. We did not find a strong relationship between cardiovascular risk factors and the cognitive impairment groups other than between hypertension and naMCI and stroke and OCI. Future studies comparing the incidence of dementia in these groups will ultimately determine their predictive utility in the oldest-old.
mild cognitive impairment; oldest-old; cardiovascular risk factors
To measure the incidence of disability in individuals aged 90 and older and examine factors that may increase risk of disability.
Design and Setting
The 90+ Study, a longitudinal study of aging initiated in January 2003 with follow-up through May 2009.
216 non-disabled, prospectively followed participants who were aged 90 or older at baseline.
The incidence of disability, measured as needing help on one or more Activities of Daily Living, and calculated using person-years. Risk factors were examined using a Cox proportional hazards analysis.
The overall incidence of disability was 16.4%per year (95% confidence interval, 13.3–20.0), and did not differ by gender. Disability incidence increased with age from 8.3%in the 90–94 age group to 25.7%in the 95 and older age group. Several factors were associated with increased risk of disability including history of congestive heart failure, history of depression poor self-rated quality of life and cognitive impairment.
Disability incidence is high and increases rapidly with age in the oldest-old, with rates essentially tripling between ages 90–94 and 95+. Some factors associated with increased risk of disability in younger elderly continue to be risk factors in the oldest-old. Because of the tremendous social and financial impact of disability and the rapid growth of the oldest-old, the development of strategies to delay disability in the elderly should be a priority for health care research.
The emergence of longevity in the modern world has brought a sense of urgency to understanding age-related neurodegenerative diseases such as Alzheimer's disease. Unfortunately, there is a lack of consensus regarding the correlation between the pathological substrates of neurodegeneration and dementia status, particularly in the oldest-old. To better understand the pathological correlates of dementia in the oldest-old, we characterized the topographical spread and severity of amyloid-β, tau, TDP-43 and α-synuclein pathologies in the 90+ Study, a prospective longitudinal population-based study of ageing and dementia. Neuropathological analysis with immunohistochemically labelled sections was carried out blind to clinical diagnosis on the first 108 participants of the 90+ Study who came to autopsy including participants with dementia (n = 66) and without dementia (n = 42). We used quantitative and/or semi-quantitative measures to assess the burden of amyloid-β, tau, TDP-43 and α-synuclein pathologies as well as hippocampal sclerosis. Amyloid-β and tau were the predominant pathologies in the 90+ Study cohort and both amyloid-β area and tau area occupied measures were strongly associated with the presence of dementia, as was Braak staging but semi-quantitative plaque scores were not. Notably, TDP-43 pathology also correlated with dementia, while α-synuclein distribution did not. In addition, hippocampal sclerosis was specific to participants with dementia and correlated with the presence of limbic TDP-43. In contrast to previous reports, we found that tau and amyloid-β continue to be robust pathological correlates of dementia, even in the oldest-old. While individuals with no dementia had limited hippocampal tau and neocortical amyloid-β pathology, dementia associated with an expansion in pathology, including increased neocortical tau and hippocampal amyloid-β plaques, more abundant neocortical amyloid-β deposition and hippocampal sclerosis with its attendant TDP-43 pathology.
Alzheimer's; tau; amyloid; dementia; oldest-old
To examine the incidence of dementia among the oldest-old people with normal cognition and different types of cognitive impairment.
This study included 395 participants without dementia (mean age 93.3 years) from The 90+ Study, a prospective, population-based study of aging and dementia in people aged 90 years and older. The participants had evaluations for dementia every 6 months, and their average follow-up was 2.5 years. We examined the incidence of all-cause dementia in participants stratified into 4 cognitive groups: normal, amnestic mild cognitive impairment (aMCI), nonamnestic mild cognitive impairment (naMCI), and other cognitive impairment (OCI).
Dementia incidence was highest for participants with aMCI (31.4% per year) and OCI (39.9% per year). Participants with naMCI had an incidence of 14.1% per year, and participants with normal cognition had an incidence of 8.4% per year. Dementia incidence was associated with increasing age in both normal and cognitively impaired participants; however, an APOE4 allele was associated with a higher dementia incidence only in participants with baseline cognitive impairment.
The risk of developing dementia in the oldest-old is high and increases to higher rates when cognitive impairment is present. Similar to results of studies in younger elderly individuals, cognitive impairment and increasing age were related to increased dementia incidence. High dementia incidence rates in the oldest-old individuals, particularly when cognitively impaired, emphasize the need to further study cognitive impairment and dementia in this rapidly expanding age group.
The “oldest-old” comprise the fastest growing segment of the population in much of the world. Rates of dementia are extremely high in this age group and will present a major public health burden as the numbers of these individuals quadruple by the middle of the century. Studies in this age group are rare and frequently have small numbers of participants. In research studies and the clinic, the diagnosis of dementia and determination of the etiology of the disorder are challenging. In this review, we include some of our experiences in a population-based longitudinal investigation, The 90+ Study. Oldest-old individuals are more likely to suffer from medical comorbidities and have high rates of sensory loss, psychoactive medication usage, frailty and fatigue. Moreover, social and cultural expectations affect the reporting and interpretation of behavioral changes. These and other factors make it difficult to determine the relative contributions of cognitive losses and non-cognitive losses in the development of functional disability. Contributing further to the complexities of diagnosis, current research suggests that dementia in the oldest-old, compared to younger people, is more likely to be related to mixed disease pathologies. Frequent cerebral neuropathologies include Alzheimer’s disease neurodegeneration, small and large vessel vascular disease, and hippocampal sclerosis. More research is necessary in the oldest-old to better understand the etiologies of dementia in this age group, and factors that may affect the expression of disease as we age.
Dementia; Oldest-Old; Diagnosis; Alzheimer’s Disease
Population-based longitudinal clinicopathological studies provide an ideal opportunity to study a variety of risk and protective factors in relation to pathology associated with dementia in individuals who are representative of the general population. The 90+ Study is a population-based study designed specifically to study aging and dementia as well as its neuropathological correlates in participants 90 years of age and older. We present demographic and pathological data on the first 104 participants to come to autopsy from the brain donation component of the study, The 90+ Autopsy Study. Cognitive diagnosis was assigned according to Diagnostic and Statistical Manual 4th edition criteria for dementia and neuropathological diagnoses were made according to the Consortium to Establish a Registry for Alzheimer’s Disease protocol. Dementia was present in 61% of autopsied participants, the majority of whom were diagnosed with Alzheimer’s disease (85%). Many different types of pathology typically associated with dementia were common in the oldest-old, and included neurofibrillary tangles, neuritic plaques, diffuse plaques, Lewy bodies, hippocampal sclerosis, and cerebral infarctions. Most types of pathology were more frequently found in participants suffering from dementia but there was extensive overlap in pathology among those with and without dementia. In addition, 22% of demented participants did not have sufficient pathology to account for their cognitive loss. Our results highlight the poor associations between these common pathological lesions and dementia in the oldest-old and the importance of considering many different types of pathology, possibly including some yet to be identified, in order to account for all dementias in the oldest-old.
Dementia; Alzheimer’s disease; cohort study; longitudinal studies; neuropathology; oldest-old
The oldest old are the fastest growing segment of the US population, and accurate estimates of dementia incidence in this group are crucial for healthcare planning. Although dementia incidence doubles every 5 years from ages 65 to 90 years, it is unknown if this exponential increase continues past age 90 years. Here, we estimate age- and sex-specific incidence rates of all-cause dementia in people aged 90 years and older, including estimates for centenarians.
Participants are from The 90+ Study, a population-based longitudinal study of aging and dementia. Three hundred thirty nondemented participants aged 90 years and older at baseline were followed between January 2003 and December 2007. Age- and sex-specific incidence rates of all-cause dementia were estimated by person-years analysis.
The overall incidence rate of all-cause dementia was 18.2% (95% confidence interval [CI], 15.3-21.5) per year and was similar for men and women (risk ratio, 0.94; 95% CI, 0.65–1.37). Rates increased exponentially with age from 12.7% per year in the 90–94-year age group, to 21.2% per year in the 95–99-year age group, to 40.7% per year in the 100+-year age group. The doubling time based on a Poisson regression was 5.5 years.
Incidence of all-cause dementia is very high in people aged 90 years and older and continues to increase exponentially with age in both men and women. Projections of the number of people with dementia should incorporate this continuing increase of dementia incidence after age 90 years. Our results foretell the growing public health burden of dementia in an increasingly aging population.
modifiable behavioural risk factors including smoking and alcohol consumption are major contributing or actual causes of mortality.
to examine the effect of alcohol intake on all-cause mortality in older adults.
Design and Setting
prospective population-based cohort study of residents of a California, United States retirement community.
8,877 women and 5,101 men (median age, 74 years) who in the early 1980s completed a postal health survey including details on alcohol consumption.
participants were followed for 23 years (1981–2004) including two follow-up questionnaires (in 1992 and 1998) asking about current alcohol intake. Age-adjusted and multivariate-adjusted risk ratios of death and 95% confidence intervals were calculated separately for men and women, using proportional hazard regression.
of the 8,644 women and 4,980 men with complete information on the variables of interest and potential confounders, 6,930 women and 4,456 men had died (median age, 87 years). Both men and women who drank alcohol had decreased mortality compared with non-drinkers. Those who drank two or more drinks per day had a 15% reduced risk of death. The reduced risk was not limited to one type of alcohol. Stable drinkers (those who reported drinking both at baseline and follow-up) had a significantly decreased risk of death compared with stable non-drinkers. Those who started drinking at follow-up also had a significantly lower risk. Women who quit drinking were at increased risk of death.
in elderly men and women, moderate alcohol intake exhibits a beneficial effect on mortality. Those who quit may do so for health reasons that affect mortality.
alcohol; beer; wine; spirits; mortality; elderly
Study findings have suggested an association between Alzheimer’s disease (AD) risk and several vitamins and have speculated about their use as preventive agents. Here, we examine whether total intake (intake from diet plus supplements) of antioxidant vitamins (E, C, carotenoids) and B vitamins (folate, B6, and B12) is associated with a reduced risk of AD.
Participants were 579 nondemented elderly volunteers from the Baltimore Longitudinal Study of Aging who completed dietary diaries and recorded supplement intake for a 7-day period. Cox regression was used to estimate the relative risk (RR) of AD associated with total vitamin intake categorized into levels above or below the Recommended Dietary Allowance (RDA).
After a mean follow-up of 9.3 years, AD developed in 57 participants. Higher intake of folate (RR, 0.41; 95% confidence interval [CI], 0.22 to 0.76), vitamin E (RR, 0.56; 95% CI, 0.30 to 1.06), and vitamin B6 (RR, 0.41; 95% CI, 0.20 to 0.84) were associated individually with a decreased risk of AD after adjusting for age, gender, education, and caloric intake. When these 3 vitamins were analyzed together, only total intake of folate at or above the RDA (RR, 0.45; 95% CI, 0.21 to 0.97) was associated with a significant decreased risk of AD. No association was found between total intake of vitamins C, carotenoids, or vitamin B12 and risk of AD.
These findings suggest that total intake of folate at or above the RDA is associated with a reduced risk of AD. Additional studies are necessary to further investigate whether folate or other(s) unmeasured factor(s) may be responsible for this reduction in risk.
Alzheimer’s disease; Antioxidants; B vitamins; Dementia; Folate; Prospective studies; Longitudinal studies
Alzheimer’s disease (AD) is the most common type of dementia in the US and much of the world with rates increasing exponentially from age 65. Increases in life expectancy in the last century have resulted in a large number of people living to old ages and will result in a quadrupling of AD cases by the middle of the century. Preventing or delaying the onset of AD could have a huge impact in the number of cases expected to develop. The oldest-old are the fastest growing segment of the population and are estimated to account for 12% of the population over 65. Establishing accurate estimates of dementia and AD rates in this group is crucial for public health planning. Prevalence and incidence estimates above age 85 are imprecise and inconsistent because of the lack of very old individuals in most studies. Moreover, risk and protective factors in our oldest citizens have been studied little, and clinical-pathological correlations appear to be poor. We introduce The 90+ Study, established to address some of the unanswered questions about AD and dementia in the oldest-old. Our preliminary results show that close to half of demented oldest-old do not have known cerebral pathology to account for their cognitive deficits. Furthermore, the APOE-e4 allele appears to be a risk factor for AD only in the women in our study. In addition to the challenge of preventing and treating AD, the oldest-old will require major investigative energy to better understand the concomitants of longevity, the causes of dementia, and the factors that promote successful aging in oldest citizens.
Aging; Alzheimer’s disease; dementia; longevity; nonagenarians; oldest-old
Memories are the gifts from friends and family that stay with us forever, unless a person develops Alzheimer's disease. Leon J. Thal left many, many memories, along with his desire to create a world where people did not lose them to the ravages of dementing illnesses. Working from the bench to the clinic, he was an incomparable leader, scientist, and educator to whom many, including myself, owe much. The present description of a clinical, genetic, and pathologic study of the oldest old contains much of Leon's influence. With data from >950 subjects, a brain repository, and our collection of DNA, the investigators of the 90+ Study are receptive to collaborations. Through our collective efforts, we will continue the scientific work that Leon so strongly supported.
Oldest old; Dementia; Alzheimer's disease
The authors explored the relation of body mass index (BMI; weight (kg)/height (m)2) and weight change to all-cause mortality in the elderly, using data from a large, population-based California cohort study, the Leisure World Cohort Study. They estimated relative risks of mortality associated with self-reported BMI at study entry, BMI at age 21 years, and weight change between age 21 and study entry. Participants were categorized as underweight (BMI <18.5), normal weight (BMI 18.5–24.9), overweight (BMI 25–29.9), or obese (BMI ≥30). Of 13,451 participants aged 73 years (on average) at study entry (1981–1985), 11,203 died during 23 years of follow-up (1981–2004). Relative to normal weight, being underweight (relative risk (RR) = 1.51, 95% confidence interval (CI): 1.38, 1.65) or obese (RR = 1.25, 95% CI: 1.13, 1.38) at study entry was associated with increased mortality. People who were either overweight or obese at age 21 also had increased mortality (RR = 1.17, 95% CI: 1.09, 1.25). Participants who lost weight between age 21 and study entry had increased mortality regardless of their BMI category at age 21. Obesity was significantly associated with increased mortality only among persons under age 75 years and among never or past smokers. This study highlights the influence on older-age mortality risk of being overweight or obese in young adulthood and underweight or obese in later life.
aged; body mass index; body weight changes; longevity; mortality; risk factors
To evaluate the sensitivity and specificity of the Mini-Mental State Examination (MMSE) in identifying dementia in the oldest-old when stratified by age and education.
Research clinic and in-home visits.
Population-based sample of adults aged 90 and older (n = 435) who are enrolled in the 90+ Study, a longitudinal, population-based study.
Neurological examination to determine dementia diagnosis, MMSE, and demographic data.
Receiver operating characteristic (ROC) analyses indicated that the MMSE had high diagnostic accuracy for identifying dementia in subjects aged 90 and older across different age and education groups (area under the ROC curve values ranged from 0.82 to 0.98). A range of possible cutoff values and corresponding sensitivity and specificity are provided for the following age groups: 90–93, 94–96, and ≥97. Age groups were subdivided by educational attainment (≤high school, vocational school or some college, college degree or higher). In subjects aged 90 to 93 with a college degree or higher, the suggested MMSE cutoff score is ≥25 (sensitivity = 0.82, specificity = 0.80). In those aged 94 to 96 with a college degree or higher, the suggested cutoff is ≤24 (sensitivity = 0.85, specificity = 0.80). Those aged 97 and older with an education of high school or less had the lowest suggested cutoff ≤22 (sensitivity = 0.80, specificity = 0.76).
Overall, the MMSE had good sensitivity and specificity across all age and educational groups. Optimal cutoff points were lower in the older age groups and those with less education, primarily to preserve specificity. This screening instrument is appropriate for use with the oldest-old.
dementia; MMSE; oldest-old; sensitivity; specificity
To examine the effect of postmenopausal estrogen therapy (ET), including duration and recency of use, on all-cause mortality in older women.
As part of a prospective cohort study of residents of a California retirement community begun in the early 1980s, Leisure World Cohort women (median age, 73 y) completed a postal health survey including details on ETuse and were followed up for 22 years (1981–2003). Age- and multivariate-adjusted risk ratios (RR) and 95% CIs were calculated using proportional hazard regression.
Of the 8,801 women, 6,626 died during follow-up (median age, 88 y). ET users had an age-adjusted mortality rate of 52.9 per 1,000 person-years compared with 56.5 among lifetime nonusers (RR = 0.91; 95% CI, 0.87–0.96). Risk of death decreased with both increasing duration of ET and decreasing years since last use (P for trend <0.001). The risk was lowest among long-term (≥15 y) users (RR = 0.83; 95% CI, 0.74–0.93 for 15–19 y and RR = 0.87; 95% CI, 0.80–0.94 for 20+ y). For long-term users, the age-adjusted mortality rate was 50.4 per 1,000 person-years. Lower-dose users (≤0.625 mg) had a slightly better survival rate than higher-dose users (RR = 0.84; 95% CI, 0.78–0.91 vs RR = 0.91; 95% CI, 0.83–0.97). Risk did not differ by route of administration (P = 0.56). Further adjustment for potential confounders had little effect on the observed RRs for ET.
Long-term ET is associated with lower all-cause mortality in older women.
Mortality; Longevity; Estrogen therapy; Risk factors
Although physical activity has substantial health benefits and reduces mortality, few studies have examined its impact on survival beyond age 75.
Using the population-based Leisure World Cohort Study, we explored the association of activity on all-cause mortality in older adults (median age at baseline = 74 years). We followed 8,371 women and 4,828 men for 28 years or until death (median = 13 years) and calculated relative risks for various measures of activity at baseline using Cox regression analysis for four age groups (<70, 70–74, 75–79, and 80+ years) in men and women separately.
Time spent in active activities, even ½ hour/day, resulted in significantly lower (15–35%) mortality risks compared with no time in active activities. This reduction was evident in all sex–age groups except the youngest men. Participants who reported spending 6 or more hours/day in other less physically demanding activities also had significantly reduced risks of death of 15–30%. The beneficial effect of activities was observed in both those who did and those who did not cut down their activities due to illness or injury. Neither adjustment for potential confounders, exclusion of the first 5 years of follow-up, nor exclusion of individuals with histories of chronic disease substantially changed the findings.
Participation in leisure-time activities is an important health promoter in aging populations. The association of less physically demanding activities as well as traditional physical activities involving moderate exertion with reduced mortality suggests that the protective effect of engagement in activities is a robust one.
Mortality; Physical activity; Elderly; Exercise; Longitudinal
The National Institute on Aging and the Alzheimer’s Association charged a workgroup with the task of revising the 1984 criteria for Alzheimer’s disease (AD) dementia. The workgroup sought to ensure that the revised criteria would be flexible enough to be used by both general healthcare providers without access to neuropsychological testing, advanced imaging, and cerebrospinal fluid measures, and specialized investigators involved in research or in clinical trial studies who would have these tools available. We present criteria for all-cause dementia and for AD dementia. We retained the general framework of probable AD dementia from the 1984 criteria. On the basis of the past 27 years of experience, we made several changes in the clinical criteria for the diagnosis. We also retained the term possible AD dementia, but redefined it in a manner more focused than before. Bio-marker evidence was also integrated into the diagnostic formulations for probable and possible AD dementia for use in research settings. The core clinical criteria for AD dementia will continue to be the cornerstone of the diagnosis in clinical practice, but biomarker evidence is expected to enhance the pathophysiological specificity of the diagnosis of AD dementia. Much work lies ahead for validating the biomarker diagnosis of AD dementia.
Alzheimer’s disease; Dementia; Diagnosis; Magnetic resonance brain imaging; Position emission tomography; Cerebrospinal fluid
This article focuses on the effects of operational differences in case ascertainment on estimates of prevalence and incidence of cognitive impairment/dementia of the Alzheimer type. Experience and insights are discussed by investigators from the Framingham Heart Study, the East Boston Senior Health Project, the Chicago Health and Aging Project, the Mayo Clinic Study of Aging, the Baltimore Longitudinal Study of Aging, and the Aging, Demographics, and Memory Study. There is a general consensus that the single most important factor regulating prevalence estimates of Alzheimer’s disease (AD) is the severity of cognitive impairment used for case ascertainment. Studies that require a level of cognitive impairment in which persons are unable to provide self-care will have much lower estimates than studies aimed at identifying persons in the earliest stages of AD. There is limited autopsy data from the above-mentioned epidemiologic studies to address accuracy in the diagnosis of etiologic subtype, namely the specification of AD alone or in combination with other types of pathology. However, other community-based cohort studies show that many persons with mild cognitive impairment (MCI) meet pathologic criteria for AD, and a large minority of persons without dementia or MCI also meets pathologic criteria for AD, thereby suggesting that the number of persons who would benefit from an effective secondary prevention intervention is probably higher than the highest published prevalence estimates. Improved accuracy in the clinical diagnosis of AD is anticipated with the addition of molecular and structural biomarkers in the next generation of epidemiologic studies.
Alzheimer’s disease; Dementia; Mild cognitive impairment; Cognitive impairment not dementia; Diagnostic criteria; Population-based; Prevalence, Incidence
Dementia with Lewy Bodies (DLB) is a common neurodegenerative disorder of the aging population characterized by α–synuclein accumulation in cortical and subcortical regions. Although neuropathology in advanced age has been investigated in dementias such as Alzheimer Disease (AD), severity of the neuropathology in the oldest old with DLB remains uncharacterized. For this purpose we compared characteristics of DLB cases divided into three age groups 70–79, 80–89 and ≥90 years (oldest old). Neuropathological indicators and levels of synaptophysin were assessed and correlated with clinical measurements of cognition and dementia severity. These studies showed that frequency and severity of DLB was lower in 80–89 and ≥90 year cases compared to 70–79 year old group but cognitive impairment did not vary with age. The extent of AD neuropathology correlated with dementia severity only in the 70–79 year group, while synaptophysin immunoreactivity more strongly associated with dementia severity in the older age group in both DLB and AD. Taken together these results suggest that the oldest old with DLB might represent a distinct group.
Cognition; Neuropsychological assessment
People aged 90 and older (oldest-old), the fastest growing segment of the United States population, are known to have high rates of spells of all types, including strokes, transient ischemic attacks, and seizures. This study examined the prevalence of EEG abnormalities in 12 physically and cognitively healthy oldest-old (mean age=94) with no history of seizures or spells. Abnormalities were found in 83% of participants: temporal intermittent polymorphic slowing was seen in 67%, background slowing (alpha rhythm <8 Hz) was present in 33%, and temporal intermittent rhythmic delta was found in 17%. The high rates of EEG abnormalities found in these physically and cognitively healthy participants prompt reappraisal of pathological significance in this unique population.
Electroencephalography (EEG); aging; oldest-old; temporal intermittent rhythmic delta activity (TIRDA)
To evaluate whether high levels of C-reactive protein (CRP) in serum are associated with increased risk of all-cause dementia or mortality in the oldest-old.
Research clinic and in-home visits.
Population-based sample of adults (n = 227; age, 93.9 ± 2.8 years) from The 90+ Study, a longitudinal cohort study of people aged 90 and older.
CRP levels were divided into three groups according to the assay detection limit: Undetectable (< 0.5 mg/dL), detectable (0.5-0.7 mg/dL) and elevated (≥ 0.8 mg/dL). Neurological examination was used to determine dementia diagnosis (DSM-IV criteria). Adjusted hazards ratios (HR) and 95% confidence intervals (CI) were computed using Cox regression and results were stratified by gender and apolipoprotein E4 (APOE4) genotype.
Subjects with detectable CRP levels had significantly increased risk of mortality (HR 1.7, 95% CI 1.0-2.9), but not dementia (HR 1.2, 95% CI 0.6-2.1), 0.4-4.5 years later relative to subjects with undetectable CRP. The highest relative risk for both dementia and mortality was in APOE4 carriers with detectable CRP (dementia HR: 4.5, 95% CI 0.9-23.3; mortality HR: 5.6, 95% CI 1.0-30.7).
High levels of CRP are associated with increased risk of mortality in those aged 90 and older, particularly in APOE4 carriers. There was a trend towards an increased risk of dementia in APOE4 carriers with high CRP levels, although this relationship did not reach significance. High levels of CRP in the oldest-old represent a risk factor for negative outcomes.
c-reactive protein; dementia; mortality; nonagenarian; serum
C-reactive protein (CRP) is a nonspecific marker of inflammation that is increased in the brain and serum of patients with Alzheimer’s disease (AD) and has been associated with increased risk of developing dementia. Inflammation increases with age and the number of people reaching the age of 90 and older is growing, making the association between inflammation and dementia increasingly relevant. Using a cross-sectional design, we examined if high levels of serum CRP are associated with increased odds of prevalent dementia in the oldest-old.
Serum CRP levels of 305 participants (mean age 94.3 ± 2.9 years) from The 90+ Study, a longitudinal cohort study of people 90 and older, were evaluated with respect to all-cause dementia (DSM-IV criteria). CRP levels were divided into three categories: undetectable (< 0.5 mg/dL), detectable (0.5 – 0.7 mg/dL) and elevated (≥0.8 mg/dL). Odds ratios (OR) were calculated using logistic regression and adjusted for covariates.
Relative to participants with undetectable CRP levels, participants with detectable or elevated CRP levels had increased odds of all-cause dementia (detectable: OR 3.0, 95% CI 1.2 – 7.3; elevated: OR 5.0, 95% CI 1.9 – 12.9). When participants were subdivided by gender, significantly increased odds ratios were seen only in women.
In the oldest-old, high CRP levels are associated with increased odds of all-cause dementia, particularly in women. Prospective studies are necessary to confirm if increased CRP levels are associated with increased risk of developing dementia in this age group.
C-reactive protein; dementia; nonagenarian; serum; inflammation
Many studies have examined the role of Apolipoprotein E (APOE) genotype in the development of dementia, specifically Alzheimer’s disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathological AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathological criteria for AD.
The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using NINCDS-ADRDA criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurological examination and medical records. Neuropathological examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathological AD using NIA-Reagan criteria.
Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathological criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE 3/3), APOE4 carriers were more likely to be diagnosed with dementia (OR=12.2,95%CI=1.5–102.0), whereas APOE2 carriers were not (OR=0.3,95%CI=0.1–1.3). Surprisingly, both APOE4 (OR=4.6,95%CI=1.3–16.5) and APOE2 (OR=7.8,95%CI=1.5–40.2) carriers were more likely to meet neuropathological criteria for AD than those with APOE3/3 genotype.
In the oldest-old, the presence of APOE2 was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased AD neuropathology. Therefore, oldest-old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.
Background: Many studies have examined the role of APOE genotype in the development of dementia, specifically Alzheimer disease (AD). The APOE ε4 allele (APOE4) is a risk factor for both clinical and neuropathologic AD whereas the APOE ε2 allele (APOE2) seems to be protective. This would predict, even with advanced age, that APOE2 carriers would be less likely to have dementia and less likely to meet pathologic criteria for AD.
Methods: The first 85 genotyped participants from The 90+ Study to come to autopsy were included. All-cause dementia (using DSM-IV criteria) and AD (using National Institute of Neurological and Communicative Disorders and Stroke–Alzheimer's Disease and Related Disorders Association criteria) diagnoses were made by consensus conference using all available information including neuropsychological testing, neurologic examination, and medical records. Neuropathologic examination included Braak and Braak staging for plaques and tangles and diagnosis of neuropathologic AD using National Institute on Aging–Reagan criteria.
Results: Across all genotypes, 58.5% of subjects were diagnosed with clinical dementia (81% of dementia was AD) and 50.0% met neuropathologic criteria for AD. Compared to those with an APOE ε3/ε3 genotype (APOE3/3), APOE4 carriers were more likely to be diagnosed with dementia (odds ratio [OR] = 12.2, 95% confidence interval [CI] = 1.5–102.0), whereas APOE2 carriers were not (OR = 0.3, 95% CI = 0.1–1.3). Surprisingly, both APOE4 (OR = 4.6, 95% CI = 1.3–16.5) and APOE2 (OR = 7.8, 95% CI = 1.5–40.2) carriers were more likely to meet neuropathologic criteria for AD than those with APOE3/3 genotype.
Conclusions: In the oldest old, the presence of the APOE ε2 allele (APOE2) was associated with a somewhat reduced risk of dementia, but paradoxically was associated with increased Alzheimer disease (AD) neuropathology. Therefore, oldest old APOE2 carriers may have some mechanism that contributes to the maintenance of cognition independently of the formation of AD pathology.