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1.  Amyloid imaging and cognitive decline in non-demented oldest-old: The 90+ Study 
The goal of this study was to examine cross-sectional and longitudinal associations between cognitive performance and beta amyloid (Aβ) load determined by florbetapir F18 positron emission tomography (PET) in non-demented oldest-old.
Thirteen non-demented (normal or cognitively impaired non-demented) participants (median age=94.2 years) from The 90+ Study underwent florbetapir-PET scanning within 3 months of baseline neuropsychological testing. Amyloid load was measured with a semiautomated quantitative analysis of average cortical to cerebellar standard uptake values (SUVr) ratio and a visual interpretation (Aβ- or Aβ+). Neuropsychological testing was repeated every 6 months.
At baseline, SUVr correlated significantly with tests of global cognition and memory. During follow-up (median=1.5 years), the Aβ+ group had steeper declines on most cognitive tests, particularly global cognitive measures.
This preliminary study suggests that greater amyloid load is associated with poorer cognition and faster cognitive decline in non-demented oldest-old. Amyloid load may identify individuals at increased risk of developing Alzheimer's disease.
PMCID: PMC3604036  PMID: 23164550
2.  Medications and Diet Protective Factors for AD? 
Alzheimer Disease and Associated Disorders  2006;20(3 Suppl 2):S89-S96.
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.
PMCID: PMC3373253  PMID: 16917203
risk factor; medications; diet; Alzheimer disease
3.  Perforant path synaptic loss correlates with cognitive impairment and Alzheimer's disease in the oldest-old 
Brain  2014;137(9):2578-2587.
Cognitive impairment in the oldest-old remains poorly understood. In a study of post-mortem tissue, Robinson et al. find that individuals with cognitive impairment remain pathologically indistinguishable from cognitively intact controls. Tangles, perforant pathway synaptic loss and hippocampal sclerosis are the major pathologies underlying dementia in the oldest-old.
Alzheimer’s disease, which is defined pathologically by abundant amyloid plaques and neurofibrillary tangles concurrent with synaptic and neuronal loss, is the most common underlying cause of dementia in the elderly. Among the oldest-old, those aged 90 and older, other ageing-related brain pathologies are prevalent in addition to Alzheimer’s disease, including cerebrovascular disease and hippocampal sclerosis. Although definite Alzheimer’s disease pathology can distinguish dementia from normal individuals, the pathologies underlying cognitive impairment, especially in the oldest-old, remain poorly understood. We therefore conducted studies to determine the relative contributions of Alzheimer’s disease pathology, cerebrovascular disease, hippocampal sclerosis and the altered expression of three synaptic proteins to cognitive status and global cognitive function. Relative immunohistochemistry intensity measures were obtained for synaptophysin, Synaptic vesicle transporter Sv2 (now known as SV2A) and Vesicular glutamate transporter 1 in the outer molecular layer of the hippocampal dentate gyrus on the first 157 participants of ‘The 90+ Study’ who came to autopsy, including participants with dementia (n = 84), those with cognitive impairment but no dementia (n = 37) and those with normal cognition (n = 36). Thal phase, Braak stage, cerebrovascular disease, hippocampal sclerosis and Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) were also analysed. All measures were obtained blind to cognitive diagnosis. Global cognition was tested by the Mini-Mental State Examinaton. Logistic regression analysis explored the association between the pathological measures and the odds of being in the different cognitive groups whereas multiple regression analyses explored the association between pathological measures and global cognition scores. No measure clearly distinguished the control and cognitive impairment groups. Comparing the cognitive impairment and dementia groups, synaptophysin and SV2 were reduced, whereas Braak stage, TDP-43 and hippocampal sclerosis frequency increased. Thal phase and VGLUT1 did not distinguish the cognitive impairment and dementia groups. All measures distinguished the dementia and control groups and all markers associated with the cognitive test scores. When all markers were analysed simultaneously, a reduction in synaptophysin, a high Braak stage and the presence of TDP-43 and hippocampal sclerosis associated with global cognitive function. These findings suggest that tangle pathology, hippocampal sclerosis, TDP-43 and perforant pathway synaptic loss are the major contributors to dementia in the oldest-old. Although an increase in plaque pathology and glutamatergic synaptic loss may be early events associated with cognitive impairment, we conclude that those with cognitive impairment, but no dementia, are indistinguishable from cognitively normal subjects based on the measures reported here.
PMCID: PMC4132652  PMID: 25012223
Alzheimer’s disease; Braak stage; Thal phase; synaptic loss; oldest-old; cognitive impairment
4.  High Levels of Serum C-Reactive Protein (CRP) are Associated with Increased Risk of All-Cause Mortality, but not Dementia, in the Oldest-Old: Results from The 90+ Study 
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.
PMCID: PMC2913621  PMID: 19245412
c-reactive protein; dementia; mortality; nonagenarian; serum
5.  Poor Physical Performance and Dementia in the Oldest Old 
JAMA neurology  2013;70(1):107-113.
To examine the cross-sectional relationship between physical performance and dementia in the oldest old (those ≥90 years of age).
Cross-sectional study.
The 90+ Study is a population-based, longitudinal, epidemiologic study of aging and dementia performed at the University of California, Irvine, from January 1, 2003, through November 30, 2009.
A total of 629 participants from The 90+ Study were included in the study. The mean age was 94 years, and most (72.5%) were women.
Main Outcome Measures
All-cause dementia, based on Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition) criteria, was the main outcome measure. The independent variables were physical performance measures, including 4-m walk, 5 chair stands, standing balance, and grip strength, each scored from 0 to 4 (0, unable to perform; 4, best performance). Odds of dementia in relation to the physical performance measures were estimated by logistic regression after adjustment for age and sex.
Poor physical performance in all measures was significantly associated with increased odds of dementia (P < .001). Odds ratios for every unit decrease in physical performance score were 2.1 for 4-m walk, 2.1 for chair stands, 1.9 for standing balance, and 1.7 for grip strength.
We found a strong cross-sectional relationship between poor physical performance and dementia in people 90 years and older. Our findings suggest that dementia is a complex neurodegenerative process that may affect physical performance and cognition. Additional research is necessary to determine the temporal relationship between poor physical performance and cognitive dysfunction.
PMCID: PMC4454472  PMID: 23090391
6.  ABCC9 gene polymorphism is associated with hippocampal sclerosis of aging pathology 
Acta neuropathologica  2014;127(6):825-843.
Hippocampal sclerosis of aging (HS-Aging) is a high-morbidity brain disease in the elderly but risk factors are largely unknown. We report the first genome-wide association study (GWAS) with HS-Aging pathology as an endophenotype. In collaboration with the Alzheimer’s Disease Genetics Consortium, data were analyzed from large autopsy cohorts: (#1) National Alzheimer’s Coordinating Center (NACC); (#2) Rush University Religious Orders Study and Memory and Aging Project; (#3) Group Health Research Institute Adult Changes in Thought study; (#4) University of California at Irvine 90+ Study; and (#5) University of Kentucky Alzheimer’s Disease Center. Altogether, 363 HS-Aging cases and 2,303 controls, all pathologically confirmed, provided statistical power to test for risk alleles with large effect size. A two-tier study design included GWAS from cohorts #1–3 (Stage I) to identify promising SNP candidates, followed by focused evaluation of particular SNPs in cohorts #4–5 (Stage II). Polymorphism in the ATP-binding cassette, sub-family C member 9 (ABCC9) gene, also known as sulfonylurea receptor 2, was associated with HS-Aging pathology. In the meta-analyzed Stage I GWAS, ABCC9 polymorphisms yielded the lowest p values, and factoring in the Stage II results, the meta-analyzed risk SNP (rs704178:G) attained genome-wide statistical significance (p = 1.4 × 10−9), with odds ratio (OR) of 2.13 (recessive mode of inheritance). For SNPs previously linked to hippocampal sclerosis, meta-analyses of Stage I results show OR = 1.16 for rs5848 (GRN) and OR = 1.22 rs1990622 (TMEM106B), with the risk alleles as previously described. Sulfonylureas, a widely prescribed drug class used to treat diabetes, also modify human ABCC9 protein function. A subsample of patients from the NACC database (n = 624) were identified who were older than age 85 at death with known drug history. Controlling for important confounders such as diabetes itself, exposure to a sulfonylurea drug was associated with risk for HS-Aging pathology (p = 0.03). Thus, we describe a novel and targetable dementia risk factor.
PMCID: PMC4113197  PMID: 24770881
Oldest old; Neuropathology; KATP; CTAGE5; ADGC; Potassium channel
7.  Neocortical β-amyloid area is associated with dementia and APOE in the oldest-old 
Apolipoprotein E (APOE) ε2 carriers may be protected from dementia because of reduced levels of cortical β-amyloid. In the oldest-old, however, APOE ε2 carriers have high β-amyloid plaque scores and preserved cognition. We compared different measures of β-amyloid pathology across APOE genotypes in the oldest-old, and their relationship with dementia.
The study included 96 participants from The 90+ Study. Using all information, dementia diagnoses were made. Neuropathological examination included staging for amyloid plaques and β-amyloid cortical percent area stained by NAB228 antibody.
Both APOE ε2 and APOE ε4 carriers had high Consortium to Establish a Registry for Alzheimer's Disease plaque scores. However, APOE ε2 carriers had low cortical β-amyloid percent areas. β-amyloid percent area was associated with dementia across APOE genotypes.
Lower levels of percent area in APOE ε2 carriers may reflect lower total β-amyloid and may contribute to APOE ε2 carriers' decreased risk of dementia, despite high β-amyloid plaque scores. The relationship between β-amyloid plaques and dementia in the oldest-old may vary by APOE genotype.
PMCID: PMC3971646  PMID: 23474043
Alzheimer; Apolipoprotein E; Beta-amyloid; Dementia; Oldest-old
8.  APOE genotype, dementia and mortality in the oldest-old: The 90+ Study 
Although the ApolipoproteinE (APOE) ε4 allele is a major genetic risk factor for Alzheimer’s disease (AD), it is not clear if this relationship persists among the oldest-old. Several European studies suggest that the effect of the APOEε4 allele on dementia and mortality disappears in very old age. We describe the APOE allele and genotype frequencies and examine whether the presence of the APOEε4 or APOEε2 alleles are related to prevalent dementia, incident dementia, and mortality in a population-based cohort of oldest-old participants in the United States.
We studied 904 participants aged 90 and older from The 90+ Study. 802 (89%) participants were genotyped and included in the prevalent dementia and mortality analyses. The 520 initially non-demented participants were included in the incident dementia analyses and were evaluated for dementia every six months.
The APOEε4 allele was significantly associated with prevalent dementia (odds ratio [OR]=2.06) and AD (OR=2.37) in women, but not in men. The APOEε2 allele was not related to prevalent dementia in either sex. After an average followup of 2.4 years, 188 incident dementia cases were identified. Neither the APOEε4 nor the APOEε2 allele was related to incident dementia or AD. 510 (64%) participants died after an average followup of 2.3 years and their mortality was not related to the presence of either the APOEε2 or APOEε4 alleles.
Our findings suggest that the associations between APOEε4, dementia and mortality are age dependent and that APOEε4 no longer plays a role in dementia and mortality at very old ages.
PMCID: PMC3543489  PMID: 23123227
Apolipoprotein E; Dementia; Alzheimer’s disease; Mortality; Oldest-old
9.  Alzheimer disease pathology and longitudinal cognitive performance in the oldest-old with no dementia 
Neurology  2012;79(9):915-921.
It has been hypothesized that individuals without dementia with Alzheimer disease (AD) neuropathology may be in the preclinical stages of dementia and could be experiencing subtle cognitive decline. The purpose of this study was to compare longitudinal cognitive performance in oldest-old individuals without dementia with and without AD neuropathology.
The study included 58 individuals without dementia from The 90+ Autopsy Study, a population-based study of aging and dementia in individuals aged 90 and older. Participants had neurologic and neuropsychological testing every 6 months with an average of 3 years of follow-up. We compared the trajectory of cognitive performance on the Modified Mini-Mental State Examination (3MS) and the California Verbal Learning Test II (CVLT) by level of AD neuropathology. Based on Consortium to Establish a Registry for Alzheimer's Disease plaque staging, individuals were categorized as having low (none or sparse) or high (moderate or frequent) plaques. Based on Braak and Braak staging, participants were classified as having low (stages I–III) or high (IV–VI) tangles.
No significant differences were found in 3MS or CVLT cognitive performance over time based on plaque or tangle staging. Both high and low pathology groups showed modest improvements on the 3MS and CVLT consistent with learning effects.
AD neuropathology at autopsy is not associated with the trajectory of cognitive performance in the 3 years before death in oldest-old without dementia. Despite the presence of AD neuropathology at death, oldest-old without dementia display learning effects on cognitive tests. Further research is necessary to understand factors other than AD neuropathology that may affect cognition in the oldest-old.
PMCID: PMC3425842  PMID: 22895581
10.  Cognitive impairment in non-1 demented oldest-old: Prevalence and relationship to cardiovascular risk factors 
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.
PMCID: PMC3276712  PMID: 22055654
mild cognitive impairment; oldest-old; cardiovascular risk factors
11.  Disability in the Oldest-old: Incidence and Risk Factors in The 90+ Study 
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.
PMCID: PMC3266513  PMID: 22273736
12.  Neocortical and hippocampal amyloid-β and tau measures associate with dementia in the oldest-old 
Brain  2011;134(12):3705-3712.
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.
PMCID: PMC3235569  PMID: 22120149
Alzheimer's; tau; amyloid; dementia; oldest-old
13.  Incidence of dementia in oldest-old with amnestic MCI and other cognitive impairments 
Neurology  2011;77(21):1906-1912.
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.
PMCID: PMC3233189  PMID: 22076544
14.  Diagnosing Dementia in the Oldest-Old 
Maturitas  2011;70(2):164-168.
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.
PMCID: PMC3171568  PMID: 21831546
Dementia; Oldest-Old; Diagnosis; Alzheimer’s Disease
15.  A Population-Based Clinicopathological Study in the Oldest-Old: The 90+ Study 
Current Alzheimer research  2012;9(6):709-717.
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.
PMCID: PMC3409303  PMID: 22471863
Dementia; Alzheimer’s disease; cohort study; longitudinal studies; neuropathology; oldest-old
16.  Dementia Incidence Continues to Increase with Age in the Oldest Old The 90+ Study 
Annals of Neurology  2010;67(1):114-121.
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.
PMCID: PMC3385995  PMID: 20186856
17.  Type of alcohol consumed, changes in intake over time and mortality: the Leisure World Cohort Study 
Age and Ageing  2007;36(2):203-209.
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.
PMCID: PMC3377489  PMID: 17350977
alcohol; beer; wine; spirits; mortality; elderly
18.  Reduced risk of Alzheimer’s disease with high folate intake: The Baltimore Longitudinal Study of Aging 
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.
PMCID: PMC3375831  PMID: 19595811
Alzheimer’s disease; Antioxidants; B vitamins; Dementia; Folate; Prospective studies; Longitudinal studies
19.  Alzheimer’s and Dementia in the Oldest-Old: A Century of Challenges 
Current Alzheimer Research  2006;3(5):411-419.
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.
PMCID: PMC3373256  PMID: 17168640
Aging; Alzheimer’s disease; dementia; longevity; nonagenarians; oldest-old
20.  The oldest old and the 90+ Study 
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.
PMCID: PMC3373258  PMID: 18632002
Oldest old; Dementia; Alzheimer's disease
21.  Diet and the Risk for Alzheimer’s Disease 
Annals of Neurology  2006;59(6):877-879.
PMCID: PMC3373259  PMID: 16718710
22.  Association of Body Mass Index and Weight Change with All-Cause Mortality in the Elderly 
American Journal of Epidemiology  2006;163(10):938-949.
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.
PMCID: PMC3373260  PMID: 16641311
aged; body mass index; body weight changes; longevity; mortality; risk factors
23.  Sensitivity and Specificity of the Mini-Mental State Examination for Identifying Dementia in the Oldest-Old: The 90+ Study 
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.
PMCID: PMC3373261  PMID: 17302668
dementia; MMSE; oldest-old; sensitivity; specificity
24.  Increased longevity in older users of postmenopausal estrogen therapy: the Leisure World Cohort Study 
Menopause (New York, N.y.)  2006;13(1):12-18.
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.
PMCID: PMC3373269  PMID: 16607094
Mortality; Longevity; Estrogen therapy; Risk factors
25.  Activities and Mortality in the Elderly: The Leisure World Cohort Study 
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.
PMCID: PMC3074957  PMID: 21350247
Mortality; Physical activity; Elderly; Exercise; Longitudinal

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