Genotypic Effects of the TOMM40'523 Variant and APOE on Longitudinal Cognitive Change over 4 Years: The TOMMORROW Study.

BACKGROUND: The 523 poly-T length polymorphism (rs10524523) in TOMM40 has been reported to influence longitudinal cognitive test performance within APOE ε3/3 carriers. The results from prior studies are inconsistent. It is also unclear whether specific APOE and TOMM40 genotypes contribute to heterogeneity in longitudinal cognitive performance during the preclinical stages of AD. OBJECTIVES: To determine the effects of these genes on longitudinal cognitive change in early preclinical stages of AD, we used the clinical trial data from the recently concluded TOMMORROW study to examine the effects of APOE and TOMM40 genotypes on neuropsychological test performance. DESIGN: A phase 3, double-blind, placebo-controlled, randomized clinical trial. SETTING: Academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. PARTICIPANTS: Cognitively normal older adults aged 65 to 83. INTERVENTION: Pioglitazone tablet. MEASUREMENTS: Participants from the TOMMORROW trial were stratified based on APOE genotype (APOE ε3/3, APOE ε3/4, APOE ε4/4). APOE ε3/3 carriers were further stratified by TOMM40'523 genotype. The final analysis dataset consists of 1,330 APOE ε3/3 carriers and 7,001 visits. Linear mixed models were used to compare the rates of decline in cognition across APOE groups and the APOE ε3/3 carriers with different TOMM40'523 genotypes. RESULTS: APOE ε3/4 and APOE ε4/4 genotypes compared with the APOE ε3/3 genotype were associated with worse performance on measures of global cognition, episodic memory, and expressive language. Further, over the four years of observation, the APOE ε3/3 carriers with the TOMM40'523-S/S genotype showed better global cognition and accelerated rates of cognitive decline on tests of global cognition, executive function, and attentional processing compared to APOE ε3/3 carriers with TOMM40'523-S/VL and VL/VL genotypes and compared to the APOE ε3/4 and APOE ε4/4 carriers. CONCLUSIONS: We suggest that both APOE and TOMM40 genotypes may independently contribute to cognitive heterogeneity in the pre-MCI stages of AD. Controlling for this genetic variability will be important in clinical trials designed to slow the rate of cognitive decline and/or prevent symptom onset in preclinical AD.

Adjudicating Mild Cognitive Impairment Due to Alzheimer's Disease as a Novel Endpoint Event in the TOMMORROW Prevention Clinical Trial.

BACKGROUND: The onset of mild cognitive impairment (MCI) is an essential outcome in Alzheimer's disease (AD) prevention trials and a compelling milestone for clinically meaningful change. Determining MCI, however, may be variable and subject to disagreement. Adjudication procedures may improve the reliability of these determinations. We report the performance of an adjudication committee for an AD prevention trial. METHODS: The TOMMORROW prevention trial selected cognitively normal participants at increased genetic risk for AD and randomized them to low-dose pioglitazone or placebo treatment. When adjudication criteria were triggered, a participant's clinical information was randomly assigned to a three-member panel of a six-member independent adjudication committee. Determination of whether or not a participant reached MCI due to AD or AD dementia proceeded through up to three review stages - independent review, collaborative review, and full committee review - requiring a unanimous decision and ratification by the chair. RESULTS: Of 3494 participants randomized, the committee adjudicated on 648 cases from 386 participants, resulting in 96 primary endpoint events. Most participants had cases that were adjudicated once (n = 235, 60.9%); the rest had cases that were adjudicated multiple times. Cases were evenly distributed among the eight possible three-member panels. Most adjudicated cases (485/648, 74.8%) were decided within the independent review (stage 1); 14.0% required broader collaborative review (stage 2), and 11.1% needed full committee discussion (stage 3). The primary endpoint event decision rate was 39/485 (8.0%) for stage 1, 29/91 (31.9%) for stage 2, and 28/72 (38.9%) for stage 3. Agreement between the primary event outcomes supported by investigators' clinical diagnoses and the decisions of the adjudication committee increased from 50% to approximately 93% (after around 100 cases) before settling at 80-90% for the remainder of the study. CONCLUSIONS: The adjudication process was designed to provide independent, consistent determinations of the trial endpoints. These outcomes demonstrated the extent of uncertainty among trial investigators and agreement between adjudicators when the transition to MCI due to AD was prospectively assessed. These methods may inform clinical endpoint determination in future AD secondary prevention studies. Reliable, accurate assessment of clinical events is critical for prevention trials and may mean the difference between success and failure.

Clinical Ratings of White Matter Hyperintensities, Hippocampal Ratings, and Neuropsychological Functioning from The Cache County Memory Study.

Objective: White matter burden and medial temporal atrophy are associated with cognitive health. A large epidemiological database, such as the Cache County Memory Study (CCMS), can provide additional insight into how visual clinical ratings of brain structural integrity predict cognition in older adults. Method: We used the Scheltens Ratings Scale to quantify white matter lesion burden and medial temporal atrophy in the CCMS sample to determine if these qualitative markers are predictive of memory function. We performed clinical ratings of MRI scans across two ascertainment periods among 187 community-dwelling older adults and correlated these ratings with MMSE, CERAD memory performance, and general cognitive ability. Results: Higher Scheltens ratings measuring white matter and basal ganglia hyperintensities were associated with lower memory performance (r = 0.21). The strongest correlations were observed between medial temporal atrophy and general cognition performance (r = 0.32). Conclusions: The current findings support previous research that the integrity of different regions of the brain correlate to function in a meaningful way.

Combination Therapy for Alzheimer's Disease: Perspectives of the EU/US CTAD Task Force.

Combination therapy is expected to play an important role for the treatment of Alzheimer's disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches.

MRI Clinical Ratings and Cognitive Function in a Cross-Sectional Population Study of Dementia: The Cache County Memory Study.

BACKGROUND: White matter integrity in aging populations is associated with increased risk of cognitive decline, dementia diagnosis, and mortality. Population-based data can elucidate this association. OBJECTIVES: To examine the association between white matter integrity, as measured by a clinical rating scale of hyperintensities, and mental status in older adults including advanced aging. DESIGN: Scheltens Ratings Scale was used to qualitatively assess white matter (WM) hyperintensities in participants of the Cache County Memory Study (CCMS), an epidemiological study of Alzheimer's disease in an exceptionally long-lived population. Further, the relation between Mini-Mental State Exam (MMSE) and WM hyperintensities were explored. METHOD: Participants consisted of 415 individuals with dementia and 22 healthy controls. RESULTS: CCMS participants, including healthy controls, had high levels of WM pathology as measured by Scheltens Ratings Scale score. While age did not significantly relate to WM pathology, higher Scheltens Ratings Scale scores were associated with lower MMSE findings (correlation between -0.14 and -0.22; p < .05). CONCLUSIONS: WM pathology was common in this county-wide population sample of those ranging in age from 65 to 106. Increased WM burden was found to be significantly associated with decreased overall MMSE performance.

Neuropsychiatric symptoms as risk factors for progression from CIND to dementia: the Cache County Study.

OBJECTIVES: To examine the association of neuropsychiatric symptom (NPS) severity with risk of transition to all-cause dementia, Alzheimer disease (AD), and vascular dementia (VaD). DESIGN: Survival analysis of time to dementia, AD, or VaD onset. SETTING: Population-based study. PARTICIPANTS: 230 participants diagnosed with cognitive impairment, no dementia (CIND) from the Cache County Study of Memory Health and Aging were followed for a mean of 3.3 years. MEASUREMENTS: The Neuropsychiatric Inventory (NPI) was used to quantify the presence, frequency, and severity of NPS. Chi-squared statistics, t-tests, and Cox proportional hazard ratios were used to assess associations. RESULTS: The conversion rate from CIND to all-cause dementia was 12% per year, with risk factors including an APOE ε4 allele, lower Mini-Mental State Examination, lower 3MS, and higher CDR sum-of-boxes. The presence of at least one NPS was a risk factor for all-cause dementia, as was the presence of NPS with mild severity. Nighttime behaviors were a risk factor for all-cause dementia and of AD, whereas hallucinations were a risk factor for VaD. CONCLUSIONS: These data confirm that NPS are risk factors for conversion from CIND to dementia. Of special interest is that even NPS of mild severity are a risk for all-cause dementia or AD.

Using genetics to enable studies on the prevention of Alzheimer's disease.

Curing Alzheimer's disease (AD) remains an elusive goal; indeed, it may even prove to be impossible, given the nature of the disease. Although modulating disease progression is an attractive target and will alleviate the burden of the most severe stages, this strategy will not reduce the prevalence of the disease itself. Preventing or (as described in this article) delaying the onset of cognitive impairment and AD will provide the greatest benefit to individuals and society by pushing the onset of disease into the later years of life. Because of the high variability in the age of onset of the disease, AD prevention studies that do not stratify participants by age-dependent disease risk will be operationally challenging, being large in size and of long duration. We present a composite genetic biomarker to stratify disease risk so as to facilitate clinical studies in high-risk populations. In addition, we discuss the rationale for the use of pioglitazone to delay the onset of AD in individuals at high risk.

The association of psychotropic medication use with the cognitive, functional, and neuropsychiatric trajectory of Alzheimer's disease.

OBJECTIVE: The use of psychotropic medications in Alzheimer's disease (AD) has been associated with both deleterious and potentially beneficial outcomes. We examined the longitudinal association of psychotropic medication use with cognitive, functional, and neuropsychiatric symptom (NPS) trajectories among community-ascertained incident AD cases from the Cache County Dementia Progression Study. METHODS: A total of 230 participants were followed for a mean of 3.7 years. Persistency index (PI) was calculated for all antidepressants, selective serotonin reuptake inhibitors (SSRIs), antipsychotics (atypical and typical), and benzodiazepines as the proportion of observed time of medication exposure. Mixed-effects models were used to examine the association between PI for each medication class and Mini-Mental State Exam (MMSE), Clinical Dementia Rating Sum of Boxes (CDR-Sum), and Neuropsychiatric Inventory - Total (NPI-Total) trajectories, controlling for appropriate demographic and clinical covariates. RESULTS: At baseline, psychotropic medication use was associated with greater severity of dementia and poorer medical status. Higher PI for all medication classes was associated with a more rapid decline in MMSE. For antidepressant, SSRI, benzodiazepine, and typical antipsychotic use, a higher PI was associated with a more rapid increase in CDR-Sum. For SSRIs, antipsychotics, and typical antipsychotics, a higher PI was associated with more rapid increase in NPI-Total. CONCLUSIONS: Psychotropic medication use was associated with more rapid cognitive and functional decline in AD, and not with improved NPS. Clinicians may tend to prescribe psychotropic medications to AD patients at risk of poorer outcomes, but one cannot rule out the possibility of poorer outcomes being caused by psychotropic medications.

Intracranial volume and dementia: some evidence in support of the cerebral reserve hypothesis.

The brain reserve hypothesis has been posited as being one important mediating factor for developing dementia, especially Alzheimer's disease (AD). Evidence for this hypothesis is mixed though different methodologies have made these findings difficult to interpret. We examined imaging data from a large cohort (N=194) of mixed dementia patients and controls, 65years old and older from the Cache County, Utah Study of Memory and Aging for evidence of the brain reserve hypothesis using total intracranial volume (TICV) as a quantitative measure of pre-morbid brain size and a vicarious indicator of reserve. A broader spectrum of non-demented elderly control subjects from previous studies was also included for comparison (N=423). In addition, non-parametric Classification and Regression Tree (CART) analyses were performed to model group heterogeneity and identify any subgroups of patients where TICV might be an important predictor of dementia. Parametrically, no main effect was found for TICV when predicting a dementia diagnosis; however, the CART analysis did reveal important TICV subgroups, including a sex differential wherein ε4 APOE allele presence in males and low TICV predicted AD classification. TICV, APOE, and other potential mediator/moderator variables are discussed in the context of the brain reserve hypothesis.

Occupational exposure to pesticides increases the risk of incident AD: the Cache County study.

BACKGROUND: Commonly used organophosphate and organochlorine pesticides inhibit acetylcholinesterase at synapses in the somatic, autonomic, and central nervous systems and may therefore have lasting effects on the nervous system. Few studies have examined the relationship of pesticide exposure and risk of dementia or Alzheimer disease (AD). We sought to examine the association of occupational pesticide exposure and the risk of incident dementia and AD in later life. METHODS: Residents of the agricultural community of Cache County, UT, who were aged 65 years and older as of January 1995, were invited to participate in the study. At baseline, participants completed detailed occupational history questionnaires that included information about exposures to various types of pesticides. Cognitive status was assessed at baseline and after 3, 7, and 10 years. Standardized methods were used for detection and diagnosis of dementia and AD. Cox proportional hazards survival analyses were used to evaluate the risk of incident dementia and AD associated with pesticide exposure. RESULTS: Among 3,084 enrollees without dementia, more men than women reported pesticide exposure (p < 0.0001). Exposed individuals (n = 572) had more years of education (p < 0.01) but did not differ from others in age. Some 500 individuals developed incident dementia, 344 with AD. After adjustment for baseline age, sex, education, APOE epsilon4 status, and baseline Modified Mini-Mental State Examination scores, Cox proportional hazards models showed increased risks among pesticide-exposed individuals for all-cause dementia, with hazard ratio (HR) 1.38 and 95% confidence interval (CI) 1.09-1.76, and for AD (HR 1.42, 95% CI 1.06-1.91). The risk of AD associated with organophosphate exposure (HR 1.53, 95% CI 1.05-2.23) was slightly higher than the risk associated with organochlorines (HR 1.49, 95% CI 0.99-2.24), which was nearly significant. CONCLUSIONS: Pesticide exposure may increase the risk of dementia and Alzheimer disease in late life.

A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease.

The ɛ4 allele of the apolipoprotein E (APOE) gene is currently the strongest and most highly replicated genetic factor for risk and age of onset of late-onset Alzheimer's disease (LOAD). Using phylogenetic analysis, we have identified a polymorphic poly-T variant, rs10524523, in the translocase of outer mitochondrial membrane 40 homolog (TOMM40) gene that provides greatly increased precision in the estimation of age of LOAD onset for APOE ɛ3 carriers. In two independent clinical cohorts, longer lengths of rs10524523 are associated with a higher risk for LOAD. For APOE ɛ3/4 patients who developed LOAD after 60 years of age, individuals with long poly-T repeats linked to APOE ɛ3 develop LOAD on an average of 7 years earlier than individuals with shorter poly-T repeats linked to APOE ɛ3 (70.5 ± 1.2 years versus 77.6 ± 2.1 years, P=0.02, n=34). Independent mutation events at rs10524523 that occurred during Caucasian evolution have given rise to multiple categories of poly-T length variants at this locus. On replication, these results will have clinical utility for predictive risk estimates for LOAD and for enabling clinical disease prevention studies. In addition, these results show the effective use of a phylogenetic approach for analysis of haplotypes of polymorphisms, including structural polymorphisms, which contribute to complex diseases.

The COMT Val158Met polymorphism and cognition in depressed and nondepressed older adults.

OBJECTIVE: The objective of the current study was to examine the relationship between the COMT Val(158)Met polymorphism and neuropsychological performance in depressed and nondepressed older adults. METHODS: One hundred and twenty-six clinically depressed older adults and 105 nondepressed comparison participants were compared on neuropsychological performance and COMT Val(158)Met (Val/Val, Val/Met, Met/Met). RESULTS: Based on multivariate regression models, the COMT Val(158)Met polymorphism was not associated with cognitive performance among depressed or nondepressed individuals, nor did this polymorphism account for the fact that depressed individuals performed worse than nondepressed individuals on several neuropsychological tests that are typically affected by depression. There was also no difference in frequency of the COMT Val(158)Met alleles between depressed and nondepressed individuals. CONCLUSIONS: Although the current study found no association between COMT Val(158)Met polymorphism on a number of clinical neuropsychological tests that are typically found to be sensitive to depression, differential effects of the COMT Val(158)Met polymorphism on dopamine transmission in psychiatric and non-psychiatric populations may be further clarified by clinical research with neuroscience-based paradigms that segregate cognitive tasks into component processes with precise neural substrates, particularly with respect to the complex functions of the prefrontal cortex. Negative results can be important to narrowing down target processes and understanding the influence of clinical and demographic characteristics in studies of psychiatric genetics.

Neuropsychological correlates of magnetic resonance imaging-defined subcortical ischemic depression.

OBJECTIVE: The goal of the current study was to examine the neuropsychological profile of magnetic resonance imaging (MRI)-defined subcortical ischemic depression (SID). METHODS: Clinically depressed older adults with MRI-defined SID (n = 70) and depressed elders without SID (n = 75) were compared on neuropsychological performance, depression symptoms, and medical burden. RESULTS: Group comparisons revealed that the SID was associated with worse performance on all neuropsychological measures, but also with greater age, higher cardiac illness burden, and greater deficits in the depression symptoms of self-initiation and concentration. In multivariate regression models, auditory working memory and nonverbal memory remained worse among the SID group after controlling for contributions of age, cardiovascular risk, and depression symptoms. CONCLUSIONS: Although auditory working memory span and nonverbal memory appear to be specifically associated with the ischemic pathology that defines SID, the typical individual with SID is also likely to have a broader profile of neuropsychological deficits than those without SID because they are typically older and have specific depression symptoms that predispose them to compromised neurocognitive performance.

Effects of cardiovascular medications on rate of functional decline in Alzheimer disease.

BACKGROUND: Evidence suggests that cardiovascular medications, including statins and antihypertensive medications, may delay cognitive decline in patients with Alzheimer dementia (AD). We examined the association of cardiovascular medication use and rate of functional decline in a population-based cohort of individuals with incident AD. METHODS: In the Dementia Progression Study of the Cache County Study on Memory, Health, and Aging, 216 individuals with incident AD were identified and followed longitudinally with in-home visits for a mean of 3.0 years and 2.1 follow-up visits. The Clinical Dementia Rating (CDR) was completed at each follow-up. Medication use was inventoried during in-home visits. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) as the outcome and cardiovascular medication use as the major predictors. RESULTS: CDR-Sum increased an average of 1.69 points annually, indicating a steady decline in functioning. After adjustment for demographic variables and the baseline presence of cardiovascular conditions, use of statins (p = 0.03) and beta-blockers (p = 0.04) was associated with a slower annual rate of increase in CDR-Sum (slower rate of functional decline) of 0.75 and 0.68 points respectively, while diuretic use was associated with a faster rate of increase in CDR-Sum (p = 0.01; 0.96 points annually). Use of calcium-channel blockers, angiotensin-converting enzyme inhibitors, digoxin, or nitrates did not affect the rate of functional decline. CONCLUSIONS: In this population-based study of individuals with incident AD, use of statins and beta-blockers was associated with delay of functional decline. Further studies are needed to confirm these results and to determine whether treatment with these medications may help delay AD progression.

No advantage of A beta 42-lowering NSAIDs for prevention of Alzheimer dementia in six pooled cohort studies.

INTRODUCTION: Observational studies show reduced incidence of Alzheimer dementia (AD) in users of nonsteroidal anti-inflammatory drugs (NSAIDs). One hypothesis holds that the subset of NSAIDs known as selective A beta(42)-lowering agents (SALAs) is responsible for this apparent reduction in AD risk. METHODS: We pooled individual-level data from six prospective studies to obtain a sufficient sample to examine AD risk in users of SALA vs non-SALA NSAIDs. RESULTS: Of 13,499 initially dementia-free participants (70,863 person-years), 820 developed incident AD. Users of NSAIDs (29.6%) showed reduced risk of AD (adjusted hazard ratio [aHR] 0.77, 95% CI 0.65-0.91). The point estimates were similar for SALAs (aHR 0.87, CI 0.72-1.04) and non-SALAs (aHR 0.75, CI 0.56-1.01). Because 573 NSAID users (14.5%) reported taking both a SALA and non-SALA, we examined their use alone and in combination. Resulting aHRs were 0.82 (CI 0.67-0.99) for SALA only, 0.60 (CI 0.40-0.90) for non-SALA only, and 0.87 (CI 0.57-1.33) for both NSAIDs (Wald test for differences, p = 0.32). The 40.7% of participants who used aspirin also showed reduced risk of AD, even when they used no other NSAIDs (aHR 0.78, CI 0.66-0.92). By contrast, there was no association with use of acetaminophen (aHR 0.93, CI 0.76-1.13). CONCLUSIONS: In this pooled dataset, nonsteroidal anti-inflammatory drug (NSAID) use reduced the risk of Alzheimer dementia (AD). However, there was no apparent advantage in AD risk reduction for the subset of NSAIDs shown to selectively lower A beta(42), suggesting that all conventional NSAIDs including aspirin have a similar protective effect in humans.

Longitudinal follow-up of late-onset Alzheimer disease families.

Historically, data for genetic studies are collected at one time point. However, for diseases with late onset or with complex phenotypes, such as Alzheimer disease (AD), restricting diagnosis to a single ascertainment contact may not be sufficient. Affection status may change over time and some initial diagnoses may be inconclusive. Follow-up provides the opportunity to resolve these complications. However, to date, previous studies have not formally demonstrated that longitudinally re-contacting families is practical or productive. To update data initially collected for linkage analysis of late-onset Alzheimer disease (LOAD), we successfully re-contacted 63 of 81 (78%) multiplex families (two to 17 years after ascertainment). Clinical status changed for 73 of the 230 (32%) non-affected participants. Additionally, expanded family history identified 20 additional affected individuals to supplement the data set. Furthermore, fostering ongoing relationships with participating families helped recruit 101 affected participants into an autopsy and tissue donation program. Despite similar presentations, discordance between clinical diagnosis and neuropathologic diagnosis was observed in 28% of those with tissue diagnoses. Most of the families were successfully re-contacted, and significant refinement and supplementation of the data was achieved. We concluded that serial contact with longitudinal evaluation of families has significant implications for genetic analyses.

Vascular factors predict rate of progression in Alzheimer disease.

BACKGROUND: While there is considerable epidemiologic evidence that cardiovascular risk factors increase risk of incident Alzheimer disease (AD), few studies have examined their effect on progression after an established AD diagnosis. OBJECTIVE: To examine the effect of vascular factors, and potential age modification, on rate of progression in a longitudinal study of incident dementia. METHODS: A total of 135 individuals with incident AD, identified in a population-based sample of elderly persons in Cache County, UT, were followed with in-home visits for a mean of 3.0 years (range: 0.8 to 9.5) and 2.1 follow-up visits (range: 1 to 5). The Clinical Dementia Rating (CDR) Scale and Mini-Mental State Examination (MMSE) were administered at each visit. Baseline vascular factors were determined by interview and physical examination. Generalized least-squares random-effects regression was performed with CDR Sum of Boxes (CDR-Sum) or MMSE as the outcome, and vascular index or individual vascular factors as independent variables. RESULTS: Atrial fibrillation, systolic hypertension, and angina were associated with more rapid decline on both the CDR-Sum and MMSE, while history of coronary artery bypass graft surgery, diabetes, and antihypertensive medications were associated with a slower rate of decline. There was an age interaction such that systolic hypertension, angina, and myocardial infarction were associated with greater decline with increasing baseline age. CONCLUSION: Atrial fibrillation, hypertension, and angina were associated with a greater rate of decline and may represent modifiable risk factors for secondary prevention in Alzheimer disease. The attenuated decline for diabetes and coronary artery bypass graft surgery may be due to selective survival. Some of these effects appear to vary with age.

Does NSAID use modify cognitive trajectories in the elderly? The Cache County study.

BACKGROUND: Epidemiologic studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be useful for the prevention of Alzheimer disease (AD). By contrast, clinical trials have not supported NSAID use to delay or treat AD. Few studies have evaluated cognitive trajectories of NSAID users over time. METHODS: Residents of Cache County, UT, aged 65 or older on January 1, 1995, were invited to participate in the study. At baseline, participants provided a detailed inventory of their medications and completed a revised Modified Mini-Mental State Examination (3MS). Participants (n = 3,383) who were cognitively normal at baseline were re-examined after 3 and 8 years. The association between NSAID use and 3MS scores over time was estimated using random effects modeling. RESULTS: Associations depended upon when NSAIDs were started and APOE genotype. In participants who started NSAID use prior to age 65, those with no APOE epsilon4 alleles performed similarly to nonusers (a difference of 0.10 points per year; p = 0.19), while those with one or more epsilon4 allele(s) showed more protection (0.40 points per year; p = 0.0005). Among participants who first used NSAIDs at or after age 65, those with one or more epsilon4 alleles had higher baseline scores (0.95 points; p = 0.03) but did not show subsequent difference in change in score over time (0.06 points per year; p = 0.56). Those without an epsilon4 allele who started NSAID use after age 65 showed greater decline than nonusers (-0.16 points per year; p = 0.02). CONCLUSIONS: Nonsteroidal anti-inflammatory drug use may help to prevent cognitive decline in older adults if started in midlife rather than late life. This effect may be more notable in those who have one or more APOE epsilon4 alleles.

Antioxidant intake and cognitive function of elderly men and women: the Cache County Study.

OBJECTIVE: We prospectively examined associations between intakes of antioxidants (vitamins C, vitamin E, and carotene) and cognitive function and decline among elderly men and women of the Cache County Study on Memory and Aging in Utah. PARTICIPANTS AND DESIGN: In 1995, 3831 residents 65 years of age or older completed a baseline survey that included a food frequency questionnaire and cognitive assessment. Cognitive function was assessed using an adapted version of the Modified Mini-Mental State examination (3MS) at baseline and at three subsequent follow-up interviews spanning approximately 7 years. Multivariable-mixed models were used to estimate antioxidant nutrient effects on average 3MS score over time. RESULTS: Increasing quartiles of vitamin C intake alone and combined with vitamin E were associated with higher baseline average 3MS scores (p-trend = 0.013 and 0.02 respectively); this association appeared stronger for food sources compared to supplement or food and supplement sources combined. Study participants with lower levels of intake of vitamin C, vitamin E and carotene had a greater acceleration of the rate of 3MS decline over time compared to those with higher levels of intake. CONCLUSION: High antioxidant intake from food and supplement sources of vitamin C, vitamin E, and carotene may delay cognitive decline in the elderly.

Conversion to dementia from mild cognitive disorder: the Cache County Study.

OBJECTIVE: To examine 3-year rates of conversion to dementia, and risk factors for such conversion, in a population-based sample with diverse types of cognitive impairment. METHODS: All elderly (aged 65 or older) residents of Cache County, UT, were invited to undergo two waves of dementia screening and assessment. Three-year follow-up data were available for 120 participants who had some form of mild cognitive impairment at baseline. Of these, 51 had been classified at baseline with prodromal Alzheimer disease (proAD), and 69 with other cognitive syndromes (CS). RESULTS: Three-year rates of conversion to dementia were 46% among those with cognitive impairment at baseline. By comparison, 3.3% without impairment converted to dementia in the interval. Among converters, AD was the most common type of dementia. In individuals with at least one APOE epsilon4 allele, those with proAD or CS exhibited a 22- to 25-fold higher risk of dementia than cognitively unimpaired individuals (vs 5- to 10-fold higher risk in those without epsilon4). CONCLUSIONS: Individuals with all types of mild cognitive impairment have an elevated risk of dementia over 3 years, more so in those with an APOE epsilon4 allele. These results suggest value in dementia surveillance for broad groups of cognitively impaired individuals beyond any specific category, and utility of APOE genotyping as a prognostic method.