Deborah E. Barnes

The projected effect of risk factor reduction on Alzheimer's disease prevalence

At present, about 33·9 million people worldwide have Alzheimers disease (AD), and prevalence is expected to triple over the next 40 years. The aim of this Review was to summarise the evidence regarding seven potentially modifiable risk factors for AD: diabetes, midlife hypertension, midlife obesity, smoking, depression, cognitive inactivity or low educational attainment, and physical inactivity. Additionally, we projected the effect of risk factor reduction on AD prevalence by calculating population attributable risks (the percent of cases attributable to a given factor) and the number of AD cases that might be prevented by risk factor reductions of 10% and 25% worldwide and in the USA. Together, up to half of AD cases worldwide (17·2 million) and in the USA (2·9 million) are potentially attributable to these factors. A 10-25% reduction in all seven risk factors could potentially prevent as many as 1·1-3·0 million AD cases worldwide and 184,000-492,000 cases in the USA.

Potential for primary prevention of Alzheimer's disease: an analysis of population-based data

BACKGROUND Recent estimates suggesting that over half of Alzheimers disease burden worldwide might be attributed to potentially modifiable risk factors do not take into account risk-factor non-independence. We aimed to provide specific estimates of preventive potential by accounting for the association between risk factors. METHODS Using relative risks from existing meta-analyses, we estimated the population-attributable risk (PAR) of Alzheimers disease worldwide and in the USA, Europe, and the UK for seven potentially modifiable risk factors that have consistent evidence of an association with the disease (diabetes, midlife hypertension, midlife obesity, physical inactivity, depression, smoking, and low educational attainment). The combined PAR associated with the risk factors was calculated using data from the Health Survey for England 2006 to estimate and adjust for the association between risk factors. The potential of risk factor reduction was assessed by examining the combined effect of relative reductions of 10% and 20% per decade for each of the seven risk factors on projections for Alzheimers disease cases to 2050. FINDINGS Worldwide, the highest estimated PAR was for low educational attainment (19·1%, 95% CI 12·3-25·6). The highest estimated PAR was for physical inactivity in the USA (21·0%, 95% CI 5·8-36·6), Europe (20·3%, 5·6-35·6), and the UK (21·8%, 6·1-37·7). Assuming independence, the combined worldwide PAR for the seven risk factors was 49·4% (95% CI 25·7-68·4), which equates to 16·8 million attributable cases (95% CI 8·7-23·2 million) of 33·9 million cases. However, after adjustment for the association between the risk factors, the estimate reduced to 28·2% (95% CI 14·2-41·5), which equates to 9·6 million attributable cases (95% CI 4·8-14·1 million) of 33·9 million cases. Combined PAR estimates were about 30% for the USA, Europe, and the UK. Assuming a causal relation and intervention at the correct age for prevention, relative reductions of 10% per decade in the prevalence of each of the seven risk factors could reduce the prevalence of Alzheimers disease in 2050 by 8·3% worldwide. INTERPRETATION After accounting for non-independence between risk factors, around a third of Alzheimers diseases cases worldwide might be attributable to potentially modifiable risk factors. Alzheimers disease incidence might be reduced through improved access to education and use of effective methods targeted at reducing the prevalence of vascular risk factors (eg, physical inactivity, smoking, midlife hypertension, midlife obesity, and diabetes) and depression. FUNDING National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Cambridgeshire and Peterborough.

A Longitudinal Study of Cardiorespiratory Fitness and Cognitive Function in Healthy Older Adults

OBJECTIVES: To determine whether cardiorespiratory fitness at baseline is associated with maintenance of cognitive function over 6 years or with level of cognitive function on tests performed 6 years later in a longitudinal study of healthy older people.

Posttraumatic Stress Disorder and Risk of Dementia Among US Veterans

CONTEXT Posttraumatic stress disorder (PTSD) is highly prevalent among US veterans because of combat and may impair cognition. OBJECTIVE To determine whether PTSD is associated with the risk of developing dementia among older US veterans receiving treatment in the Department of Veterans Affairs medical centers. DESIGN A stratified, retrospective cohort study conducted using the Department of Veterans Affairs National Patient Care Database. SETTING Department of Veterans Affairs medical centers in the United States. PARTICIPANTS A total of 181 093 veterans 55 years or older without dementia from fiscal years 1997 through 2000 (53 155 veterans with and 127 938 veterans without PTSD). MAIN OUTCOME MEASURES During the follow-up period between October 1, 2000, and December 31, 2007, 31 107 (17.2%) veterans were ascertained to have newly diagnosed dementia according to International Classification of Diseases, Ninth Revision, Clinical Modification codes. RESULTS The mean baseline age of the veterans was 68.8 years, and 174 806 (96.5%) were men. Veterans with PTSD had a 7-year cumulative incident dementia rate of 10.6%, whereas those without had a rate of 6.6% (P < .001). With age as the time scale, Cox proportional hazards models indicated that patients with PTSD were more than twice as likely to develop incident dementia compared with those without PTSD (hazard ratio, 2.31; 95% confidence interval, 2.24-2.39). After multivariable adjustment, patients with PTSD were still more likely to develop dementia (hazard ratio, 1.77; 95% confidence interval, 1.70-1.85). Results were similar when we excluded those with a history of head injury, substance abuse, or clinical depression. CONCLUSIONS In a predominantly male veteran cohort, those diagnosed as having PTSD were at a nearly 2-fold-higher risk of developing dementia compared with those without PTSD. Mechanisms linking these important disorders need to be identified with the hope of finding ways to reduce the increased risk of dementia associated with PTSD.

Midlife vs late-life depressive symptoms and risk of dementia: differential effects for Alzheimer disease and vascular dementia.

CONTEXT Depression and dementia are common in older adults and often co-occur, but it is unclear whether depression is an etiologic risk factor for dementia. OBJECTIVE To clarify the timing and nature of the association between depression and dementia. DESIGN We examined depressive symptoms assessed in midlife (1964-1973) and late life (1994-2000) and the risks of dementia, Alzheimer disease (AD), and vascular dementia (VaD) (2003-2009) in a retrospective cohort study. Depressive symptoms were categorized as none, midlife only, late life only, or both. Cox proportional hazards models (age as timescale) adjusted for demographics and medical comorbidities were used to examine depressive symptom category and risk of dementia, AD, or VaD. SETTING Kaiser Permanente Medical Care Program of Northern California. PARTICIPANTS Thirteen thousand five hundred thirty-five long-term Kaiser Permanente members. MAIN OUTCOME MEASURE Any medical record diagnosis of dementia or neurology clinic diagnosis of AD or VaD. RESULTS Subjects had a mean (SD) age of 81.1 (4.5) years in 2003, 57.9% were women, and 24.2% were nonwhite. Depressive symptoms were present in 14.1% of subjects in midlife only, 9.2% in late life only, and 4.2% in both. During 6 years of follow-up, 22.5% were diagnosed with dementia (5.5% with AD and 2.3% with VaD). The adjusted hazard of dementia was increased by approximately 20% for midlife depressive symptoms only (hazard ratio, 1.19 [95% CI, 1.07-1.32]), 70% for late-life symptoms only (1.72 [1.54-1.92]), and 80% for both (1.77 [1.52-2.06]). When we examined AD and VaD separately, subjects with late-life depressive symptoms only had a 2-fold increase in AD risk (hazard ratio, 2.06 [95% CI, 1.67-2.55]), whereas subjects with midlife and late-life symptoms had more than a 3-fold increase in VaD risk (3.51 [2.44-5.05]). CONCLUSIONS Depressive symptoms in midlife or in late life are associated with an increased risk of developing dementia. Depression that begins in late life may be part of the AD prodrome, while recurrent depression may be etiologically associated with increased risk of VaD.

Computer-Based Cognitive Training for Mild Cognitive Impairment: Results from a Pilot Randomized, Controlled Trial

We performed a pilot randomized, controlled trial of intensive, computer-based cognitive training in 47 subjects with mild cognitive impairment. The intervention group performed exercises specifically designed to improve auditory processing speed and accuracy for 100 min/d, 5 d/wk for 6 weeks; the control group performed more passive computer activities (reading, listening, visuospatial game) for similar amounts of time. Subjects had a mean age of 74 years and 60% were men; 77% successfully completed training. On our primary outcome, Repeatable Battery for Assessment of Neuropsychological Status total scores improved 0.36 standard deviations (SD) in the intervention group (P=0.097) compared with 0.03 SD in the control group (P=0.88) for a nonsignificant difference between the groups of 0.33 SD (P=0.26). On 12 secondary outcome measures, most differences between the groups were not statistically significant. However, we observed a pattern in which effect sizes for verbal learning and memory measures tended to favor the intervention group whereas effect sizes for language and visuospatial function measures tended to favor the control group, which raises the possibility that these training programs may have domain-specific effects. We conclude that intensive, computer-based mental activity is feasible in subjects with mild cognitive impairment and that larger trials are warranted.

The Mental Activity and eXercise (MAX) Trial A Randomized Controlled Trial to Enhance Cognitive Function in Older Adults

IMPORTANCE The prevalence of cognitive impairment and dementia are projected to rise dramatically during the next 40 years, and strategies for maintaining cognitive function with age are critically needed. Physical or mental activity alone result in relatively small, domain-specific improvements in cognitive function in older adults; combined interventions may have more global effects. OBJECTIVE To examine the combined effects of physical plus mental activity on cognitive function in older adults. DESIGN Randomized controlled trial with a factorial design. SETTING San Francisco, California. PARTICIPANTS A total of 126 inactive, community-residing older adults with cognitive complaints. INTERVENTIONS All participants engaged in home-based mental activity (1 h/d, 3 d/wk) plus class-based physical activity (1 h/d, 3 d/wk) for 12 weeks and were randomized to either mental activity intervention (MA-I; intensive computer) or mental activity control (MA-C; educational DVDs) plus exercise intervention (EX-I; aerobic) or exercise control (EX-C; stretching and toning); a 2 × 2 factorial design was used so that there were 4 groups: MA-I/EX-I, MA-I/EX-C, MA-C/EX-1, and MA-C/EX-C. MAIN OUTCOME MEASURES Global cognitive change based on a comprehensive neuropsychological test battery. RESULTS Participants had a mean age of 73.4 years; 62.7% were women, and 34.9% were Hispanic or nonwhite. There were no significant differences between the groups at baseline. Global cognitive scores improved significantly over time (mean, 0.16 SD; P < .001) but did not differ between groups in the comparison between MA-I and MA-C (ignoring exercise, P = .17), the comparison between EX-I and EX-C (ignoring mental activity, P = .74), or across all 4 randomization groups (P = .26). CONCLUSIONS AND RELEVANCE In inactive older adults with cognitive complaints, 12 weeks of physical plus mental activity was associated with significant improvements in global cognitive function with no evidence of difference between intervention and active control groups. These findings may reflect practice effects or may suggest that the amount of activity is more important than the type in this subject population. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00522899.

Physical Activity Over the Life Course and Its Association with Cognitive Performance and Impairment in Old Age

OBJECTIVE: To determine how physical activity at various ages over the life course is associated with cognitive impairment in late life.

Use of a Modified Informed Consent Process among Vulnerable Patients: A Descriptive Study

BACKGROUND: Little is known about patient characteristics associated with comprehension of consent information, and whether modifications to the consent process can promote understanding.OBJECTIVE: To describe a modified research consent process, and determine whether literacy and demographic characteristics are associated with understanding consent information.DESIGN: Descriptive study of a modified consent process: consent form (written at a sixth-grade level) read to participants, combined with 7 comprehension questions and targeted education, repeated until comprehension achieved (teach-to-goal).PARTICIPANTS: Two hundred and four ethnically diverse subjects, aged ≥50, consenting for a trial to improve the forms used for advance directives.MEASUREMENTS: Number of passes through the consent process required to achieve complete comprehension. Literacy assessed in English and Spanish with the Short Form Test of Functional Health Literacy in Adults (scores 0 to 36).RESULTS: Participants had a mean age of 61 years and 40% had limited literacy (s-TOHFLA<23). Only 28% of subjects answered all comprehension questions correctly on the first pass. After adjustment, lower literacy (P=.04) and being black (P=.03) were associated with requiring more passes through the consent process. Not speaking English as a primary language was associated with requiring more passes through the consent process in bivariate analyses (P<.01), but not in multivariable analyses (P>.05). After the second pass, most subjects (80%) answered all questions correctly. With a teach-to-goal strategy, 98% of participants who engaged in the consent process achieved complete comprehension.CONCLUSIONS: Lower literacy and minority status are important determinants of understanding consent information. Using a modified consent process, little additional education was required to achieve complete comprehension, regardless of literacy or language barriers.

Predicting risk of dementia in older adults The late-life dementia risk index

Objective: To develop a late-life dementia risk index that can accurately stratify older adults into those with a low, moderate, or high risk of developing dementia within 6 years. Methods: Subjects were 3,375 participants in the Cardiovascular Health Cognition Study without evidence of dementia at baseline. We used logistic regression to identify those factors most predictive of developing incident dementia within 6 years and developed a point system based on the logistic regression coefficients. Results: Subjects had a mean age of 76 years at baseline; 59% were women and 15% were African American. Fourteen percent (n = 480) developed dementia within 6 years. The final late-life dementia risk index included older age (1–2 points), poor cognitive test performance (2–4 points), body mass index <18.5 (2 points), ≥1 apolipoprotein E ε4 alleles (1 point), cerebral MRI findings of white matter disease (1 point) or ventricular enlargement (1 point), internal carotid artery thickening on ultrasound (1 point), history of bypass surgery (1 point), slow physical performance (1 point), and lack of alcohol consumption (1 point) (c statistic, 0.81; 95% confidence interval, 0.79–0.83). Four percent of subjects with low scores developed dementia over 6 years compared with 23% of subjects with moderate scores and 56% of subjects with high scores. Conclusions: The late-life dementia risk index accurately stratified older adults into those with low, moderate, and high risk of developing dementia. This tool could be used in clinical or research settings to target prevention and intervention strategies toward high-risk individuals.