Elevated vascular risk and beta-amyloid (Aβ) burden have been synergistically associated with cognitive decline in preclinical Alzheimer's disease (AD), although the underlying mechanisms remain unclear. We examined whether accelerated longitudinal tau accumulation mediates the vascular risk-Aβ interaction on cognitive decline.We included 175 cognitively unimpaired older adults (age 70.5 ± 8.0 years). Baseline vascular risk was quantified using the office-based Framingham Heart Study general cardiovascular disease risk score (FHS-CVD). Baseline Aβ burden was measured with Pittsburgh Compound-B positron emission tomography (PET). Tau burden was measured longitudinally (3.6 ± 1.5 years) with Flortaucipir PET, focusing on inferior temporal cortex (ITC). Cognition was assessed longitudinally (7.0 ± 2.0 years) using the Preclinical Alzheimer's Cognitive Composite. Linear mixed effects models examined the interactive effects of baseline vascular risk and Aβ on longitudinal ITC tau. Additionally, moderated mediation was used to determine whether tau accumulation mediated the FHS-CVD*Aβ effect on cognitive decline.We observed a significant interaction between elevated baseline FHS-CVD and Aβ on greater ITC tau accumulation (p = 0.004), even in individuals with Aβ burden below the conventional threshold for amyloid positivity. Examining individual vascular risk factors, we found elevated systolic blood pressure and body mass index showed independent interactions with Aβ on longitudinal tau (both p < 0.0001). ITC tau accumulation mediated 33% of the interactive association of FHS-CVD and Aβ on cognitive decline.Vascular risks interact with subthreshold levels of Aβ to promote cognitive decline, partially by accelerating early neocortical tau accumulation. Our findings support vascular risk reduction, especially treating hypertension and obesity, to attenuate Aβ-related tau pathology and reduce late-life cognitive decline. ANN NEUROL 2022;92:745-755.
Background:Muscle power is a key predictor of physical function in older adults; however, clinically meaningful improvements in leg-extensor muscle power have yet to be identified. The purpose of this study is to establish the minimal clinically important improvement (MCII) and substantial improvement (SI) for leg-extensor power and muscle contraction velocity in mobility-limited older adults.
In the absence of disease-modifying therapies for Alzheimer disease, there is a critical need to identify modifiable risk factors that may delay the progression of Alzheimer disease.To examine whether physical activity moderates the association of β-amyloid (Aβ) burden with longitudinal cognitive decline and neurodegeneration in clinically normal individuals and to examine whether these associations are independent of vascular risk.This longitudinal observational study included clinically normal participants from the Harvard Aging Brain Study. Participants were required to have baseline Aβ positron emission tomography data, baseline medical data to quantify vascular risk, and longitudinal neuropsychological and structural magnetic resonance imaging data. Data were collected from April 2010 to June 2018. Data were analyzed from August to December 2018.Baseline physical activity was quantified with a pedometer (mean steps per day). Baseline Aβ burden was measured with carbon 11-labeled Pittsburgh Compound B positron emission tomography. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite (PACC; median [interquartile range] follow-up, 6.0 [4.3-6.3] years). Neurodegeneration was assessed with longitudinal structural magnetic resonance imaging (2 to 5 scans per participant; median [interquartile range] follow-up, 4.5 [3.0-5.0] years), with a focus on total gray matter volume and regional cortical thickness. Physical activity and Aβ burden were examined as interactive predictors of PACC decline and volume loss in separate linear mixed models, adjusting for age, sex, education, apolipoprotein E ε4 status, and, where appropriate, intracranial volume. Secondary models adjusted for vascular risk and its interaction with Aβ burden.Of the 182 included participants, 103 (56.6%) were female, and the mean (SD) age was 73.4 (6.2) years. In models examining PACC decline and volume loss, there was a significant interaction of physical activity with Aβ burden, such that greater physical activity was associated with slower Aβ-related cognitive decline (β, 0.03; 95% CI, 0.02-0.05; P < .001) and volume loss (β, 482.07; 95% CI, 189.40-774.74; P = .002). Adjusting for vascular risk did not alter these associations. In these models, lower vascular risk was independently associated with slower Aβ-related PACC decline (β, -0.04; 95% CI, -0.06 to -0.02; P < .001) and volume loss (β, -483.41; 95% CI, -855.63 to -111.20; P = .01).Greater physical activity and lower vascular risk independently attenuated the negative association of Aβ burden with cognitive decline and neurodegeneration in asymptomatic individuals. These findings suggest that engaging in physical activity and lowering vascular risk may have additive protective effects on delaying the progression of Alzheimer disease.
Nutritional supplementation and physical activity have been shown to positively influence muscle mass and strength in older adults. The efficacy of long-term nutritional supplementation in combination with physical activity in older adults remains unclear.Mobility-limited (short physical performance battery [SPPB] ≤9) and vitamin D insufficient (serum 25(OH) D 9-24 ng/mL) older adults were recruited for this study. All subjects participated in a physical activity program. Subjects were randomized to consume a daily nutritional supplement (150 kcal, 20 g whey protein, 800 IU vitamin D, 119 mL beverage) or placebo (30 kcal, nonnutritive, 119 mL). In a prespecified secondary analysis, we examined total-body composition (dual energy X-ray absorptiometry), thigh composition (computed tomography), and muscle strength, power, and quality before and after the 6-month intervention.One hundred and forty-nine subjects were randomized into the study [mean (standard deviation, SD) age 78.5 (5.4) years; 46.3% female; mean (SD) short physical performance battery 7.9 (1.2); mean (SD) vitamin D 18.7 (6.4) ng/mL]. After the intervention period both groups demonstrated improvements in muscle strength, body composition, and thigh composition. Nutritional supplementation lead to further losses of intermuscular fat (p = .049) and increased normal muscle density (p = .018).Six months of physical activity resulted in improvements in body composition, subcutaneous fat, intermuscular fat, and strength measures. The addition of nutritional supplementation resulted in further declines in intermuscular fat and improved muscle density compared to placebo. These results suggest nutritional supplementation provides additional benefits to mobility-limited older adults undergoing exercise training. ClinicalTrials.gov Identifier: NCT01542892.
Abstract Background Latinos are the fastest growing subpopulation of older adults in the U.S. and have a higher risk for dementia than non‐Latino Whites. Depressive symptoms are prevalent among US Latinos. However, these symptoms often go undiagnosed and are undertreated. Depressive symptoms may be early manifestations of Alzheimer’s Disease (AD) before the onset of mild cognitive impairment and dementia. It’s unclear whether depressive symptoms in the presence of incipient neurodegeneration are associated with cognitive function in older Latino adults. Here, we examined the associations among depressive symptoms, cognition and hippocampal volume in older Latinos. Method A total of 65 Spanish‐speaking Latinos enrolled in the Boston Latino Aging Study (BLAST) and the Harvard Aging Brain Study (HABS) were included. Depressive symptoms were assessed with the 30‐item‐Geriatric Depression Scale (GDS) and cognition with the Preclinical Alzheimer’s Cognitive Composite (PACC5), which includes the Mini‐Mental State Examination (MMSE), Digit Symbol Coding, Free and Cued Selective Reminding Test, Category Fluency (animals) and Logical Memory Delayed Recall (NEUROPSI Stories for BLAST participants). A subset of 34 participants also underwent a structural brain MRI on a 3T scanner. Spearman correlations were used to determine cross‐sectional associations among depressive symptoms, hippocampal volume, and cognition. Models were adjusted for age and education. Results Participants had a mean age of 66 +/‐ 7.2 years, a mean education of 12.9 +/‐ 5.1 years, and 74% were female. They had a mean MMSE score of 26.7 +/‐ 2.8, a mean GDS score of 6.1 +/‐ 5.5 and a mean adjusted hippocampal volume of 7836.5 +/ = 630.9 mm 3 . Correlation analyses revealed that higher depressive symptoms were associated with lower years of education (r = ‐0.39, p<0.001), worse performance on cognitive measures (r = ‐0.33, p = 0.009) and smaller hippocampal volume (r = ‐0.61, p = <0.001). Conclusions Preliminary results of this ongoing biomarker study suggest that depressive symptoms in older Latinos are associated with markers of neurodegeneration (i.e., hippocampal volume) and worse cognition. Future work will focus on investigating predictors of long‐term emotional and cognitive functioning in Spanish‐speaking, older Latino populations.
Abstract Background Improving the demographic diversity of clinical trial participants, including preclinical Alzheimer’s disease (AD) trial participants, is a scientific, social, and ethical imperative. Method The AHEAD Study is an ongoing preclinical AD trial evaluating the efficacy of lecanemab (BAN2401) in biological and cognitive disease progression in cognitively unimpaired biomarker eligible individuals ages 55‐80. The study has an overall goal of at least 15% randomizations from underrepresented populations. The AHEAD Recruitment and Retention Workgroup designed a comprehensive and collaborative recruitment plan tailored to increase diverse participation. Result Recruitment strategies spanned central infrastructure and national initiatives, existing trial ready cohorts, enhanced site engagement, community outreach, and whenever possible, implementation of evidence‐based tactics. Central infrastructure includes a national call center, a study website with capacity for prescreening and site referral, including priority flags for underrepresented groups at the pre‐screener level; establishment of a website dedicated to Spanish speakers; and implementation of blood‐based screening across all sites and targeted communities. Site engagement approaches include disbursement of specialized funding to support local recruitment efforts tailored to diverse populations and the development of partnerships with community organizations or across sites within a region. Outreach activities, at the national, regional, and local level, include earned media and social media campaigns and award‐winning plays and videos surrounding themes of participation of diverse groups in clinical trials. Throughout, additional funding opportunities enable testing of innovative approaches and novel partnerships for recruitment of underrepresented groups at individual sites. Evaluation and additional support of these initiatives will be based on number of underrepresented participants pre‐screened, screened, and randomized in the study. Conclusion Focused, multipronged approaches and sustainable partnerships with demographically diverse communities are required to promote the participation of underrepresented groups into preclinical AD trials like AHEAD. Our initiatives demonstrate the commitment to increase recruitment of underrepresented groups by supporting successful efforts centrally, at the site‐level and the participant level using a combination of traditional and modern recruitment approaches.
Objectives Amyloid‐beta (Aβ) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. Methods One hundred thirty‐seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aβ ( 11 C‐Pittsburgh compound B) and tau ( 18 F‐flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aβ PET measures were assessed in regions of interest (ROIs) as well as vertex‐wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. Results Higher levels of Aβ and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aβ was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aβ. A significant interaction between tau and Aβ was observed in both ROI and map‐level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. Interpretation Our results are consistent with the supposition that both Aβ and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1–3 ANN NEUROL 2019;85:181–193.
Identifying asymptomatic individuals at high risk of impending cognitive decline because of Alzheimer disease is crucial for successful prevention of dementia. Vascular risk and β-amyloid (Aβ) pathology commonly co-occur in older adults and are significant causes of cognitive impairment.To determine whether vascular risk and Aβ burden act additively or synergistically to promote cognitive decline in clinically normal older adults; and, secondarily, to evaluate the unique influence of vascular risk on prospective cognitive decline beyond that of commonly used imaging biomarkers, including Aβ burden, hippocampal volume, fludeoxyglucose F18-labeled (FDG) positron emission tomography (PET), and white matter hyperintensities, a marker of cerebrovascular disease.In this longitudinal observational study, we examined clinically normal older adults from the Harvard Aging Brain Study. Participants were required to have baseline imaging data (FDG-PET, Aβ-PET, and magnetic resonance imaging), baseline medical data to quantify vascular risk, and at least 1 follow-up neuropsychological visit. Data collection began in 2010 and is ongoing. Data analysis was performed on data collected between 2010 and 2017.Vascular risk was quantified using the Framingham Heart Study general cardiovascular disease (FHS-CVD) risk score. We measured Aβ burden with Pittsburgh Compound-B PET. Cognition was measured annually with the Preclinical Alzheimer Cognitive Composite. Models were corrected for baseline age, sex, years of education, and apolipoprotein E ε4 status.Of the 223 participants, 130 (58.3%) were women. The mean (SD) age was 73.7 (6.0) years, and the mean (SD) follow-up time was 3.7 (1.2) years. Faster cognitive decline was associated with both a higher FHS-CVD risk score (β = -0.064; 95% CI, -0.094 to -0.033; P < .001) and higher Aβ burden (β = -0.058; 95% CI, -0.079 to -0.037; P < .001). The interaction of the FHS-CVD risk score and Aβ burden with time was significant (β = -0.040, 95% CI, -0.062 to -0.018; P < .001), suggesting a synergistic effect. The FHS-CVD risk score remained robustly associated with prospective cognitive decline (β = -0.055; 95% CI, -0.086 to -0.024; P < .001), even after adjustment for Aβ burden, hippocampal volume, FDG-PET uptake, and white matter hyperintensities.In this study, vascular risk was associated with prospective cognitive decline in clinically normal older adults, both alone and synergistically with Aβ burden. Vascular risk may complement imaging biomarkers in assessing risk of prospective cognitive decline in preclinical Alzheimer disease.
