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This study used path analysis to examine effects of cognitive activity and physical activity on cognitive functioning in older adults, through pathways involving beta-amyloid (Aβ) burden, cerebrovascular lesions, and neural injury within the brain regions affected in Alzheimer's disease (AD). Ninety-two cognitively normal older adults (75.2 ± 5.6 years) reported lifetime cognitive activity and current physical activity using validated questionnaires. For each participant, we evaluated cortical Aβ burden (using [(11)C] labeled Pittsburgh-Compound-B positron emission tomography), cerebrovascular lesions (using magnetic resonance imaging-defined white matter lesion [WML]), and neural integrity within AD regions (using a multimodal neuroimaging biomarker). Path models (adjusted for age, gender, and education) indicated that higher lifetime cognitive activity and higher current physical activity was associated with fewer WMLs. Lower WML volumes were in turn related to higher neural integrity and higher global cognitive functioning. As shown previously, higher lifetime cognitive activity was associated with lower [(11)C] labeled Pittsburgh-Compound-B retention, which itself moderated the impact of neural integrity on cognitive functioning. Lifestyle activity may thus promote cognitive health in aging by protecting against cerebrovascular pathology and Aβ pathology thought to be relevant to AD development.

ObjectiveThe objective of this study was to define whether vascular risk factors interact with β-amyloid (Aβ) in producing changes in brain structure that could underlie the increased risk of Alzheimer disease (AD).MethodsSixty-six cognitively normal and mildly impaired older individuals with a wide range of vascular risk factors were included in this study. The presence of Aβ was assessed using [(11)C]Pittsburgh compound B-PET imaging, and cortical thickness was measured using 3-tesla MRI. Vascular risk was measured with the Framingham Coronary Risk Profile Index.ResultsIndividuals with high levels of vascular risk factors have thinner frontotemporal cortex independent of Aβ. These frontotemporal regions are also affected in individuals with Aβ deposition, but the latter show additional thinning in parietal cortices. Aβ and vascular risk were found to interact in posterior (especially in parietal) brain regions, where Aβ has its greatest effect. In this way, the negative effect of Aβ in posterior regions is increased by the presence of vascular risk.ConclusionAβ and vascular risk interact to enhance cortical thinning in posterior brain regions that are particularly vulnerable to AD. These findings give insight concerning the mechanisms whereby vascular risk increases the likelihood of developing AD and supports the therapeutic intervention of controlling vascular risk for the prevention of AD.

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

ObjectiveTo investigate the associations among β-amyloid (Aβ), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease.MethodsIn 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Aβ deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index.ResultsIncreased Aβ was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Aβ deposition. Increased Aβ was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Aβ and memory performance. While age had a marginal effect on these associations, the relationship between Aβ and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B-positive subjects, in whom Aβ remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Aβ and memory after controlling for vascular risk.ConclusionThese results suggest strong links among Aβ, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Aβ, cortical thickness, and memory.

ImportanceCriteria for preclinical Alzheimer disease (AD) propose β-amyloid (Aβ) plaques to initiate neurodegeneration within AD-affected regions. However, some cognitively normal older individuals harbor neural injury similar to patients with AD, without concurrent Aβ burden. Such findings challenge the proposed sequence and suggest that Aβ-independent precursors underlie AD-typical neurodegenerative patterns. OBJECTIVE To examine relationships between Aβ and non-Aβ factors as well as neurodegeneration within AD regions in cognitively normal older adults. The study quantified neurodegenerative abnormalities using imaging biomarkers and examined cross-sectional relationships with Aβ deposition; white matter lesions (WMLs), a marker of cerebrovascular disease; and cognitive functions.Design, setting, and participantsCross-sectional study in a community-based convenience sample of 72 cognitively normal older individuals (mean [SD] age, 74.9 [5.7] years; 48 women; mean [SD] 17.0 [1.9] years of education) of the Berkeley Aging Cohort.InterventionEach individual underwent a standardized neuropsychological test session, magnetic resonance imaging, and positron emission tomography scanning.Main outcomes and measuresFor each individual, 3 AD-sensitive neurodegeneration biomarkers were measured: hippocampal volume, glucose metabolism, and gray matter thickness, the latter 2 sampled from cortical AD-affected regions. To quantify neurodegenerative abnormalities, each biomarker was age adjusted, dichotomized into a normal or abnormal status (using cutoff thresholds derived from an independent AD sample), and summarized into 0, 1, or more than 1 abnormal neurodegenerative biomarker. Degree and topographic patterns of neurodegenerative abnormalities were assessed and their relationships with cognitive functions, WML volume, and Aβ deposition (quantified using carbon 11-labeled Pittsburgh compound B positron emission tomography).ResultsOf our cognitively normal elderly individuals, 40% (n = 29) displayed at least 1 abnormal neurodegenerative biomarker, 26% (n = 19) of whom had no evidence of elevated Pittsburgh compound B retention. In those people who were classified as having abnormal cortical thickness, degree and topographic specificity of neurodegenerative abnormalities were similar to patients with AD. Accumulation of neurodegenerative abnormalities was related to poor memory and executive functions as well as larger WML volumes but not elevated Pittsburgh compound B retention.Conclusions and relevanceOur study confirms that a substantial proportion of cognitively normal older adults harbor neurodegeneration, without Aβ burden. Associations of neurodegenerative abnormalities with cerebrovascular disease and cognitive performance indicate that neurodegenerative pathology can emerge through non-Aβ pathways within regions most affected by AD.

β-Amyloid (Aβ) plaque deposition and neurodegeneration within temporoparietal and hippocampal regions may indicate increased risk of Alzheimer's disease (AD). This study examined relationships between AD biomarkers of Aβ and neurodegeneration as well as cognitive performance in cognitively normal older individuals. Aβ burden was quantified in 72 normal older human subjects from the Berkeley Aging Cohort (BAC) using [(11)C] Pittsburgh compound B (PIB) positron emission tomography. In the same individuals, we measured hippocampal volume, as well as glucose metabolism and cortical thickness, which were extracted from a template of cortical AD-affected regions. The three functional and structural biomarkers were merged into a highly AD-sensitive multimodality biomarker reflecting neural integrity. In the normal older individuals, there was no association between elevated PIB uptake and either the single-modality or the multimodality neurodegenerative biomarkers. Lower neural integrity within the AD-affected regions and a control area (the visual cortex) was related to lower scores on memory and executive function tests; the same association was not found with PIB retention. The relationship between cognition and the multimodality AD biomarker was stronger in individuals with the highest PIB uptake. The findings indicate that neurodegeneration occurs within AD regions regardless of Aβ deposition and accounts for worse cognition in cognitively normal older people. The impact of neural integrity on cognitive functions is, however, enhanced in the presence of high Aβ burden for brain regions that are most affected in AD.

Background: Non‐pharmacological interventions are a potential strategy to maintain or promote cognitive functioning in older adults. We investigated the effects of 18‐months meditation or non‐native language training versus no intervention on cognition in older adults. Method: Age‐Well was an observer‐blind, randomised, controlled clinical trial with three parallel arms. Cognitively healthy adults aged ≥ 65 years and were recruited in France. Participants were randomised (1:1:1) to a meditation training, non‐native language (English) training, or a no intervention group for 18 months. Cognition (a pre‐specified secondary outcome) was assessed pre‐ and post‐intervention via the Preclinical Alzheimer's Cognitive Composite 5 (PACC5), and composites assessing episodic memory, executive function, and attention. Linear mixed models, adjusted for age, sex, and education, evaluated cognitive changes between arms. Baseline neocortical amyloid deposition was added as a fixed effect in a sensitivity analysis. Additional sensitivity analyses assessed intervention effects for participants who attended at least 20% of intervention classes or were classified as 'responders'. Results: 137 participants were randomly assigned to meditation training (n = 45), non‐native language training (n = 46), or no intervention (n = 46). Two participants were excluded for not meeting eligibility criteria, and one died during follow‐up (Figure 1). A positive effect of non‐native language training was observed on episodic memory relative to the no intervention group (0·32 [95% CI: 0·04‐0·61], p = 0·025), and on PACC5 scores compared to meditation training (0·33 [95% CI: 0·01‐0·66], p = 0·045; Figure 2). In sensitivity analyses, neither the inclusion of amyloid as an additional covariate nor the exclusion of participants who attended <20% of intervention classes affected results. Following exclusion of 'non‐responders', evidence for beneficial effects (relative to the no intervention group) on episodic memory became significant for meditation training (0·33 [0·01, 0·66]), and was weakened for non‐native language training (0·30 [‐0·02, 0·62]). No other between‐group differences emerged. Conclusion: Among cognitively healthy older adults, there was limited evidence for positive effects of 18‐months meditation training on cognition. However, in addition to having real‐life utility, non‐native language learning in late life may have beneficial effects on cognitive domains affected early in Alzheimer's disease. Studies investigating whether these effects are long‐lasting are warranted. [ABSTRACT FROM AUTHOR]

Excitatory anodal transcranial direct current stimulation (A-tDCS) over the left dorsal prefrontal cortex (DPFC) has been shown to improve language production. The present study examined neurophysiological underpinnings of this effect. In a single-blinded within-subject design, we traced effects of A-tDCS compared to sham stimulation over the left DPFC using electrophysiological and behavioural correlates during overt picture naming. Online effects were examined during A-tDCS by employing the semantic interference (SI-)Effect--a marker that denotes the functional integrity of the language system. The behavioural SI-Effect was found to be reduced, whereas the electrophysiological SI-Effect was enhanced over left compared to right temporal scalp-electrode sites. This modulation is suggested to reflect a superior tuning of neural responses within language-related generators. After -(offline) effects of A-tDCS were detected in the delta frequency band, a marker of neural inhibition. After A-tDCS there was a reduction in delta activity during picture naming and the resting state, interpreted to indicate neural disinhibition. Together, these findings demonstrate electrophysiological modulations induced by A-tDCS of the left DPFC. They suggest that A-tDCS is capable of enhancing neural processes during and after application. The present functional and oscillatory neural markers could detect positive effects of prefrontal A-tDCS, which could be of use in the neuro-rehabilitation of frontal language functions. (Contains 1 figure and 3 tables.)

Introduction: Both elevated cortisol and hippocampal volume have been linked to an increased risk for the development of Alzheimer's disease (AD). This longitudinal study assessed the effects of plasma cortisol on hippocampal atrophy and clinical progression rates in patients with mild cognitive impairment (MCI). Methods: Patients with amnestic MCI (n = 304) were selected from the Alzheimer's Disease Neuroimaging Initiative (ADNI) based on availability of baseline plasma cortisol and hippocampal volume measures, assessed at baseline and during follow‐ups. We investigated associations between plasma cortisol, hippocampal volume, and risk of clinical progression to AD over a study period of up to 100 months (mean follow‐up time 36.8 months) using linear mixed models, Cox proportional hazards models, and Kaplan‐Meier estimators. Results: Plasma cortisol predicted greater hippocampal atrophy, such that participants with higher cortisol showed faster decline in hippocampal volume over time (interaction: β = ‐0.15, p = 0.004). Small hippocampal volume predicted a higher risk of clinical progression to AD (haard ratio [HR] = 2.15; confidence in terval [CI], 1.64–2.80; p < 0.001). A similar effect was not found for cortisol (HR = 1.206; CI, 0.82–1.37; p = 0.670) and there was no statistical evidence for an interaction between hippocampal volume and cortisol on clinical progression (HR = 0.81; CI, 0.57–0.17; p = 0.260). Discussion: Our findings suggest that higher cortisol predicts higher hippocampal atrophy, which in turn is a risk factor for progression to AD. Regulation of the hypothalamic‐pituitary‐adrenal axis through stress‐reducing lifestyle interventions might be a protective factor against hippocampal degeneration at the prodromal stage of AD. [ABSTRACT FROM AUTHOR]