Greater Hippocampal Volume Research Articles

High-Frequency Hearing Loss, Hippocampal Volume, and Motoric Cognitive Risk Syndrome in Older Adults in China: A Population-Based Study.

Little is known about the associations of hearing loss, hippocampal volume, and motoric cognitive risk syndrome (MCR) in older adults. We aimed to investigate the associations of hearing loss with MCR and hippocampal volume; and the interaction of hearing loss with hippocampal volume on MCR. This population-based cross-sectional study included 2,540 dementia-free participants (age≥60 years; 56.5% women) in the baseline examination of the Multimodal Interventions to Delay Dementia and Disability in rural China. Data were collected through face-to-face interviews, clinical examination, and laboratory tests. Hearing function was assessed using pure tone audiometry test. In the subsample (n = 661), hippocampal volume was assessed on structural magnetic resonance images. Data were analyzed with logistic regression models. In the total sample, MCR was diagnosed in 246 persons (9.7%). High-frequency hearing loss was significantly associated with an increased likelihood of MCR and slow gait. In the subsample, the restricted cubic spline plots indicated an inverted U-shaped nonlinear relationship between high-frequency hearing performance and hippocampal volume. Moreover, greater hippocampal volume was significantly associated with a deduced likelihood of MCR and subjective cognitive decline (SCD). In addition, there were statistical interactions of high-frequency hearing loss with hippocampal volume on MCR and slow gait (p for interaction < 0.05), such that the associations were statistically significant only among participants free of high-frequency hearing loss. High-frequency hearing loss was associated with an increased likelihood of MCR in older adults. The hippocampus might play a part in the relationship of high-frequency hearing loss and MCR.

Later life Body composition and Alzheimer’s disease

AbstractBackgroundMid‐life obesity is linked with increased risk for late‐life dementia, however relationships between later‐life body composition and dementia are less clear.MethodUsing a combined cohort from two major observational studies (AIBL and ADNI) and categorising Body Mass Index (BMI) according to WHO criteria, we computed multivariable linear mixed‐effects models to determine association between BMI category and outcomes: brain beta‐amyloid PET quantification (centiloid); MRI (global, hippocampal and white matter hyperintensity volume); and cognition (PACC [preclinical Alzheimer cognitive composite], composite scores for attention, executive function and episodic memory). All models were adjusted by covariables age, gender, education, APOE ε4, and study (AIBL/ADNI).ResultsThe cohort included 4,668 observations from 2,828 individuals (49.4% male, mean age 73.8 years, 38.2% APOE ε4 carriage, 61.8% normal cognition [NC], 25.6% Mild Cognitive Impairment [MCI], 12.6% dementia due to Alzheimer’s disease). The average BMI was 26.8 kg/m2 (0.6% underweight, 37.7% normal‐range, 41.7% overweight, 20.0% obese [BMI &lt;18, 18‐25, 25‐30 and &gt;30 kg/m2, respectively]).Relative to normal‐range BMI, those with overweight‐or‐obese range BMI had a significant negative association with PET centiloid level, beta = ‐0.150 (0.037 se) and ‐0.309 (0.042), respectively (i.e. greater BMI had lower amyloid level). This remained significant for obese‐range BMI in fully‐adjusted models when restricted to only NC participants. Also, obesity was associated with greater hippocampal volume, beta = 0.192 (0.046), but this was not significant when restricted to NC only. Associations with total grey matter/cortical volume and white matter hyperintensities were not significant. Obese‐range BMI was associated with stronger performance on attention and episodic memory composites, but not for PACC and executive function. For NC‐only, there was only significant negative association between obesity and attention performance. In multivariate analyses, neither obesity category nor BMI were associated with longitudinal change in cognitive scores.ConclusionPresence of obesity in later life was associated with lower brain amyloid levels and less hippocampal atrophy in a mixed cohort including older adults with dementia, mild cognitive impairment and normal cognition. While mid‐life obesity is associated greater risk for AD, later life associations appear influenced by weight loss with emerging dementia.

Successful cognitive aging is associated with thicker anterior cingulate cortex and lower tau deposition compared to typical aging.

There is no consensus on either the definition of successful cognitive aging (SA) or the underlying neural mechanisms. We examined the agreement between new and existing definitions using: (1) a novel measure, the cognitive age gap (SA-CAG, cognitive-predicted age minus chronological age), (2) composite scores for episodic memory (SA-EM), (3) non-memory cognition (SA-NM), and (4) the California Verbal Learning Test (SA-CVLT). Fair to moderate strength of agreement was found between the four definitions. Most SA groups showed greater cortical thickness compared to typical aging (TA), especially in the anterior cingulate and midcingulate cortices and medial temporal lobes. Greater hippocampal volume was found in all SA groups except SA-NM. Lower entorhinal 18 F-Flortaucipir (FTP) uptake was found in all SA groups. These findings suggest that a feature of SA, regardless of its exact definition, is resistance to tau pathology and preserved cortical integrity, especially in the anterior cingulate and midcingulate cortices. Different approaches have been used to define successful cognitive aging (SA). Regardless of definition, different SA groups have similar brain features. SA individuals have greater anterior cingulate thickness and hippocampal volume. Lower entorhinal tau deposition, but not amyloid beta is related to SA. A combination of cortical integrity and resistance to tau may be features of SA.

Physical activity engagement, memory function, and hippocampal volume in adults with down syndrome

AbstractBackgroundHigher engagement in moderate‐to‐vigorous physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the impact of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of the chromosome 21, which includes the gene for the amyloid precursor protein, resulting in an increased risk for/earlier onset of Alzheimer’s disease. The goal of this study was to understand the relationship between moderate PA engagement and memory functioning in non‐demented adults with DS.MethodAdults with DS participated in an ancillary Lifestyle study linked to the Alzheimer’s Biomarkers Consortium for Down Syndrome (N = 54). Participants completed the Cued Recall Test (CRT) to measure episodic memory. The total free + cued CRT score was used in analyses. Participants wore a wrist‐worn accelerometer (GT9X) for 7 days to measure PA. Moderate PA was classified using the Freedson cutpoints in ActiLife software and was defined as the daily average minutes. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection. Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates (age, body mass index (BMI), intracranial volume (ICV)).ResultParticipants were 37.81 years old (SD = 8.15 years) and 55.6% female. They spent ∼10.67% of their time engaged in moderate PA (SD = 7.48%). Participants recalled an average of 32.09 items on the CRT (SD = 6.09, range = 7‐36). After controlling for age and BMI, greater moderate PA engagement was associated with higher total recall score (b = 0.279, p = 0.044). After controlling for age and ICV, moderate PA engagement was not significantly associated with hippocampal volume (p = 0.48). Greater hippocampal volume was associated with higher total recall score after controlling for age and ICV (b = 0.496, p = 0.004).ConclusionA higher proportion of time spent engaging in moderate PA was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with moderate PA engagement. Greater moderate PA engagement may be a promising lifestyle behavior to preserve memory in aging adults with DS.

Co-twin design in brain imaging-review on biomarkers of Alzheimer's disease.

Twin samples allow to conduct a quasi-experimental co-twin case-control approach that can control for genetic and environmental confounding in brain-cognition associations, being more informative on causality compared with studies in unrelated individuals. We conducted a review of studies that have utilized discordant co-twin design to investigate the associations of brain imaging markers of Alzheimer's disease and cognition. Inclusion criteria encompassed twin pairs discordant for cognition or Alzheimer's disease imaging markers and reporting of within-twin pair comparison on the association between cognition and brain measures. Our PubMed search (2022 April 23, updated 2023 March 9) resulted in 18 studies matching these criteria. Alzheimer's disease imaging markers have been addressed only by few studies, most with small sample size. Structural magnetic resonance imaging studies have indicated greater hippocampal volume and thicker cortex in co-twins with better cognitive performance compared with their co-twins with poorer cognitive performance. No studies have looked at cortical surface area. Positron emission tomography imaging studies have suggested that lower cortical glucose metabolism rate and higher cortical neuroinflammation, amyloid, and tau accumulations are related to poorer episodic memory in within-twin pair comparisons. Thus far, only cross-sectional within-twin pair associations of cortical amyloid and hippocampal volume with cognition have been replicated.

Definitions and characteristics of successful cognitive aging

AbstractBackgroundDifferent approaches have been used to define successful agers (SA), but there is currently no consensus on either the definition of SA or the underlying neural mechanisms. The aim of this study was to compare new and existing definitions, to understand whether SA are resistant to atrophy and Alzheimer’s disease pathology or resilient to their effects, and whether this varies by SA definition.MethodMachine learning algorithms were used to predict age from neuropsychological tests in 184 cognitively normal adults over the age of 70. Differences between cognitive‐predicted age and chronological age (cognitive age gap, CAG) were used as a novel measure of SA, defined as below the 20th percentile (SA‐CAG, n = 37). In the same sample, SA were also defined as individuals performing in the top 20% on composite scores for episodic memory (SA‐EM, n = 37) and non‐memory cognition (SA‐NM, n = 37), and participants with performance comparable to individuals aged 18‐32 years on the California Verbal Learning Test long delay free recall (SA‐CVLT, n = 31). The four definitions were used to compare SA to typical agers (TA, n = 109) in hippocampal volume, anterior cingulate cortex (ACC) thickness, APOE genotype, PET‐measured amyloid (11C‐Pittsburgh compound‐B, PiB) and, in a subsample (n = 114), PET‐measured tau (18F‐Flortaucipir, FTP). All analyses were age and sex adjusted.ResultSA‐CAG definition showed moderate agreement with SA‐EM (Cohen’s κ = 0.46), SA‐NM (κ = 0.49), but only fair agreement with SA‐CVLT (κ = 0.24). Fair agreement was found between the other definitions (Figure 1). Compared to TA, greater hippocampal volume was found in SA‐CAG (p = 0.005), SA‐EM (p = 0.02), and SA‐CVLT (p = 0.02). Greater ACC thickness was found in SA‐CAG (p = 0.01), SA‐EM (p = 0.02), and SA‐NM (p = 0.004). Lower entorhinal FTP uptake was found in SA‐CAG (p = 0.04), SA‐EM (p = 0.007), and SA‐NM (p = 0.008) (Figure 2). No between‐group differences were detected in the proportion of APOE ε4 carriers and PiB+ participants.ConclusionDespite imperfect overlap in SA groups identified by different definitions, common brain features were found in SA‐CAG, SA‐EM, and SA‐NM compared to TA. Greater hippocampal volume, greater ACC thickness and lower entorhinal tau deposition suggests that SA, regardless of its exact definition, may be resistant to tau pathology and its downstream effects.

Becoming physically active or maintaining physical activity during midlife is associated with biomarkers of amyloid‐beta, microglia, and temporal lobe integrity

AbstractBackgroundPhysical activity (PA) has a beneficial effect on brain health in older age. Whether and how changes in PA during midlife are linked to brain health later in life remains understudied. In adults at risk for Alzheimer’s disease (AD), we investigated the change in PA during midlife in relation to biomarkers of AD pathology, microglia, and brain integrity.MethodsA questionnaire investigating the minutes of PA per week was administered to 273 cognitively unimpaired participants at baseline and after a follow‐up of 4.1 (±0.8) years. The change in PA minutes/week between the two time points was calculated. Participants were classified in groups based on their activity levels at the two time points (active≥150 minutes, inactive&lt;150 minutes): (1) maintained‐PA groups: active/active, inactive/inactive and (2) changing‐PA groups: inactive/active, active/inactive. During the follow‐up, participants had available CSF amyloid‐β42/40, phosphorylated‐tau and sTREM‐2 measured using either the exploratory Roche NeuroToolKit or the Elecsys® immunoassays, amyloid PET, and structural MRI (AD signature [medial temporal lobe structures] thickness and hippocampal volume). We conducted multiple regression analyses with AD, microglia, and brain integrity biomarkers as outcome measurements and the change in PA minutes between the two time points as predictor, to assess dose‐dependent effects within the whole group, and maintained‐PA and changing‐PA groups separately. Furthermore, we investigated the associations of maintenance and change in activity status (PA groups) on the outcome measurements. All models were adjusted by age, sex, APOE‐ε4 status, education, and time interval between baseline and follow‐up.ResultsThe associations observed were group‐specific: increased minutes of PA was associated with greater AD signature thickness in the active/active group (p = 0.05) and greater hippocampal volume in the inactive/active group (p = 0.046). In the maintained‐PA groups, being active/active predicted higher CSF amyloid‐β42/40 (p = 0.024). In the changing‐PA groups, decreased minutes of PA predicted higher sTREM2 (p = 0.036) and brain amyloid‐β burden (p = 0.021). Additionally, the active/inactive group showed higher sTREM2 (p = 0.033) and brain amyloid‐β burden (p = 0.013).ConclusionsOur results suggest that becoming or staying physically active during midlife is associated with lower amyloidosis, microglia activation, and preserved temporal lobe integrity. The results further suggest a dose‐dependent effect of PA on brain health.

Cardiorespiratory Fitness as a Moderator of Sleep-Related Associations with Hippocampal Volume and Cognition.

The objective of this study was to understand the associations of sleep and cardiorespiratory fitness with hippocampal volume and global cognition among older adults (n = 30, age = 65.8 years, female = 73.3%). Wrist actigraphy provided objective measures of nighttime sleep including sleep duration, average wake bout length (WBL; sleep disturbance), and wake-to-sleep transition probability (WTSP; sleep consolidation). Cardiorespiratory fitness was quantified via cycle exercise using a modified heart rate recovery approach. Magnetic resonance imaging was used to determine hippocampal volume and the Mini-Mental State Examination was used to assess global cognition. Fitness moderated associations of sleep with hippocampal volume and cognitive performance, whereby the association of WBL—an index of poor sleep—with hippocampal atrophy was stronger among less-fit individuals, and the association of sleep duration with cognitive performance was stronger among more-fit individuals. Across the fitness levels, a longer WBL was associated with lower cognitive performance, and a higher WTSP—an index of more consolidated sleep—was associated with greater hippocampal volume. Sleep and fitness were unrelated to the volume of an amygdala control region, suggesting a degree of neuroanatomical specificity. In conclusion, higher cardiorespiratory fitness may attenuate sleep disturbance-related hippocampal atrophy and magnify the cognitive benefits of good sleep. Prospective studies are needed to confirm these findings.

Physical activity, memory function, and hippocampal volume in adults with Down syndrome.

Higher engagement in moderate-intensity physical activity (PA) is related to better cognitive functioning in neurotypical adults; however, little is known about the effect of PA on cognitive aging in adults with Down syndrome (DS). Individuals with DS have three copies of chromosome 21, which includes the gene involved in the production of the amyloid precursor protein, resulting in an increased risk for an earlier onset of Alzheimer’s disease (AD). The goal of this study was to understand the relationship between engagement in moderate PA, memory, and hippocampal volume in adults with DS. Adults with DS participated in an ancillary Lifestyle study linked to the Alzheimer’s Biomarkers Consortium for DS (ABC- DS; N = 71). A within-sample z-score memory composite was created from performance on the Cued Recall Test (CRT) and the Rivermead Picture Recognition Test. Participants wore a wrist-worn accelerometer (GT9X) to measure PA. Variables of interest included the average percentage of time spent in moderate PA and average daily steps. Structural MRI data were acquired within 18 months of actigraphy/cognitive data collection for a subset of participants (n = 54). Hippocampal volume was extracted using Freesurfer v5.3. Associations between moderate PA engagement, memory, and hippocampal volume were evaluated with hierarchical linear regressions controlling for relevant covariates [age, body mass index, intellectual disability level, sex, and intracranial volume]. Participants were 37.77 years old (SD = 8.21) and were 55.6% female. They spent 11.1% of their time engaged in moderate PA (SD = 7.5%) and took an average of 12,096.51 daily steps (SD = 4,315.66). After controlling for relevant covariates, higher memory composite score was associated with greater moderate PA engagement (β = 0.232, p = 0.027) and more daily steps (β = 0.209, p = 0.037). In a subset of participants, after controlling for relevant covariates, PA variables were not significantly associated with the hippocampal volume (all p-values ≥ 0.42). Greater hippocampal volume was associated with higher memory composite score after controlling for relevant covariates (β = 0.316, p = 0.017). More PA engagement was related to better memory function in adults with DS. While greater hippocampal volume was related to better memory performance, it was not associated with PA. Greater PA engagement may be a promising lifestyle behavior to preserve memory in adults with DS.

Plasma high-density lipoprotein cargo is altered in Alzheimer's disease and is associated with regional brain volume.

Cholesterol levels have been repeatedly linked to Alzheimer's Disease (AD), suggesting that high levels could be detrimental, but this effect is likely attributed to Low-Density Lipoprotein (LDL) cholesterol. On the other hand, High-Density Lipoproteins (HDL) cholesterol levels have been associated with reduced brain amyloidosis and improved cognitive function. However, recent findings have suggested that HDL-functionality, which depends upon the HDL-cargo proteins associated with HDL, rather than HDL levels, appears to be the key factor, suggesting a quality over quantity status. In this report, we have assessed the HDL-cargo (Cholesterol, ApoA-I, ApoA-II, ApoC-I, ApoC-III, ApoD, ApoE, ApoH, ApoJ, CRP, and SAA) in stable healthy control (HC), healthy controls who will convert to MCI/AD (HC-Conv) and AD patients (AD). Compared to HC we observed an increased cholesterol/ApoA-I ratio in AD and HC-Conv, as well as an increased ApoD/ApoA-I ratio and a decreased ApoA-II/ApoA-I ratio in AD. Higher cholesterol/ApoA-I ratio was also associated with lower cortical grey matter volume and higher ventricular volume, while higher ApoA-II/ApoA-I and ApoJ/ApoA-I ratios were associated with greater cortical grey matter volume (and for ApoA-II also with greater hippocampal volume) and smaller ventricular volume. Additionally, in a clinical status-independent manner, the ApoE/ApoA-I ratio was significantly lower in APOE ε4 carriers and lowest in APOE ε4 homozygous. Together, these data indicate that in AD patients the composition of HDL is altered, which may affect HDL functionality, and such changes are associated with altered regional brain volumetric data.

The effects of bilingualism on hippocampal volume in ageing bilinguals

Long-term management of more than one language has been argued to contribute to changes in brain and cognition. This has been particularly well documented in older age, where bilingualism has been linked to protective effects against neurocognitive decline. Since memory difficulties are key aspects of this decline, herein we examine potential effects of bilingualism on the hippocampus, a brain structure related to memory that is particularly vulnerable to cognitive ageing. Hippocampal volume has been shown to increase as a result of second language learning and use in younger adults. However, it is unknown if this is maintained throughout the lifespan. We examine hippocampal volume and episodic memory performance in a participant sample consisting of healthy older individuals with a wide range of experiences in exposure and using a second language. Results reveal greater hippocampal volume calibrated to degree of quantified dual language use. Our results mirror those of immersive active bilingualism in younger populations, suggesting that long-term active bilingualism leads to neuroprotective effects in the hippocampus. We discuss this in the context of literature proposing bilingualism-induced brain reserve in the older age.

Second Language Learning in Older Adults: Effects on Brain Structure and Predictors of Learning Success.

It has previously been demonstrated that short-term foreign language learning can lead to structural brain changes in younger adults. Experience-dependent brain plasticity is known to be possible also in older age, but the specific effect of foreign language learning on brain structure in language-and memory-relevant regions in the old brain remains unknown. In the present study, 160 older Swedish adults (65–75 years) were randomized to complete either an entry-level Italian course or a relaxation course, both with a total duration of 11 weeks. Structural MRI scans were conducted before and after the intervention in a subset of participants to test for differential change in gray matter in the two groups in the inferior frontal gyrus, the superior temporal gyrus, and the hippocampus, and in white matter microstructure in the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF), fronto-occipital fasciculus, and the hippocampal (HC) section of the cingulum. The study found no evidence for differential structural change following language training, independent of achieved vocabulary proficiency. However, hippocampal volume and associative memory ability before the intervention were found to be robust predictors of vocabulary proficiency at the end of the language course. The results suggest that having greater hippocampal volume and better associative memory ability benefits vocabulary learning in old age but that the very initial stage of foreign language learning does not trigger detectable changes in brain morphometry in old age.

The Association Between Physical Activity Intensity, Cognition, and Brain Structure in People With Type 2 Diabetes.

Physical inactivity is a risk factor for type 2 diabetes (T2D) and dementia. However, it is unknown if physical activity (PA) intensity is associated with brain health in people with T2D. Therefore, this study aimed to determine (i) associations between PA intensity and step count with both cognition and brain structure and (ii) if apolipoprotein E-ε4 or insulin therapy modifies any associations. Participants were people with T2D (n = 220; aged 55-86 years). An accelerometer worn over the right hip was used to obtain step count and moderate-to-vigorous PA (MVPA) averaged over 7 days. Cognition in 7 domains was obtained using a battery of neuropsychological tests. Brain structure was measured by Magnetic Resonance Imaging. Linear regression models were used to examine associations between step count, MVPA and each cognitive and Magnetic Resonance Imaging measure. Apolipoprotein E-ε4 × PA and insulin therapy × PA product terms were added to the models to examine effect modification. The mean age of participants was 67.9 (SD = 6.3). Higher step count was associated with greater hippocampal volume (β = 0.028, 95% CI = 0.005, 0.051). Insulin therapy modified the association between MVPA and attention-processing speed, such that associations were significant in people receiving insulin therapy (p for interaction = .019). There were no other significant associations. Higher step count and greater time spent in MVPA may be associated with better hippocampal volume and attention-processing speed, respectively, in people with T2D. People with greater diabetes severity (receiving insulin therapy) may get more cognitive benefit from MVPA.

The Relationship Between Hippocampal Volume and Activity Diversity

The hippocampus, implicated in learning, memory, and spatial navigation, is one of the few brain structures that demonstrates neurogenesis across the lifespan. Hippocampal volume (HV), then, may be a marker of exposure to and engagement with novel events and environments, which may in turn be related to cognitive functioning. The present study examined the relationship between HV and activity diversity (AD), which characterizes the range and evenness of participation in daily activities. In 52 participants who completed the daily-diary and neuroscience projects of the Midlife in the United States Refresher study, greater levels of AD across an 8-day period were related to greater HV averaged across the left and right hemispheres when adjusting for overall brain volume, total activity time, time between projects, and relevant sociodemographic variables, b=1128mm3, t(43)=2.54, p=.015. These findings may point to a mechanism through which AD has been related to better cognitive and mental health outcomes.

Sex differences in neurodegeneration and memory performance in preclinical autosomal dominant Alzheimer’s disease: Baseline findings from the API ADAD trial

AbstractBackgroundGrowing evidence suggests that females have greater biological risk for Alzheimer’s disease (AD). As levels of AD pathology increase, females show greater tau accumulation, faster hippocampal volume loss, and faster cognitive decline than males. We sought to investigate sex differences in individuals with preclinical autosomal dominant AD (ADAD), who are destined to develop early‐onset dementia and have minimal age‐related confounds known to vary by sex (e.g., mortality, cardiovascular disease, or menopause). We plan to examine the role of sex in the associations among markers of pathology, neurodegeneration, and cognition leveraging baseline data from the Alzheimer’s Prevention Initiative (API) ADAD Colombia Trial.MethodsWe analyzed baseline data from 242 cognitively unimpaired 30‐53 year‐old prevention trial participants, including 167 PSEN1 E280A mutation carriers and 75 non‐carrier family members. Clinical ratings, CERAD word list delayed recall, hippocampal grey matter volume, florbetapir cortical‐to‐pontine standard‐uptake value ratios (SUVR), and precuneus 18F‐fludeoxyglucose (FDG) positron emission tomography were included in the analyses. T‐tests and multiple regressions models controlling for age, PSEN1 mutation status and amyloid burden were conducted.ResultsAcross groups, females had greater hippocampal volumes (p=.05) and better delayed recall (p=.005) than males. Female carriers were younger than male carriers (p=.04). Females continued to have better delayed recall after adjusting for glucose metabolism in the precuneus (Sex: β=.562, p=.023), and showed a trend towards significance after adjusting for hippocampal volumes (Sex: β=.462, p=.059). In carriers only, as age increased, males had lower hippocampal volumes than females (Slope difference: p ≤ .05), while no differences were found in amyloid levels or metabolism. There was no sex difference in the relationship between amyloid accumulation, hippocampal volumes (Sex: β=.000, p=.094), and metabolism (Sex: β=‐.004, p=.815).ConclusionFindings suggest that cognitively unimpaired female mutation carriers may have greater cognitive resilience to AD‐related neurodegeneration compared to male mutation carriers. Further investigation of sex‐specific differences in AD‐related clinical and pathological markers is key to inform AD detection, prevention, and development of treatments.

Engagement in Enriching Early-Life Activities Is Associated With Larger Hippocampal and Amygdala Volumes in Community-Dwelling Older Adults.

Numerous studies show benefits of mid- and late-life activity on neurocognitive health. Yet, few studies have examined how engagement in enriching activities during childhood, when the brain is most plastic, may confer long-term neurocognitive benefits that may be especially important to individuals raised in low-income settings. We examined associations between enriching early-life activities (EELAs) and hippocampal and amygdala volumes in a sample of predominantly African-American, community-dwelling older adults. We further assessed whether these associations were independent of current activity engagement. Ninety participants from the baseline Brain Health Substudy of the Baltimore Experience Corps Trial (mean age: 67.4) completed retrospective activity inventories and an magnetic resonance imaging scan. Volumes were segmented using FreeSurfer. Each additional EELA was associated with a 2.3% (66.6 mm3) greater amygdala volume after adjusting for covariates. For men, each additional EELA was associated with a 4.1% (278.9 mm3) greater hippocampal volume. Associations were specific to these regions when compared with the thalamus, used as a control region. Enriching lifestyle activities during an important window of childhood brain development may be a modifiable factor that impacts lifelong brain reserve, and results highlight the importance of providing access to such activities in historically underserved populations.

Association of hippocampal volume with gait variability in pre-dementia and dementia stages of Alzheimer disease: Results from a cross-sectional study.

Decreased hippocampal volume is a biomarker of Alzheimer disease (AD). The association of hippocampal volume with gait variability across the spectrum of AD, especially in early stages, has been few studied. The study aims to examine the association of hippocampal volume with the coefficient of variation (CoV) of stride time in individuals with mild and moderate to severe subjective cognitive impairment (SCI), non-amnestic mild cognitive impairment (na-MCI), amnestic mild cognitive impairment (a-MCI), and mild to moderate AD dementia. 271 individuals (79 mild SCI, 68 moderate to severe SCI, 47 na-MCI, 42 a-MCI and 35 mild to moderate AD dementia) were included in this cross-sectional study. Hippocampal volume was quantified from a three-dimensional T1-weighted MRI. CoV of stride time was recorded at self-selected pace with an electronic walkway. Age, sex, body mass index, number of drugs daily taken, history of falls, walking speed, type of MRI scanner, total intracranial volume, and white matter volume abnormality were used as covariates. Participants with moderate to severe SCI had a higher CoV of stride time compared to those with mild SCI and na-MCI (P < 0.010), and a higher hippocampal volume compared to other groups (P ≤ 0.001). Participants with moderate to severe SCI had increased hippocampal volume associated with increased CoV of stride time (coefficient of regression β = 0.750 with P = 0.041), while the other groups did not show any significant association. A positive association between greater hippocampal volume (i.e., better brain morphological structure) and an increased stride time variability (i.e., worse gait performance) in individuals with moderate to severe SCI is reported. This association confirms the key role of the hippocampus in gait control and suggests an inefficient compensatory mechanism in early stages of pathological aging like AD.

Influence of cerebrovascular disease on brain networks in prodromal and clinical Alzheimer's disease.

Network-sensitive neuroimaging methods have been used to characterize large-scale brain network degeneration in Alzheimer's disease and its prodrome. However, few studies have investigated the combined effect of Alzheimer's disease and cerebrovascular disease on brain network degeneration. Our study sought to examine the intrinsic functional connectivity and structural covariance network changes in 235 prodromal and clinical Alzheimer's disease patients with and without cerebrovascular disease. We focused particularly on two higher-order cognitive networks-the default mode network and the executive control network. We found divergent functional connectivity and structural covariance patterns in Alzheimer's disease patients with and without cerebrovascular disease. Alzheimer's disease patients without cerebrovascular disease, but not Alzheimer's disease patients with cerebrovascular disease, showed reductions in posterior default mode network functional connectivity. By comparison, while both groups exhibited parietal reductions in executive control network functional connectivity, only Alzheimer's disease patients with cerebrovascular disease showed increases in frontal executive control network connectivity. Importantly, these distinct executive control network changes were recapitulated in prodromal Alzheimer's disease patients with and without cerebrovascular disease. Across Alzheimer's disease patients with and without cerebrovascular disease, higher default mode network functional connectivity z-scores correlated with greater hippocampal volumes while higher executive control network functional connectivity z-scores correlated with greater white matter changes. In parallel, only Alzheimer's disease patients without cerebrovascular disease showed increased default mode network structural covariance, while only Alzheimer's disease patients with cerebrovascular disease showed increased executive control network structural covariance compared to controls. Our findings demonstrate the differential neural network structural and functional changes in Alzheimer's disease with and without cerebrovascular disease, suggesting that the underlying pathology of Alzheimer's disease patients with cerebrovascular disease might differ from those without cerebrovascular disease and reflect a combination of more severe cerebrovascular disease and less severe Alzheimer's disease network degeneration phenotype.

Abstract MP059: Incremental Light Activity Associated with Greater Brain Volume in Individuals Not Meeting the Physical Activity Guidelines: Cross Sectional Observations from the Framingham Heart Study

Background: Recent evidence suggests that dementia appears linked to subclinical vascular changes, which may be attenuated by physical activity. The Physical Activity Guidelines for Americans (PA-Guidelines) are currently set at 150 min of moderate-to-vigorous physical activity (MVPA) per week, as a target for adults to achieve favorable health outcomes, but make no specific recommendations for prevention of dementia. Many Americans fall well below the PA-Guidelines. The aim of this investigation was to determine whether there is a continuum of lower intensities and volumes of physical activity associated with healthy brain aging even in individuals not meeting the PA-Guidelines. Methods: We included Framingham Heart Study (FHS) participants who wore an Actical accelerometer for ≥3 valid days (&gt;10 h wear time per day) on their right hip during the most recent cohort examinations and completed brain magnetic resonance imaging (MRI) an average of 1.7 (±0.9) years later (n=2534): Offspring exam 9, Third Generation exam 2, and corresponding examinations of the Omni cohorts. Participants were excluded from this analysis if they had prevalent stroke or dementia (n=63) or met the 150 min MVPA per week PA-Guidelines (n=1158). Non-wear time (defined as 60 min of zero-counts, with two interruptions allowed) was removed. Sedentary time (&lt;200 counts/min, &lt;1.5 metabolic equivalents [METs]) and light activity (201-1485 counts/min, 1.5-3 METs) were only accumulated during 6 am-10 pm, were represented as proportions of wear time to account for differences in wear time among participants, and standardized to a 16 h day. MVPA (&gt;1486 counts/min, ≥3 METs) and steps were accumulated at any time of day. The relations of physical activity measures to brain MRI measures were assessed using multivariable linear regression. Results: More than 53% of FHS participants did not meet the PA-Guidelines for MVPA during their last exam, and were thus included in this investigation (n=1313, 56 [±14] years old, 60% women). These participants took an average of 6149 [±3079] steps, spent 10.5 [±6.1] min MVPA, 13 h 36 min [±48 min] sedentary and 2 h 14 min [±48 min] in light activities per day. Each additional 40 min of light activity (spent in 1.5-3 METs) or 42 min less time spent sedentary was associated with 0.22% [±0.07%] greater total cerebral brain volume (TCBV), after adjusting for age, sex, body mass index, smoking, diabetes mellitus, and cardiovascular disease (p=0.001), equivalent to approximately 1.1 years less brain aging. Greater light activity and lower sedentary time were also associated with greater hippocampal volume (p&lt;0.005). Conclusions: Our investigation demonstrates, in a community setting, that there may be a negative association of light physical activity with brain aging even among individuals not meeting the PA-Guidelines for MVPA.

Hippocampal Response to a 24-Month Physical Activity Intervention in Sedentary Older Adults

Greater hippocampal volume is observed in healthy older adults after short-term structured exercise. Whether long-term exposure to real-world physical activity (PA) programs has similar effects for sedentary older adults with impaired mobility and comorbid conditions is not known. A long-term moderate intensity regimen of PA is related to larger volume of the hippocampus in older adults at risk for mobility disability. We further explore whether these associations are modified by factors known to be related to dementia. Twenty-six sedentary adults at risk for mobility disability participated in a 24-month randomized intervention program of physical activity (PA, N = 10, age: 74.9 years, 7 women) or health education (HE, N = 16, age: 76.8 years, 14 women). Volumes of total hippocampus, dentate gyrus, and cornu ammonis were measured at baseline and at 24-month follow-up using 7-Tesla magnetic resonance imaging. Between-group volumetric differences at 24 months were adjusted for sessions attended and baseline volumes. The contribution of each dementia-related factor was tested separately for education, APOE, diabetes, cardiovascular diseases, white matter hyperintensities, and brain atrophy. Between-group differences were significant for left hippocampus, left cornu ammonis, and right hippocampus. Adjustment for regional baseline volume attenuated the associations to statistically nonsignificant for right hippocampus and left conru ammonis; associations for left hippocampus were robust for all adjustments. Results were similar after adjustment for dementia-related factors. In this group of sedentary older adults there was a hippocampal response to a long-term program of moderate-intensity PA. Future studies should examine whether hippocampal response could explain the beneficial effects of PA on cognition for vulnerable older adults.