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INTRODUCTION Alzheimer's disease (AD) neuropathological changes present with amnestic and nonamnestic (atypical) syndromes. The contribution of comorbid neuropathology as a substratum of atypical expression of AD remains under investigated. METHODS We examined whether atypical AD exhibited increased comorbid neuropathology compared to typical AD and if such neuropathologies contributed to the accelerated clinical decline in atypical AD. RESULTS We examined 60 atypical and 101 typical AD clinicopathological cases. The number of comorbid pathologies was similar between the groups (p = 0.09). Argyrophilic grain disease was associated with atypical presentation (p = 0.008) after accounting for sex, age of onset, and disease duration. Vascular brain injury was more common in typical AD (p = 0.022). Atypical cases had a steeper Mini‐Mental Status Examination (MMSE) decline over time (p = 0.033). DISCUSSION Comorbid neuropathological changes are unlikely to contribute to atypical AD presentation and the steeper cognitive decline seen in this cohort. Highlights Autopsy cohort of 60 atypical and 101 typical AD; does comorbid pathology explain atypical presentation? Atypical versus Typical AD: No significant differences in comorbid neuropathologies were found (p = 0.09). Argyrophilic Grain Disease Association: significantly correlates with atypical AD presentations, suggesting a unique neuropathological pattern (p = 0.008). Vascular Brain Injury Prevalence: Vascular brain injury is more common in typical AD than in atypical AD (p = 0.022). Cognitive Decline in Atypical AD: Atypical AD patients experience a steeper cognitive decline measured by MMSE than those with typical AD despite lacking more comorbid neuropathology, highlighting the severity of atypical AD pathogenesis (p = 0.033).

Genome-wide association studies (GWAS) of Alzheimer’s disease are predominantly carried out in European ancestry individuals despite the known variation in genetic architecture and disease prevalence across global populations. We leveraged published GWAS summary statistics from European, East Asian, and African American populations, and an additional GWAS from a Caribbean Hispanic population using previously reported genotype data to perform the largest multi-ancestry GWAS meta-analysis of Alzheimer’s disease and related dementias to date. This method allowed us to identify two independent novel disease-associated loci on chromosome 3. We also leveraged diverse haplotype structures to fine-map nine loci with a posterior probability >0.8 and globally assessed the heterogeneity of known risk factors across populations. Additionally, we compared the generalizability of multi-ancestry- and single-ancestry-derived polygenic risk scores in a three-way admixed Colombian population. Our findings highlight the importance of multi-ancestry representation in uncovering and understanding putative factors that contribute to risk of Alzheimer’s disease and related dementias.

Dementia is increasing globally, expected to affect 153 million people by 2050. Dance is an emerging non-pharmacological evidence-based intervention, that integrates artistic, aesthetic, and physical exercise domains. This umbrella review synthesizes evidence on the effects of dance on brain health in older adults with mild-cognitive impairment (MCI) and dementia. Systematic reviews and meta-analysis were selected according to the PICO (Population, Intervention, Comparison and Outcome): older adults with MCI or dementia; dance interventions; comparison with no intervention or other types of interventions; brain health outcomes (cognitive, physical, and emotional domains). The 10 included systematic reviews indicated potential benefit of dance on cognition, compared to control conditions. The meta-analysis of meta-analysis showed significant effects on global cognition, increasing MoCA (SMD = 0.61, 95% CI: 0.30 to 0.91, p  < 0,001) with high heterogeneity (I² = 67%); MMSE scores (SMD = 0.37, 95% CI: 0.27 to 0.47, p  < 0.001) with low heterogeneity (I² = 0%); and, combined MMSE (SMD = 0.73, 95% CI: 0.58 to 0.87, p  < 0.001) with low heterogeneity (I² = 0%). Significant effects were also observed on cognitive domains, improving TMT-A scores (SMD = 0.23, 95% CI: 0.10 to 0.36, p  < 0,01) with moderate heterogeneity (I² = 36.7%); and, TMT-B scores (SMD = 0.21, 95% CI: 0.09 to 0.32, p  < 0,01) with low heterogeneity (I² = 8%). The overall quality of evidence remains weak: 3 included systematic reviews were rated as critically low-quality, and 7 as low quality. While dance interventions are promising for supporting brain health in older adults with MCI, few systematic reviews have focused on people with dementia. This umbrella review provides a comprehensive evidence synthesis and highlights critical research gaps. Future work should focus on establishing methodological rigor, expanding studies on dementia, and integrating dance into broader brain health frameworks through global, collaborative efforts. Registration: PROSPERO, CRD42024503578.

BACKGROUND Education influences brain health and dementia. However, its impact across regions, specifically Latin America (LA) and the United States (US), is unknown. METHODS A total of 1412 participants comprising controls, patients with Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD) from LA and the US were included. We studied the association of education with brain volume and functional connectivity while controlling for imaging quality and variability, age, sex, total intracranial volume (TIV), and recording type. RESULTS Education influenced brain measures, explaining 24%–98% of the geographical differences. The educational disparities between LA and the US were associated with gray matter volume and connectivity variations, especially in LA and AD patients. Education emerged as a critical factor in classifying aging and dementia across regions. DISCUSSION The results underscore the impact of education on brain structure and function in LA, highlighting the importance of incorporating educational factors into diagnosing, care, and prevention, and emphasizing the need for global diversity in research. Highlights Lower education was linked to reduced brain volume and connectivity in healthy controls (HCs), Alzheimer's disease (AD), and frontotemporal lobar degeneration (FTLD). Latin American cohorts have lower educational levels compared to the those in the United States. Educational disparities majorly drive brain health differences between regions. Educational differences were significant in both conditions, but more in AD than FTLD. Education stands as a critical factor in classifying aging and dementia across regions.

Emerging research suggests adverse childhood experiences (ACEs) have long-lasting impacts on adult brain health, but few studies investigate these effects in older adults. The present study examined ACEs and their relationships to late-life cognitive and mental health among older adults living in the San Francisco Bay Area. 102 cognitively unimpaired older adults [mean age = 75, 58% female, 75% White, 25% Latino, mean education = 17 years] were enrolled in UC San Francisco's Alzheimer's Disease Research Center. Participants completed cognitive measures, the geriatric depression scale, and an ACEs survey (threat ACEs: e.g., abuse, discrimination; deprivation ACEs: e.g., unmet food or healthcare needs, neglect). Kruskal-Wallis tests examined ACEs by sex and ethnicity. Linear regression models examined the effects of threat and deprivation ACEs on cognitive function and depression symptoms controlling for age, sex, and ethnicity. Sex and ethnicity were examined as potential moderators of these relationships. On average, older adults reported 2.6 threat ACEs (range = 0-12) and 0.8 deprivation ACEs (range = 0-6). Females and males reported similar levels of ACEs. Latinos endorsed significantly more threat ACEs ( (1) = 6.0, p = 0.01) and deprivation ACEs ( (1) = 6.6, p = 0.01) compared to Whites. Older adults who reported more deprivation ACEs performed significantly worse on verbal memory (β = -0.30; p = 0.006) and visual memory tasks (β = -0.26, p = 0.04) while controlling for age, sex, and ethnicity. No significant relationships were observed between deprivation and executive functioning, object naming, visual-spatial construction, or depression symptoms (ps>0.50), nor between threat ACEs and any outcome (ps>0.10). Sex and ethnicity did not moderate relationships between ACEs and cognitive and mental health outcomes. Our results suggest that deprivation ACEs may negatively and selectively impact the domain of memory among cognitively unimpaired older adults. Given episodic memory deficits are an early symptom of Alzheimer's disease, this lowered memory function may increase dementia risk. Together, these findings suggest that early life interventions to support the basic needs of children could potentially reduce memory problems in late life. In future studies, cultural differences in the presentation and impacts of ACEs on late-life cognitive and mental health should be examined to inform culturally adaptive interventions to support brain health.

Background White matter hyperintensities (WMHs) are a core manifestation of normal and pathological aging and are potentially linked to geographical differences in social and physical exposomes. Previous studies have not examined the impact of WMHs burden on neurodegeneration and cognition in healthy controls (HCs) and patients with Alzheimer’s disease (AD) and behavioral variant frontotemporal dementia (bvFTD) across geographic regions. This study addressed this gap by assessing the impact of WMHs burden on participants with and without dementia from Latin America (LA) and the United States (US). Methods The study comprised 994 participants, including HCs ( n  = 402), AD ( n  = 359), and bvFTD subjects ( n  = 233) from LA and the US. WMHs and their association with grey matter (GM) atrophy, assessed through GM volume and cortical thickness, were evaluated and compared among groups (HCs, AD, and bvFTD) in LA and the US using a voxel-wise brain imaging approach ( p  < 0.05 family-wise error-corrected for multiple comparisons, minimum cluster size = 50 voxels). Multiple regressions analysis were employed to examine geographic differences in WMHs burden, WMHs-GM associations, and the effect of WMHs on cognitive performance, as assessed by the Mini-Mental State examination. Results In the LA cohort only, higher WMHs load was associated with greater GM atrophy across all groups (HCs, AD, bvFTD), with a specific neurodegenerative pattern involving orbitofrontal, cingulate, and temporal areas. HCs from LA showed a greater WMHs load than their US counterparts, and this effect was dependent on GM atrophy. Finally, WMHs burden negatively impacted cognitive performance in dementia subjects, with a greater effect observed in bvFTD subjects from the US. Conclusion WMHs have a more pronounced impact on neurodegeneration across the LA cohort, with a worse impact on HCs, which also show higher WMHs burden than their US counterparts. This could increase the risk of developing dementia. Moreover, WMHs burden differentially impacts cognition, with a greater negative effect observed in bvFTD subjects from the US. These findings highlight geographic variations in WMHs-related conditions, offering valuable insights for tailored future research.

Brain clocks, which quantify discrepancies between brain age and chronological age, hold promise for understanding brain health and disease. However, the impact of diversity (including geographical, socioeconomic, sociodemographic, sex and neurodegeneration) on the brain-age gap is unknown. We analyzed datasets from 5,306 participants across 15 countries (7 Latin American and Caribbean countries (LAC) and 8 non-LAC countries). Based on higher-order interactions, we developed a brain-age gap deep learning architecture for functional magnetic resonance imaging (2,953) and electroencephalography (2,353). The datasets comprised healthy controls and individuals with mild cognitive impairment, Alzheimer disease and behavioral variant frontotemporal dementia. LAC models evidenced older brain ages (functional magnetic resonance imaging: mean directional error = 5.60, root mean square error (r.m.s.e.) = 11.91; electroencephalography: mean directional error = 5.34, r.m.s.e. = 9.82) associated with frontoposterior networks compared with non-LAC models. Structural socioeconomic inequality, pollution and health disparities were influential predictors of increased brain-age gaps, especially in LAC ( R ² = 0.37, F ² = 0.59, r.m.s.e. = 6.9). An ascending brain-age gap from healthy controls to mild cognitive impairment to Alzheimer disease was found. In LAC, we observed larger brain-age gaps in females in control and Alzheimer disease groups compared with the respective males. The results were not explained by variations in signal quality, demographics or acquisition methods. These findings provide a quantitative framework capturing the diversity of accelerated brain aging. Analyses of neuroimaging datasets from 5,306 participants across 15 countries found generally larger brain-age gaps in Latin American compared with non-Latin American populations, which were influenced by disparities in socioeconomic and health-related factors.

Background Emerging research suggests adverse childhood experiences (ACEs) have long‐lasting impacts on adult brain health, but few studies investigate these effects in older adults. The present study examined ACEs and their relationships to late‐life cognitive and mental health among older adults living in the San Francisco Bay Area. Method 102 cognitively unimpaired older adults [mean age = 75, 58% female, 75% White, 25% Latino, mean education = 17 years] were enrolled in UC San Francisco’s Alzheimer’s Disease Research Center. Participants completed cognitive measures, the geriatric depression scale, and an ACEs survey (threat ACEs: e.g., abuse, discrimination; deprivation ACEs: e.g., unmet food or healthcare needs, neglect). Kruskal‐Wallis tests examined ACEs by sex and ethnicity. Linear regression models examined the effects of threat and deprivation ACEs on cognitive function and depression symptoms controlling for age, sex, and ethnicity. Sex and ethnicity were examined as potential moderators of these relationships. Result On average, older adults reported 2.6 threat ACEs (range = 0‐12) and 0.8 deprivation ACEs (range = 0‐6). Females and males reported similar levels of ACEs. Latinos endorsed significantly more threat ACEs (2(1) = 6.0, p = 0.01) and deprivation ACEs (2(1) = 6.6, p = 0.01) compared to Whites. Older adults who reported more deprivation ACEs performed significantly worse on verbal memory (β = ‐0.30; p = 0.006) and visual memory tasks (β = ‐0.26, p = 0.04) while controlling for age, sex, and ethnicity. No significant relationships were observed between deprivation and executive functioning, object naming, visual‐spatial construction, or depression symptoms (ps>0.50), nor between threat ACEs and any outcome (ps>0.10). Sex and ethnicity did not moderate relationships between ACEs and cognitive and mental health outcomes. Conclusion Our results suggest that deprivation ACEs may negatively and selectively impact the domain of memory among cognitively unimpaired older adults. Given episodic memory deficits are an early symptom of Alzheimer’s disease, this lowered memory function may increase dementia risk. Together, these findings suggest that early life interventions to support the basic needs of children could potentially reduce memory problems in late life. In future studies, cultural differences in the presentation and impacts of ACEs on late‐life cognitive and mental health should be examined to inform culturally adaptive interventions to support brain health.

Objective:The prevalence of dementia is higher among minoritized Hispanic/Latino populations in the U.S. Development of linguistically relevant and validated cognitive assessments are urgently needed to adequately address the care needs of this at-risk group. List learning tasks are widely used to evaluate verbal episodic memory and are consistently shown to be sensitive to memory deficits across variousneurologic etiologies. The aim of this study was to validate a Spanish list learning task developed as a linguistically appropriate measure of memory in a diverse sample of Spanish speaking Bay Area older adults who identify as Hispanic/Latino.Participants and Methods:Cognitive scores were assessed in 72 Spanish-speaking older adults living in the Bay Area, California, originally from different countries across South and Central America [(n=29 with CDR scores of 0; n=31 with CDRs of 0.5; and n=12 with CDR of 1), aged 54-96, 30% male)], who completed the Spanish list learning task and a brief neuropsychological battery. The list learning task contains 9 words, 3 words from 3 different semantic categories. Category exemplars were excluded. Administration includes three immediate recall trials, a 30-second delay free recall, 10-minute delay free and cued recall, and yes/no recognition. In this initial validation study, we selected the 10-minute delay recall trial as our primary variable and looked at several indices of construct validity. We hypothesized delayed free recall would: 1) correlate highly with other episodic memory tasks, and minimally with non-memory tests (controlling for CDR sum of boxes), and 2) show step-wise declines as total CDR increased from 0 to 1 (controlling for age, sex, and education).Results:Delayed recall scores of 30-seconds and 10-minutes showed step-wise declines as CDR scores increased (CDR 0 vs. 1, p<0.001 and CDR 0.5 vs. 1, p=0.001). There were no differences in delayed recall between CDR 0 vs. CDR 0.5 (p>0.05). 10-minute delay showed medium-to-large correlations with UDS Craft Story Delayed Recall (partial r =0.45, p<0.001) and Benson Complex Figure Recall (partial r=0.63, p<0.001). Nonsignificant, weaker associations were observed with measures of executive (F Word Verbal Fluency partial r=0.10, Digit Span Forward partial r=0.12), and language (Animal Fluency partial r=0.18) function.Conclusions:Although there is heterogeneity within Hispanic/Latino populations in the U.S., findings begin to support ecological and construct validity of the Spanish list learning task as a measure of verbal memory in older Spanish-speaking adults in the Bay Area. Supporting ecological validity, delayed recall scores significantly differentiated functionally impaired (CDR=1) from functionally mild or unimpaired older adults (CDR=0 or 0.5), though evidenced less sensitivity differentiating unimpaired from mild stages of illness. The Spanish list learning task evidenced strong construct validity as a measure of episodic memory, including strong correlations with other validated memory tasks, and non-significant correlations with non-memory tasks. Larger studies should account for diversity of Spanish speakers in the U.S to see how region of origin, education, and differences between first- and second-generation Spanish speakers influences performance on the task. Future work incorporating imaging markers of brain structure may help further validate the Spanish list learning task as an appropriate measure of memory.

A multidimensional social exposome (MSE)—the combined lifespan measures of education, food insecurity, financial status, access to healthcare, childhood experiences, and more—may shape dementia risk and brain health over the lifespan, particularly in underserved regions like Latin America. However, the MSE effects on brain health and dementia are unknown. We evaluated 2211 individuals (controls, Alzheimer’s disease, and frontotemporal lobar degeneration) from a non-representative sample across six Latin American countries. Adverse exposomes associate with poorer cognition in healthy aging. In dementia, more complex exposomes correlate with lower cognitive and functional performance, higher neuropsychiatric symptoms, and brain structural and connectivity alterations in frontal-temporal-limbic and cerebellar regions. Food insecurity, financial resources, subjective socioeconomic status, and access to healthcare emerge as critical predictors. Cumulative exposome measures surpass isolated factors in predicting clinical-cognitive profiles. Multiple sensitivity analyses confirm our results. Findings highlight the need for personalized approaches integrating MSE across the lifespan, emphasizing prevention and interventions targeting social disparities. The social exposome—lifelong social and economic adversity—can shape brain health and dementia risk. Here, the authors show that an adverse social exposome is linked to poorer clinical, cognitive, and brain changes in Latin American older adults.