Background

Recent studies showed that polymorphisms in the Fat and Obesity-Associated (FTO) gene have robust effects on obesity, obesity-related traits and endophenotypes associated with Alzheimer's disease (AD).

Methods

We used 1,877 Caucasian cases and controls from the NIA-LOAD study and 1,093 Caribbean Hispanics to further explore the association of FTO with AD. Using logistic regression, we assessed 42 SNPs in introns 1 and 2, the region previously reported to be associated with AD endophenotypes, which had been derived by genome-wide screenings. In addition, we performed gene expression analyses of neuropathologically confirmed AD cases and controls of two independent datasets (19 AD cases, 10 controls; 176 AD cases, 188 controls) using within- and between-group factors ANOVA of log(10) transformed rank invariant normalized expression data.

Results

In the NIALOAD study, one SNP was significantly associated with AD and three additional markers were close to significance (rs6499640, rs10852521, rs16945088, rs8044769, FDR p-value: 0.050.9) with the previously reported SNPs. In the Caribbean Hispanic dataset, we identified three SNPs (rs17219084, rs11075996, rs11075997, FDR p-value: 0.009ConclusionsOur data support the notion that genetic variation in Introns 1 and 2 of the FTO gene may contribute to AD risk.

Verbal fluency tasks are generally thought to be mediated by frontal brain regions for letter fluency and temporal regions for category fluency. This idea, however, is primarily based on lesion studies and adapted versions of the fluency tasks in functional neuroimaging, without fundamental evidence from structural neuroimaging in healthy individuals. We investigated the cortical structural correlates of letter and category fluency, including overlapping and different regions, in 505 individuals who participated in a community-based study of healthy aging. The correlation between cortical thickness and verbal fluency in whole-brain analyses revealed distinct cortical signatures for letter fluency, primarily in frontal regions, and category fluency, in frontal and temporal-parietal regions. There was a dissociation in the left inferior frontal gyrus between letter and category fluency, with increased thickness in the posterior-dorsal versus anterior-ventral parts, respectively. These results distinguish the detailed anatomical correlates for verbal fluency within the coarse frontal-temporal distinction inferred from lesion studies and among the mixture of regions identified in functional neuroimaging. The evidence for the anatomical substrates of letter and category fluency, each recruiting slightly different language and cognitive processes, can serve both clinical applications as well as a deeper theoretical understanding of the organization of the cerebral cortex.

In normal aging, the cognitive domain of semantic memory remains preserved, while the domain of episodic memory declines to some extent. In Alzheimers disease dementia, both semantic and episodic memory become impaired early in the disease process. Given the need to develop sensitive and accessible cognitive markers for early detection of dementia, we investigated among older adults without dementia whether item-level metrics of semantic fluency related to episodic memory decline above and beyond existing neuropsychological measures and total fluency score. Participants were drawn from the community-based Washington Heights-Inwood Columbia Aging Project cohort (N = 583 English speakers, Mage = 76.3 ± 6.8) followed up to five visits across up to 11 years. We examined the association of semantic fluency metrics with subsequent declines in memory performance using latent growth curve models covaried for age and recruitment wave. Results showed that item-level metrics (e.g., lexical frequency, age of acquisition, and semantic neighborhood density) were associated with a decline in episodic memory-even when covarying for other cognitive tests-while the standard total score was not. Moderation analyses showed that the relationship of semantic fluency metrics with memory decline did not differ across race, sex/gender, or education. In conclusion, item-level data hold a wealth of information with potential to reveal subtle semantic memory impairment, which tracks with episodic memory impairment, among older adults without dementia beyond existing neuropsychological measures. Implementation of psycholinguistic metrics may point to cognitive tools that have better prognostic value or are more sensitive to cognitive change in the context of clinical trials or observational studies. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Objective

To investigate genetic variants influencing white matter hyperintensities (WMHs) in the understudied Hispanic population.

Methods

Using 6.8 million single nucleotide polymorphisms (SNPs), we conducted a genome-wide association study (GWAS) to identify SNPs associated with WMH volume (WMHV) in 922 Hispanics who underwent brain MRI as a cross-section of 2 community-based cohorts in the Northern Manhattan Study and the Washington Heights-Inwood Columbia Aging Project. Multiple linear modeling with PLINK was performed to examine the additive genetic effects on ln(WMHV) after controlling for age, sex, total intracranial volume, and principal components of ancestry. Gene-based tests of association were performed using VEGAS. Replication was performed in independent samples of Europeans, African Americans, and Asians.

Results

From the SNP analysis, a total of 17 independent SNPs in 7 genes had suggestive evidence of association with WMHV in Hispanics (p < 1 × 10^-5) and 5 genes from the gene-based analysis with p < 1 × 10^-3. One SNP (rs9957475 in GATA6) and 1 gene (UBE2C) demonstrated evidence of association (p < 0.05) in the African American sample. Four SNPs with p < 1 × 10^-5 were shown to affect binding of SPI1 using RegulomeDB.

Conclusions

This GWAS of 2 community-based Hispanic cohorts revealed several novel WMH-associated genetic variants. Further replication is needed in independent Hispanic samples to validate these suggestive associations, and fine mapping is needed to pinpoint causal variants.

Background & aims

Evidence suggests that consuming light-to-moderate amounts of alcohol reduces the risk of dementia and is associated better cognitive function and less cardiovascular disease, relative to those consuming no or heavy alcohol. There are only minimal data on the association between alcohol and brain magnetic resonance imaging (MRI) markers. This study aimed to examine the association between alcohol and brain structure measured with MRI.

Methods

In this cross-sectional study, high-resolution structural MRI was collected on 589 multi-ethnic community residents of New York aged ≥65 with available alcohol intake assessments via a food frequency questionnaire. Total brain volume (TBV), white matter hyperintensity volume (WMHV), and presence of infarcts were derived from MRI scans with established methods. We examined the association of alcohol intake with these imaging markers using regression models adjusted for demographic, clinical, and vascular risk factors.

Results

Compared to non-drinking, light-to-moderate total alcohol (b = 0.007, p = 0.04) or wine (b = 0.008, p = 0.05) intake, but not beer or liquor intake, was associated with larger TBV. Further analysis showed a dose-response association between alcohol (p-trend = 0.03) or wine (p-trend = 0.006) and TBV. Overall, alcohol intake was not associated with WMHV or brain infarcts.

Conclusions

Our study suggests that among older adults in the community, light-to-moderate alcohol intake, in particular wine, is associated with larger TBV. These findings suggest that light to moderate alcohol consumption is potentially beneficial for brain aging, but replication is needed.

Background

Structural magnetic resonance imaging (MRI) provides key biomarkers to predict onset and track progression of Alzheimer's disease (AD). However, most published reports of relationships between MRI variables and cognition in older adults include racially, ethnically, and socioeconomically homogenous samples. Racial/ethnic differences in MRI variables and cognitive performance, as well as health, socioeconomic status and psychological factors, raise the possibility that brain-behavior relationships may be stronger or weaker in different groups. The current study tested whether MRI predictors of cognition differ in African Americans and Hispanics, compared with non-Hispanic Whites.

Methods

Participants were 638 non-demented older adults (29% non-Hispanic White, 36% African American, 35% Hispanic) in the Washington Heights-Inwood Columbia Aging Project. Composite scores of memory, language, speed/executive functioning, and visuospatial function were derived from a neuropsychological battery. Hippocampal volume, regional cortical thickness, infarcts, and white matter hyperintensity (WMH) volumes were quantified with FreeSurfer and in-house developed procedures. Multiple-group regression analysis, in which each cognitive composite score was regressed onto MRI variables, demographics, and cardiovascular health, tested which paths differed across groups.

Results

Larger WMH volume was associated with worse language and speed/executive functioning among African Americans, but not among non-Hispanic Whites. Larger hippocampal volume was more strongly associated with better memory among non-Hispanic Whites compared with Hispanics. Cortical thickness and infarcts were similarly associated with cognition across groups.

Conclusion

The main finding of this study was that certain MRI predictors of cognition differed across racial/ethnic groups. These results highlight the critical need for more diverse samples in the study of cognitive aging, as the type and relation of neurobiological substrates of cognitive functioning may be different for different groups.

Educational attainment is associated with cognition among older adults, but this association is complex and not well understood. While associated with better cognition among healthy adults, more education predicts faster decline in older adults with cognitive impairment. Education may influence cognitive functioning through mechanisms involving brain maintenance (BM: reduced age-related pathology) or cognitive reserve (CR: altered pathology-cognition association). We examined evidence for each mechanism by quantifying main and interaction effects of education within a well-studied pathway involving systolic blood pressure, white matter hyperintensities (WMH), and episodic memory in 2 samples without dementia at the baseline (total N = 1136). There were no effects of education on systolic blood pressure or WMH, suggesting a lack of evidence for BM. In the sample less likely to progress to dementia, education attenuated the effect of WMH on memory at the baseline. In the sample more likely to progress to dementia, education exacerbated this effect at the baseline. These moderations provide evidence for a CR mechanism and are consistent with previous findings of faster decline once CR is depleted.

Background and objectives

To investigate sociodemographic and medical predictors of incident mild cognitive impairment (MCI) and subsequent course of MCI at follow-up, including sustained MCI diagnosis, classification as cognitively normal, and progression to dementia.

Methods

Within a community-based cohort, diagnoses of MCI were made with a published algorithm. Diagnosis of dementia was based on clinical consensus. Cox regressions estimated hazard ratios of incident MCI associated with several predictors. Modified Poisson regressions estimated relative risks associated with predictors of diagnostic status at follow-up after incidence.

Results

Among 2,903 cognitively normal participants at baseline, 752 developed MCI over an average of 6.3 (SD 4.5) years (incidence rate 56 per 1,000 person-years). Presence of APOE ε4 and higher medical burden increased risk of incident MCI, while more years of education, more leisure activities, and higher income decreased this risk. Of the incident MCI cases, after an average of 2.4 years of follow-up, 12.9% progressed to dementia, 9.6% declined in functioning and did not meet the algorithmic criteria for MCI but did not meet the clinical criteria for dementia, 29.6% continued to meet MCI criteria, and 47.9% no longer met MCI criteria. Multidomain MCI, presence of APOE ε4, depressive symptoms, and antidepressant use increased the risk of progression to dementia.

Discussion

This community-based study showed that almost half of the individuals with incident MCI diagnoses were classified as cognitively normal at follow-up. Predictors of incident MCI demonstrably differed from those of subsequent MCI course; these findings can refine expectations for cognitive and functional course of those presenting with MCI.

Age-related changes in memory are not uniform, even in the absence of dementia. Characterization of non-disease associated cognitive changes is crucial to gain a more complete understanding of brain aging. Episodic memory was investigated in 13,037 ethnically diverse elderly (ages 72 to 85 years) with two to 15 years of follow-up, and with known dementia status, age, sex, education, and APOE genotypes. Adjusted trajectories of episodic memory performance over time were estimated using Latent Class Mixed Models. Analysis was conducted using two samples at baseline evaluation: i) non-cognitively impaired individuals, and ii) all individuals regardless of dementia status. We calculated the age-specific annual incidence rates of dementia in the non-demented elderly (n = 10,220). Two major episodic memory trajectories were estimated: 1) Stable-consisting of individuals exhibiting a constant or improved memory function, and 2) Decliner-consisting of individuals whose memory function declined. The majority of the study participants maintain their memory performance over time. Compared to those with Stable trajectory, individuals characterized as Decliners were more likely to have non-white ethnic background, fewer years of education, a higher frequency of ε4 allele at APOE gene and five times more likely to develop dementia. The steepest decline in episodic memory was observed in Caribbean-Hispanics compared to non-Hispanic whites (p = 4.3 x 10(-15)). The highest incident rates of dementia were observed in the oldest age group, among those of Caribbean-Hispanics ancestry and among Decliners who exhibited rates five times higher than those with Stable trajectories (11 per 100 person-years versus 3 per 100 person-years. Age, education, ethnic background and APOE genotype influence the maintenance of episodic memory. Declining memory is one of the strongest predictors of incident dementia.

Copy number variations (CNVs) are genomic regions that have added (duplications) or deleted (deletions) genetic material. They may overlap genes affecting their function and have been shown to be associated with disease. We previously investigated the role of CNVs in late-onset Alzheimer's disease (AD) and mild cognitive impairment using Alzheimer's Disease Neuroimaging Initiative (ADNI) and National Institute of Aging-Late Onset AD/National Cell Repository for AD (NIA-LOAD/NCRAD) Family Study participants, and identified a number of genes overlapped by CNV calls. To confirm the findings and identify other potential candidate regions, we analyzed array data from a unique cohort of 1617 Caucasian participants (1022 AD cases and 595 controls) who were clinically characterized and whose diagnosis was neuropathologically verified. All DNA samples were extracted from brain tissue. CNV calls were generated and subjected to quality control (QC). 728 cases and 438 controls who passed all QC measures were included in case/control association analyses including candidate gene and genome-wide approaches. Rates of deletions and duplications did not significantly differ between cases and controls. Case-control association identified a number of previously reported regions (CHRFAM7A, RELN and DOPEY2) as well as a new gene (HLA-DRA). Meta-analysis of CHRFAM7A indicated a significant association of the gene with AD and/or MCI risk (P = 0.006, odds ratio = 3.986 (95% confidence interval 1.490-10.667)). A novel APP gene duplication was observed in one case sample. Further investigation of the identified genes in independent and larger samples is warranted.