Rethinking the residual approach: Leveraging machine learning to operationalize cognitive resilience in Alzheimer's disease.

Cognitive resilience describes the phenomenon of individuals evading cognitive decline despite prominent Alzheimer's disease neuropathology. Operationalization and measurement of this latent construct is non-trivial as it cannot be directly observed. The residual approach has been widely applied to estimate CR, where the degree of resilience is estimated through a linear model's residuals. We demonstrate that this approach makes specific, uncontrollable assumptions and likely leads to biased and erroneous resilience estimates. We propose an alternative strategy which overcomes the standard approach's limitations using machine learning principles. Our proposed approach makes fewer assumptions about the data and construct to be measured and achieves better estimation accuracy on simulated ground-truth data.

Leptin bioavailability and markers of brain atrophy and vascular injury in the middle age.

INTRODUCTION: We investigated the associations of leptin markers with cognitive function and magnetic resonance imaging (MRI) measures of brain atrophy and vascular injury in healthy middle-aged adults. METHODS: We included 2262 cognitively healthy participants from the Framingham Heart Study with neuropsychological evaluation; of these, 2028 also had available brain MRI. Concentrations of leptin, soluble leptin receptor (sOB-R), and their ratio (free leptin index [FLI]), indicating leptin bioavailability, were measured using enzyme-linked immunosorbent assays. Cognitive and MRI measures were derived using standardized protocols. RESULTS: Higher sOB-R was associated with lower fractional anisotropy (FA, ß = -0.114 ± 0.02, p < 0.001), and higher free water (FW, ß = 0.091 ± 0.022, p < 0.001) and peak-width skeletonized mean diffusivity (PSMD, ß = 0.078 ± 0.021, p < 0.001). Correspondingly, higher FLI was associated with higher FA (ß = 0.115 ± 0.027, p < 0.001) and lower FW (ß = -0.096 ± 0.029, p = 0.001) and PSMD (ß = -0.085 ± 0.028, p = 0.002). DISCUSSION: Higher leptin bioavailability was associated with better white matter (WM) integrity in healthy middle-aged adults, supporting the putative neuroprotective role of leptin in late-life dementia risk. HIGHLIGHTS: Higher leptin bioavailability was related to better preservation of white matter microstructure. Higher leptin bioavailability during midlife might confer protection against dementia. Potential benefits might be even stronger for individuals with visceral obesity. DTI measures might be sensitive surrogate markers of subclinical neuropathology.

Protocol for hybrid structured-light three-dimensional scanning and modeling of human postmortem brains.

Despite numerous neuropathological criteria for the evaluation of microscopic tissue slides, there are no systemic standards for sectioning postmortem human brain tissue. Here, we present a protocol for postmortem brain hybrid structured-light scanning to facilitate 3D printing of sectioning matrices. We describe steps for tissue preparation, 3D scanning and printing, and matrix-guided sectioning. This protocol can be used for streamlining tissue histopathology as well as in brain morphology volumetric analyses and applications in medical education. For complete details on the use and execution of this protocol, please refer to Barannikov et al.1.

Association of longitudinal changes in 24-h blood pressure level and variability with cognitive decline.

OBJECTIVE: A high office blood pressure (BP) is associated with cognitive decline. However, evidence of 24-h ambulatory BP monitoring is limited, and no studies have investigated whether longitudinal changes in 24-h BP are associated with cognitive decline. We aimed to test whether higher longitudinal changes in 24-h ambulatory BP measurements are associated with cognitive decline. METHODS: We included 437 dementia-free participants from the Maracaibo Aging Study with prospective data on 24-h ambulatory BP monitoring and cognitive function, which was assessed using the selective reminding test (SRT) and the Mini-Mental State Examination (MMSE). Using multivariate linear mixed regression models, we analyzed the association between longitudinal changes in measures of 24-h ambulatory BP levels and variability with cognitive decline. RESULTS: Over a median follow-up of 4 years (interquartile range, 2-5 years), longitudinal changes in 24-h BP level were not associated with cognitive function (P ≥ 0.09). Higher longitudinal changes in 24-h and daytime BP variability were related to a decline in SRT-delayed recall score; the adjusted scores lowered from -0.10 points [95% confidence interval (CI), -0.16 to -0.04) to -0.07 points (95% CI, -0.13 to -0.02). We observed that a higher nighttime BP variability during follow-up was associated with a decline in the MMSE score (adjusted score lowered from -0.08 to -0.06 points). CONCLUSION: Higher 24-h BP variability, but not BP level, was associated with cognitive decline. Prior to or in the early stages of cognitive decline, 24-h ambulatory BP monitoring might guide strategies to reduce the risk of major dementia-related disorders including Alzheimer's disease.

Biological and Methodological Variability in Retinal Nerve Fiber Layer OCT: The Framingham Heart Study.

Objective: To explore participant-level biological attributes and scan-level methodological attributes associated with retinal nerve fiber layer (RNFL) thickness variability in a population-based sample of elderly United States adults. Design: Cross-sectional analysis using data from the Framingham Heart Study. Participants: One thousand three hundred forty-seven eyes from 825 participants with ≥1 OCT scan and axial length data were included. Methods: Three or more successive RNFL scans of each eye of each participant were obtained in a single session. Multivariable linear mixed models were employed to explore the associations between average RNFL thickness with participant-level biological attributes (age, gender, race, ethnicity, and axial length) and scan-level attributes (signal strength [SS]) as independent variables in the whole population as well as a subsample of adults with no self-reported history of glaucoma. Similar analyses were designed to assess methodological variability with average within-eye standard deviation (SD) for repeated scans as the dependent variable. Main Outcomes Measures: (1) Biological variability: average RNFL thickness, and (2) methodological variability: average within-participant SD across repeated scans. Results: Age (ß =  - 0.19 microns/year, [95% confidence interval {CI}: - 0.29, - 0.09]), female gender (ß = +1.48 microns vs. male, [95% CI: 0.09, 2.86]), axial length (ß =  - 1.24 microns/mm of greater length, [95% CI: - 1.80, - 0.67]), and SS (ß = +1.62 microns/1 unit greater SS, [95% CI: 1.16, 2.09]) were significantly associated with RNFL thickness, while race and ethnicity were not (P > 0.05). In analyses designed to assess methodological variability, higher RNFL thickness (ß = +0.02 per micron increase, [95% CI: 0.01, 0.03]), and lower SS (ß = +0.19 per 1 unit lower SS, [95% CI: 0.10, 0.27]) were significantly associated with greater RNFL variability. In adults with no self-reported history of glaucoma (n of eyes = 1165, n of participants = 712), female gender was not associated with RNFL, while African American race was associated with thicker RNFL (ß = +4.65 microns vs. Whites, [95% CI: 1.28, 8.03]). Conclusions: Retinal nerve fiber layer thickness is lower with older age, male gender, greater axial length, lower SS, and Whites (as compared with African Americans) without self-reported glaucoma. Measurement variability (SD) is higher with greater RNFL thickness and lower SS. Understanding these biological and methodological variations is important to aid in OCT interpretation. Financial Disclosures: Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Differential Patterns of Gut and Oral Microbiomes in Hispanic Individuals with Cognitive Impairment.

Alzheimer's disease and related dementias (ADRD) have been associated with alterations in both oral and gut microbiomes. While extensive research has focused on the role of gut dysbiosis in ADRD, the contribution of the oral microbiome remains relatively understudied. Furthermore, the potential synergistic interactions between oral and gut microbiomes in ADRD pathology are largely unexplored. This study aims to evaluate distinct patterns and potential synergistic effects of oral and gut microbiomes in a cohort of predominantly Hispanic individuals with cognitive impairment (CI) and without cognitive impairment (NC). We conducted 16S rRNA gene sequencing on stool and saliva samples from 32 participants (17 CI, 15 NC; 62.5% female, mean age = 70.4 ± 6.2 years) recruited in San Antonio, Texas, USA. Correlation analysis through MaAslin2 assessed the relationship between participants' clinical measurements (e.g., fasting glucose and blood cholesterol) and their gut and saliva microbial contents. Differential abundance analysis evaluated taxa with significant differences between CI and NC groups, and alpha and beta diversity metrics assessed within-sample and group compositional differences. Our analyses revealed no significant differences between NC and CI groups in fasting glucose or blood cholesterol levels. However, a clear association was observed between gut microbiome composition and levels of fasting glucose and blood cholesterol. While alpha and beta diversity metrics showed no significant differences between CI and NC groups, differential abundance analysis revealed an increased presence of oral genera such as Dialister , Fretibacterium , and Mycoplasma in CI participants. Conversely, CI individuals exhibited a decreased abundance of gut genera, including Shuttleworthia , Holdemania , and Subdoligranulum , which are known for their anti-inflammatory properties. No evidence was found for synergistic contributions between oral and gut microbiomes in the context of ADRD. Our findings suggest that similar to the gut microbiome, the oral microbiome undergoes significant modifications as individuals transition from NC to CI. Notably, the identified oral microbes have been previously associated with periodontal diseases and gingivitis. These results underscore the necessity for further investigations with larger sample sizes to validate our findings and elucidate the complex interplay between oral and gut microbiomes in ADRD pathogenesis.

Identification of a specific APOE transcript and functional elements associated with Alzheimer's disease.

BACKGROUND: The APOE gene is the strongest genetic risk factor for late-onset Alzheimer's Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. METHODS: To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. RESULTS: We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. CONCLUSION: The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

Bridging the gap: Multi-omics profiling of brain tissue in Alzheimer's disease and older controls in multi-ethnic populations.

INTRODUCTION: Multi-omics studies in Alzheimer's disease (AD) revealed many potential disease pathways and therapeutic targets. Despite their promise of precision medicine, these studies lacked Black Americans (BA) and Latin Americans (LA), who are disproportionately affected by AD. METHODS: To bridge this gap, Accelerating Medicines Partnership in Alzheimer's Disease (AMP-AD) expanded brain multi-omics profiling to multi-ethnic donors. RESULTS: We generated multi-omics data and curated and harmonized phenotypic data from BA (n = 306), LA (n = 326), or BA and LA (n = 4) brain donors plus non-Hispanic White (n = 252) and other (n = 20) ethnic groups, to establish a foundational dataset enriched for BA and LA participants. This study describes the data available to the research community, including transcriptome from three brain regions, whole genome sequence, and proteome measures. DISCUSSION: The inclusion of traditionally underrepresented groups in multi-omics studies is essential to discovering the full spectrum of precision medicine targets that will be pertinent to all populations affected with AD. HIGHLIGHTS: Accelerating Medicines Partnership in Alzheimer's Disease Diversity Initiative led brain tissue profiling in multi-ethnic populations. Brain multi-omics data is generated from Black American, Latin American, and non-Hispanic White donors. RNA, whole genome sequencing and tandem mass tag proteomicsis completed and shared. Multiple brain regions including caudate, temporal and dorsolateral prefrontal cortex were profiled.

Associations of cerebral amyloid beta and tau with cognition from midlife.

INTRODUCTION: Understanding early neuropathological changes and their associations with cognition may aid dementia prevention. This study investigated associations of cerebral amyloid and tau positron emission tomography (PET) retention with cognition in a predominately middle-aged community-based cohort and examined factors that may modify these relationships. METHODS: 11C-Pittsburgh compound B amyloid and 18F-flortaucipir tau PET imaging were performed. Associations of amyloid and tau PET with cognition were evaluated using linear regression. Interactions with age, apolipoprotein E (APOE) ε4 status, and education were examined. RESULTS: Amyloid and tau PET were not associated with cognition in the overall sample (N = 423; mean: 57 ± 10 years; 50% female). However, younger age (< 55 years) and APOE ε4 were significant effect modifiers, worsening cognition in the presence of higher amyloid and tau. DISCUSSION: Higher levels of Aß and tau may have a pernicious effect on cognition among APOE ε4 carriers and younger adults, suggesting a potential role for targeted early interventions. HIGHLIGHTS: Risk and resilience factors influenced cognitive vulnerability due to Aß and tau. Higher fusiform tau associated with poorer visuospatial skills in younger adults. APOE ε4 interacted with Aß and tau to worsen cognition across multiple domains.

Admixture mapping of cognitive function in diverse Hispanic and Latino adults: Results from the Hispanic Community Health Study/Study of Latinos.

INTRODUCTION: We conducted admixture mapping and fine-mapping analyses to identify ancestry-of-origin loci influencing cognitive abilities. METHODS: We estimated the association of local ancestry intervals across the genome with five neurocognitive measures in 7140 diverse Hispanic and Latino adults (mean age 55 years). We prioritized genetic variants in associated loci and tested them for replication in four independent cohorts. RESULTS: We identified nine local ancestry-associated regions for the five neurocognitive measures. There was strong biological support for the observed associations to cognitive function at all loci and there was statistical evidence of independent replication at 4q12, 9p22.1, and 13q12.13. DISCUSSION: Our study identified multiple novel loci harboring genes implicated in cognitive functioning and dementia, and uncovered ancestry-relevant genetic variants. It adds to our understanding of the genetic architecture of cognitive function in Hispanic and Latino adults and demonstrates the power of admixture mapping to discover unique haplotypes influencing cognitive function, complementing genome-wide association studies. HIGHLIGHTS: We identified nine ancestry-of-origin chromosomal regions associated with five neurocognitive traits. In each associated region, we identified single nucleotide polymorphisms (SNPs) that explained, at least in part, the admixture signal and were tested for replication in independent samples of Black, non-Hispanic White, and Hispanic/Latino adults with the same or similar neurocognitive tests. Statistical evidence of independent replication of the prioritized SNPs was observed for three of the nine associations, at chr4q12, chr9p22.1, and chr13q12.13. At all loci, there was strong biological support for the observed associations to cognitive function and dementia, prioritizing genes such as KIT, implicated in autophagic clearance of neurotoxic proteins and on mast cell and microglial-mediated inflammation; SLC24A2, implicated in synaptic plasticity associated with learning and memory; and MTMR6, implicated in phosphoinositide lipids metabolism.

Dementia Prevalence and Onchocerca volvulus Infection among Rural Elderly Persons in the Ntui Health District, Cameroon: A Population-Based Study.

Recent research suggests that infection with Onchocerca volvulus induces neurocognitive decline. This study sought to compare the cognitive outcomes of elderly persons based on onchocerciasis infection status and report the overall prevalence of dementia in the rural Ntui Health District in Cameroon. A community-based approach was used to recruit 103 participants aged ≥60 years. Dementia screening was done using the Community Screening Interview for Dementia (CSID) tool with a cut-off value of ≤29.5. O. volvulus infection was determined via microscopic examination of skin snips and serological testing of Ov16 antibodies using rapid diagnostic tests. Overall, the prevalence of dementia was 10.7%. Among the tested individuals, 17.9% (15/84) and 62.1% (41/66) were positive for O. volvulus and Ov16 antibodies, respectively. A multivariable linear regression model of CSID scores found a significant positive association with education level (8.654; 95% CI: 2.0870 to 15.222). However, having a positive skin snip for O. volvulus (-3.399; 95% CI: -6.805 to 0.007) and inhaling tobacco (-5.441; 95% CI: -9.137 to -1.744) tended to lower the CSID scores. Ongoing onchocerciasis transmission in the Ntui Health District may constitute a risk factor for dementia. Strengthening onchocerciasis elimination and adopting healthier lifestyles would contribute to dementia prevention among the elderly residing in endemic communities.

Proteogenomics in cerebrospinal fluid and plasma reveals new biological fingerprint of cerebral small vessel disease.

Cerebral small vessel disease (cSVD) is a leading cause of stroke and dementia with no specific mechanism-based treatment. We used Mendelian randomization to combine a unique cerebrospinal fluid (CSF) and plasma pQTL resource with the latest European-ancestry GWAS of MRI-markers of cSVD (white matter hyperintensities, perivascular spaces). We describe a new biological fingerprint of 49 protein-cSVD associations, predominantly in the CSF. We implemented a multipronged follow-up, across fluids, platforms, and ancestries (Europeans and East-Asian), including testing associations of direct plasma protein measurements with MRI-cSVD. We highlight 16 proteins robustly associated in both CSF and plasma, with 24/4 proteins identified in CSF/plasma only. cSVD-proteins were enriched in extracellular matrix and immune response pathways, and in genes enriched in microglia and specific microglial states (integration with single-nucleus RNA sequencing). Immune-related proteins were associated with MRI-cSVD already at age twenty. Half of cSVD-proteins were associated with stroke, dementia, or both, and seven cSVD-proteins are targets for known drugs (used for other indications in directions compatible with beneficial therapeutic effects. This first cSVD proteogenomic signature opens new avenues for biomarker and therapeutic developments.

Deep Sleep, Olfactory Loss, and Cognition in Early-stage Parkinson's Disease: Pilot Study Results.

Individuals with Parkinson's disease (PD) have a higher risk of developing dementia compared to age-matched controls. Rapid eye movement sleep behavior disorder (RBD) and hyposmia can influence symptoms severity. We report associations between polysomnography-assessed sleep architecture, olfactory identification, and cognition. Twenty adults with early-stage PD (mean age 69 ± 7.9; 25% female) completed cognitive assessments, the Brief Smell Identification Test (BSIT), and overnight in-clinic polysomnography. A global cognitive score was derived from principal component analysis. Linear regression models examined associations between sleep variables, BSIT performance, and cognition. Cognitive performance was compared between participants with and without RBD. Deep sleep attainment (ß ± SE: 1.18 ± 0.45, p = .02) and olfactory identification (0.37 ± 0.12, p = .01) were associated with better cognition. Light sleep, REM sleep, arousal index, and sleep efficiency were not (all p > .05). Participants with RBD had significantly worse cognition (t-test = -1.06 ± 0.44, p = .03) compared to those without RBD; none entered deep sleep. Deep sleep attainment was associated with better memory (1.20 ± 0.41, p = .01) and executive function (2.94 ± 1.13, p = .02); sleep efficiency was associated with executive function (0.05 ± 0.02, p = .02). These findings suggest interrelationships between lack of deep sleep, hyposmia, and poorer cognition in PD, particularly among individuals with RBD. Assessing these markers together may improve early identification of high-risk individuals and access to interventions.

Cerebrovascular reactivity MRI as a biomarker for cerebral small vessel disease-related cognitive decline: Multi-site validation in the MarkVCID Consortium.

INTRODUCTION: Vascular contributions to cognitive impairment and dementia (VCID) represent a major factor in cognitive decline in older adults. The present study examined the relationship between cerebrovascular reactivity (CVR) measured by magnetic resonance imaging (MRI) and cognitive function in a multi-site study, using a predefined hypothesis. METHODS: We conducted the study in a total of three analysis sites and 263 subjects. Each site performed an identical CVR MRI procedure using 5% carbon dioxide inhalation. A global cognitive measure of Montreal Cognitive Assessment (MoCA) and an executive function measure of item response theory (IRT) score were used as outcomes. RESULTS: CVR and MoCA were positively associated, and this relationship was reproduced at all analysis sites. CVR was found to be positively associated with executive function. DISCUSSION: The predefined hypothesis on the association between CVR and a global cognitive score was validated in three independent analysis sites, providing support for CVR as a biomarker in VCID. HIGHLIGHTS: This study measured a novel functional index of small arteries referred to as cerebrovascular reactivity (CVR). CVR was positively associated with global cognition in older adults. This finding was observed in three independent cohorts at three sites. Our statistical analysis plan was predefined before beginning data collection.

Associations of Physical Activity Engagement with Cerebral Amyloid-ß and Tau from Midlife.

Background: Higher midlife physical activity engagement has been associated with lower dementia risk in late life. However, the underlying mechanisms contributing to the protective effect remain unclear. Objective: The goal of the current study was to evaluate the associations of physical activity with cerebral amyloid-ß (Aß) and tau in a predominately middle-aged community-based cohort, as well as to explore whether the associations differ by sex or age. Methods: Participants from the Framingham Heart Study underwent 11C-Pittsburgh Compound B amyloid and 18F-Flortaucipir tau positron emission tomography (PET) imaging. Total physical activity levels were evaluated by self-report using the Physical Activity Index (PAI). Cross-sectional associations between total PAI with regional Aß and tau PET retention were evaluated using linear regression models adjusted for demographic and cardiovascular risk factors. Interactions with sex and age group were examined and stratified analyses were performed when significant. FDR-correction for multiple comparisons was applied. Results: The sample included 354 participants (mean age 53±8 years, 51% female). Higher total PAI scores were associated with lower entorhinal cortex tau PET binding (ß (SE) = -0.021(0.008), p = 0.049). There were significant interactions with sex. In men alone, total PAI inversely associated with entorhinal cortex (ß (SE) = -0.035(0.009), p = 0.001), inferior temporal (ß (SE) = -0.029(0.010), p = 0.012), and rhinal cortex tau(ß (SE) = -0.033(0.010), p = 0.002). Conclusions: The results suggest that higher midlife physical activity engagement may confer resistance to tau pathology. However, the effects may vary based on sex, highlighting the importance of better understanding and tailoring lifestyle interventions to address sex disparities.

Associations Between Stroke Type, Ischemic Stroke Subtypes, and Post-Stroke Cognitive Trajectories.

Background: It is unclear how post-stroke cognitive trajectories differ by stroke type and ischemic stroke subtype. We studied associations between stroke types (ischemic, hemorrhagic), ischemic stroke subtypes (cardioembolic, large artery atherosclerotic, lacunar/small vessel, cryptogenic/other determined etiology), and post-stroke cognitive decline. Methods: This pooled cohort analysis from four US cohort studies (1971-2019) identified 1,143 dementia-free individuals with acute stroke during follow-up: 1,061 (92.8%) ischemic, 82 (7.2%) hemorrhagic, 49.9% female, 30.8% Black. Median age at stroke was 74.1 (IQR, 68.6, 79.3) years. Outcomes were change in global cognition (primary) and changes in executive function and memory (secondary). Outcomes were standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median follow-up for the primary outcome was 6.0 (IQR, 3.2, 9.2) years. Linear mixed-effects models estimated changes in cognition after stroke. Results: On average, the initial post-stroke global cognition score was 50.78 points (95% CI, 49.52, 52.03) in ischemic stroke survivors and did not differ in hemorrhagic stroke survivors (difference, -0.17 points [95% CI, -1.64, 1.30]; P=0.82) after adjusting for demographics and pre-stroke cognition. On average, ischemic stroke survivors showed declines in global cognition, executive function, and memory. Post-stroke declines in global cognition, executive function, and memory did not differ between hemorrhagic and ischemic stroke survivors. 955 ischemic strokes had subtypes: 200 (20.9%) cardioembolic, 77 (8.1%) large artery atherosclerotic, 207 (21.7%) lacunar/small vessel, 471 (49.3%) cryptogenic/other determined etiology. On average, small vessel stroke survivors showed declines in global cognition and memory, but not executive function. Initial post-stroke cognitive scores and cognitive declines did not differ between small vessel survivors and survivors of other ischemic stroke subtypes. Post-stroke vascular risk factor levels did not attenuate associations. Conclusion: Stroke survivors had cognitive decline in multiple domains. Declines did not differ by stroke type or ischemic stroke subtype.

Concurrent nutrient deficiencies are associated with dementia incidence.

INTRODUCTION: While observational research suggests a protective role for nutrition in brain aging, intervention studies remain inconclusive. This failing translation from observational to interventional research may result from overlooking nutrient interactions. METHODS: We developed a nutrient status index capturing the number of suboptimal statuses of omega-3 fatty acids, homocysteine, and vitamin D (range 0 to 3). We associated this index with dementia incidence in a subsample (age ≥ 50 years) of the Framingham Heart Study Offspring cohort. RESULTS: Among 968 participants, 79 developed dementia over 15.5 years (median follow-up). Each point increase in nutrient status index was associated with a 50% higher risk of dementia (hazard ratio [HR] = 1.50; 95% confidence interval [CI] = 1.16, 1.96). Participants with three high-risk statuses had a four-fold increased risk of dementia compared to participants without high-risk status (HR = 4.68; 95% CI = 1.69, 12.94). DISCUSSION: Concurrent nutrient deficiencies are associated with the risk of dementia. The potential of optimizing nutritional status to lower dementia risk warrants further study. HIGHLIGHTS: Nutrition and dementia research calls for multiple-nutrient approaches. We studied combined suboptimal statuses of omega-3 polyunsaturated fatty acids, homocysteine, and vitamin D. Suboptimal status of the three nutrients was associated with dementia risk. The risk estimate was larger than for other factors (ie, diabetes, apolipoprotein E Îµ4 carrier). Future studies should assess the effect of improving nutrient status on dementia risk.

Associations of Plasma Tau with Amyloid and Tau PET: Results from the Community-Based Framingham Heart Study.

Background: Associations of plasma total tau levels with future risk of AD have been described. Objective: To examine the extent to which plasma tau reflects underlying AD brain pathology in cognitively healthy individuals. Methods: We examined cross-sectional associations of plasma total tau with 11C-Pittsburgh Compound-B (PiB)-PET and 18F-Flortaucipir (FTP)-PET in middle-aged participants at the community-based Framingham Heart Study. Results: Our final sample included 425 participants (mean age 57.6± 9.9, 50% F). Plasma total tau levels were positively associated with amyloid-ß deposition in the precuneus region (ß±SE, 0.11±0.05; p = 0.025). A positive association between plasma total tau and tau PET in the rhinal cortex was suggested in participants with higher amyloid-PET burden and in APOEɛ4 carriers. Conclusions: Our study highlights that plasma total tau is a marker of amyloid deposition as early as in middle-age.

The association between levels of brain-derived neurotrophic factor and comorbid depression in patients with cardiovascular disease: The Framingham Heart Study.

AIM: The current study aims to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with symptoms of depression in adults with and without prevalent cardiovascular disease (CVD), an often burdensome comorbidity. METHODS: This cross-sectional study included participants from FHS (Framingham Heart Study) who had available serum BDNF levels. Depressive symptoms were assessed using the Center for Epidemiological Studies-Depression Scale (CES-D) with a score ≥16 indicating mild to moderate and ≥21 severe depression. Participants taking antidepressant medications were excluded from the study. RESULTS: Altogether 3716 FHS participants were included in the final analysis (mean age, 64.3 ± 11.5 years; 55% women). After adjusting for potential confounders, greater BDNF levels were associated with reduced severe depression risk (odds ratio [OR], 0.78 [95% CI, 0.64-0.96]; P = 0.016). Among participants with CVD, greater BDNF levels were related to lower risk of depressive symptoms (CES-D ≥ 16 OR, 0.63 [95% CI, 0.45-0.89], P = 0.008; CES-D ≥ 21 OR, 0.49 [95% CI, 0.31-0.76], P = 0.002). The inverse relationship between BDNF and depressive symptom risk was present in women with CVD (CES-D ≥ 16 OR, 0.63 [95% CI, 0.40-0.99], P = 0.047; CES-D ≥ 21 OR, 0.38 [95% CI, 0.21-0.70], P = 0.002) but not in men. CONCLUSION: Lower serum BDNF levels are associated with a higher risk of depressive symptoms in CVD, particularly among women. These findings implicate BDNF in the complex biological mechanisms that underlie prior associations observed between CVD and depression. To reduce the burden of depression in the large proportion of midlife and older adults with CVD, a better understanding of how BDNF may modify these pathways is merited.

Changes in prevalence and incidence of dementia and risk factors for dementia: an analysis from cohort studies.

BACKGROUND: Some cohort studies have reported a decline in dementia prevalence and incidence over time, although these findings have not been consistent across studies. We reviewed evidence on changes in dementia prevalence and incidence over time using published population-based cohort studies that had used consistent methods with each wave and aimed to quantify associated changes in risk factors over time using population attributable fractions (PAFs). METHODS: We searched for systematic reviews of cohort studies examining changes in dementia prevalence or incidence over time. We searched PubMed for publications from database inception up to Jan 12, 2023, using the search terms "systematic review" AND "dementia" AND ("prevalence" OR "incidence"), with no language restrictions. We repeated this search on March 28, 2024. From eligible systematic reviews, we searched the references and selected peer-reviewed publications about cohort studies where dementia prevalence or incidence was measured in the same geographical location, at a minimum of two timepoints, and that reported age-standardised prevalence or incidence of dementia. Additionally, data had to be from population-based samples, in which participants' cognitive status was assessed and where validated criteria were used to diagnose dementia. We extracted summary-level data from each paper about dementia risk factors, contacting authors when such data were not available in the published paper, and calculated PAFs for each risk factor at all available timepoints. Where possible, we linked changes in dementia prevalence or incidence with changes in the prevalence of risk factors. FINDINGS: We identified 1925 records in our initial search, of which five eligible systematic reviews were identified. Within these systematic reviews, we identified 71 potentially eligible primary papers, of which 27 were included in our analysis. 13 (48%) of 27 primary papers reported change in prevalence of dementia, ten (37%) reported change in incidence of dementia, and four (15%) reported change in both incidence and prevalence of dementia. Studies reporting change in dementia incidence over time in Europe (n=5) and the USA (n=5) consistently reported a declining incidence in dementia. One study from Japan reported an increase in dementia prevalence and incidence and a stable incidence was reported in one study from Nigeria. Overall, across studies, the PAFs for less education or smoking, or both, generally declined over time, whereas PAFs for obesity, hypertension, and diabetes generally increased. The decrease in PAFs for less education and smoking was associated with a decline in the incidence of dementia in the Framingham study (Framingham, MA, USA, 1997-2013), the only study with sufficient data to allow analysis. INTERPRETATION: Our findings suggest that lifestyle interventions such as compulsory education and reducing rates of smoking through country-level policy changes could be associated with an observed reduction, and therefore future reduction, in the incidence of dementia. More studies are needed in low-income and middle-income countries, where the burden of dementia is highest, and continues to increase. FUNDING: National Institute for Health and Care Research Three Schools' Dementia Research Programme.