bluuebunny/crossref_metadata_2025 huggingface dataset:
Genetic evidence that the causal association of educational attainment with reduced risk of Alzheimer’s disease is driven by intelligence
Authors: Thorp Jackson G , Mitchell Brittany L , Gerring Zachary F , Ong Jue‐Sheng , Gharahkhani Puya , Derks Eske M , Lupton Michelle K
Published: December 2022

Background

Alzheimer’s disease (AD) is predicted to affect 132 million people by 2050. Targeting modifiable lifestyle risk factors that are associated with an increased risk of AD could prevent a large proportion of dementia cases, allowing people to reach the end of their life dementia free. However, evidence obtained from observational studies does not take into account how risk factors are correlated with one another, and whether they causally contribute to increased AD risk. In this study, we determine whether the relationship between twelve previously speculated AD risk factors and AD susceptibility is consistent with causality using large‐scale genetic data (table 1).

Method

We conduct multivariable Mendelian Randomization (MR) analyses to identify causal risk factors of AD while controlling for genetic pleiotropy, using genetic instruments from the most well powered GWAS studies currently available. We also use GWAS‐by‐subtraction implemented with genomic structural equation modelling (genomic SEM) to understand the cognitive and non‐cognitive components of the causal association of EA on AD risk.

Result

We identified significant positive correlations between AD and physical activity and loneliness, and significant negative correlations with educational attainment (EA), intelligence and household income. Using GWAS‐by‐subtraction to partition EA into cognitive (intelligence) and noncognitive genetic factors, we showed a significant genetic correlation between AD and the cognitive factor, but not the noncognitive factor (figure 1).

Univariable MR found EA, intelligence, household income and the cognitive factor to all be causally protective against AD. Multivariable MR analysis showed that higher intelligence lowers AD risk, independent of EA and household income. There was no evidence that EA lowers AD risk, independent of intelligence. In addition the cognitive (intelligence) component of EA decreased AD risk with no significant influence of the noncognitive factor (table 2).

Conclusion

From the risk factors tested only the cognitive component of EA (i.e., intelligence) is an independent causal risk factor for AD. To reduce incidence of AD this cognitive aspect of EA would need to be modified. It is questionable whether substantial modification of intelligence is achievable through simple interventions such as improving access to extended education.
Higher fiber‐tract myelin levels predict lower longitudinal rates of fibrillar tau independent of amyloid
Authors: Rubinski Anna , Franzmeier Nicolai , Dewenter Anna , Luan Ying , Smith Ruben , Strandberg Olof , Ossenkoppele Rik , Dichgans Martin , Hansson Oskar , Ewers Michael ,   Alzheimer’s Disease Neuroimaging Initiative (ADNI)
Published: December 2022

Background

Fibrillar tau progresses from initial epicenters of high tau accumulation to closely connected cortical regions during the course of Alzheimer’s disease (AD). Myelin ensheaths the interregional axonal connections, where ontogenetically late and thinly myelinated fibers are more susceptible to damage and may propel the propagation of fibrillar tau, as suggested by post‐mortem data (https://doi.org/10.1093/brain/awv236). Here we tested for the first time, in two independent samples of AD patients whether 1) regions connected to epicenters by more thickly myelinated fiber tracts show lower rates of tau‐PET accumulation, and 2) differences in regional amyloid‐PET levels explain the association between myelin and tau‐PET accumulation.

Methods

We included two independently recruited samples with longitudinal AV1451‐tau‐PET of amyloid‐PET positive non‐demented and demented individuals (ADNI: n = 123, mean FU = 1.53[0.69‐3.95] years; BioFINDER: n = 39, mean FU = 1.87[1.21‐2.78] years). Adopting our previously established connectivity‐based prediction approach (https://doi.org/10.1126/sciadv.abd1327), we first determined tau epicenters by selecting the top 10% ROIs with highest tau‐PET uptake. Next, we computed for each tau epicenter the connectivity‐based distance to the ROIs in the remainder of the brain, based on resting‐state fMRI data from the Human Connectome Project (HCP). To determine the myelin levels in the underlying fiber tracts, we reconstructed fiber‐tracts for each epicenter‐to‐ROI pair based on DWI data from HCP and extracted regional myelin‐water‐fraction (MWF) values for each tract from an overlaid myelin‐water‐imaging atlas (https://doi.org/10.1111/jon.12657). In order to test whether fiber tract myelination attenuates the connectivity‐based tau‐spreading, we tested the interaction between epicenter connectivity‐based distance and MWF in the corresponding fiber‐tracts on the rate of tau‐PET accumulation in the connected regions. In a sensitivity analysis restricted to the sufficiently powered ADNI‐sample, we controlled the interaction analysis for regional amyloid‐PET levels within target ROIs.

Results

We found a significant interaction of connectivity‐based distance by fiber‐tract MWF on the rate of tau‐PET accumulation (ADNI: β = 2.08, p = 0.009; BioFINDER: β = 1.876, p = 0.028; Figure 1), such that regions connected by highly myelinated fiber‐tracts showed lower rates of connectivity‐dependent tau accumulation. When controlling for regional amyloid‐PET levels, the interaction remained significant (ADNI: β = 2.23, p = 0.006).

Conclusion

Higher fiber‐tract myelination is associated with lower rates of tau progression in AD, independent of beta‐amyloid.
Orthostatic hypo‐ and hyper‐tension are associated with cognitive decline: the S.AGES cohort
Authors: Strumia Mathilde , Vidal Jean‐Sebastien , Hanon Olivier , Rouch Laure
Published: December 2022

Background

The association between orthostatic hypotension (OHYPO) and cognition has reported conflicting results. Although orthostatic hypertension (OHYPER) is an emerging cardiovascular risk factor, only very few studies investigated its association with cognition. We aimed to assess the impact of OHYPO and OHYPER on cognitive performances in non‐institutionalized subjects aged ≥ 65 years.

Method

The S.AGES (Sujets Âgés) cohort followed for three years non‐institutionalized subjects aged ≥ 65 years without major neurocognitive impairment at inclusion. OHYPO was defined as a decrease in systolic blood pressure (SBP) of at least 20 mmHg and/or diastolic blood pressure (DBP) of at least 10 mmHg from a sitting to a standing position. In contrast, OHYPER was defined as an increase in SBP of at least 20 mmHg and/or DBP of at least 10 mmHg under the same measurement conditions. Cognition was assessed using the Mini‐Mental State Examination (MMSE). Linear mixed models were used for the analyses.

Result

We included 3,170 subjects (mean age 78 years, 56% women). 209 (6.5%) had OHYPO at inclusion and 226 (7.1%) had OHYPER. Over time, MMSE was on average 0.5 points lower in patients with OHYPO compared to those without OHYPO or OHYPER (adjusted β [IC95%] = ‐0.52 [‐0.97; ‐0.08], p = 0.021) after adjustment for age, sex, education, baseline body mass index, smoking, alcohol intake, atrial fibrillation, congestive heart failure, transient ischemic attack or stroke, coronary artery disease, type 2 diabetes, dyslipidemia, seated SBP/DBP and antihypertensive treatment. Similarly, patients with OHYPER had, on average, poorer cognitive performances over time compared to those without pathological blood pressure (BP) postural changes (adjusted β [IC95%] = ‐0.54 [‐0.98; ‐0.09], p = 0.017).

Conclusion

Both OHYPO and OHYPER were associated with cognitive decline. Considering that BP postural changes are common in the elderly and easy to detect, orthostatic BP measurements could help identify patients with greater risk of cognitive impairment.
Evaluation of Longitudinal [18F]GTP1 Tau Burden Metrics in the Tauriel Phase II Study
Authors: Bohorquez Sandra Sanabria , Manser Paul T , Baker Suzanne L. , Blendstrup Mira , Pickthorn Karen , Teng Edmond
Published: December 2022

Background

Conventional measures of tau PET longitudinal change focus on SUVR. However, a small (n=57) observational [18F]GTP1 study including a broad range of Alzheimer’s disease (AD) participants suggested tau Extent and Load could measure disease progression over 12 months with greater precision than SUVR. We assess the performance of these metrics in a larger 73‐week study in prodromal‐to‐mild AD.

Methods

We analyzed 109 prodromal (pAD) and 180 mild (mAD) [18F]GTP1 scans in the semorinemab Phase 2 Tauriel study (NCT03289143). Quantification was performed using the cerebellum as reference. In a given ROI, extent was defined as the fraction of voxels above a scan‐specific threshold (mean cerebellar gray SUVR plus 2 standard deviations). Load was defined as Extant multiplied by the product of the mean SUVR of above‐threshold voxels. Analyses included the whole cortical gray (WCG), temporal meta‐ROI (excluding Braak 1/2, TMP), and Braak ROIs. As no treatment effects were observed with semorinemab, data were pooled across treatment and placebo arms. Relationships between endpoints were assessed with Spearman correlations (ρs), and endpoints changes were compared using Cohen’s D effect size (ES).

Results

At baseline, a slightly higher correlation was observed between SUVR and Load (ρs=0.89‐0.97) than between SUVR and Extent (ρs=0.64‐0.91) partly due to the smaller dynamic range for Extent in high‐tau burden regions (Figure 1). Longitudinal changes were correlated and consistent across endpoints (Figure 2). Extent ES values were lower than SUVR and Load ES, which showed similar performance (Table 1). Prognostic associations with baseline WCG measures were similar in pAD and mAD for predominantly cognitive measures ADAS‐COG and RBANS. Weaker prognostic associations were observed for CDR‐SB and ADCS‐ADL incorporating functional status (Table 2).

Conclusion

Higher baseline tau burden was associated with faster clinical decline in pAD and mAD. There was not obvious advantage of using Extent or Load; [18F]GTP1 SUVR is a robust measurement for assessing longitudinal change in multi‐site clinical trials settings.

Figure 1. Relationship between tau burden metrics.

Figure 2. Relationship between change in tau burden.

Table 1. Cohen’s D ES±95%CI of imaging endpoints change over 73 weeks.

Table 2. Prognostic associations of baseline WCG tau burden measurements with cognitive change measures.
Understanding Alzheimer’s disease resilience at the cellular level
Authors: Castanho Isabel , Yeganeh Pourya Naderi , Hide Winston
Published: December 2022

Background

Until recently, postmortem observation of amyloid beta (Aβ) and tau neurofibrillary tangles was sufficient for a definitive diagnosis of AD. Observations of resilient subjects exhibiting Alzheimer's‐associated neuropathology but no dementia have challenged this concept. Understanding the molecular mechanisms of resilience can provide a powerful suite of targets for therapeutic interventions.

Method

Building upon our studies of bulk brain transcriptional signatures of AD resilience, and in order to identify cell‐specific signatures, we have leveraged recently available single nucleus RNA‐seq data (n = 30) from the Religious Order Study and Memory and Aging Project (ROSMAP) to perform differential gene expression analyses. We classified individuals into AD, Resilience (RES), and Control (CTRL) using levels of Aβ plaques and neurofibrillary tangles, and presence/absence of cognitive impairment.

Result

Resilience signatures are shared between different cell types, but few are broadly distributed. Certain cell types show higher response to early events (e.g., excitatory neurons), while others seem to be particularly important in driving resilience to AD (e.g., inhibitory neurons and oligodendrocytes). Among cell‐specific differences, we noticed patterns where cells from the RES group had an opposing direction compared to AD and CTRL, suggesting protective events, or even resistance to AD neuropathology. For instance, in excitatory neurons, we identified 1,437 differentially expressed genes (DEGs) between RES/CTRL and 179 DEGs between AD/RES. CAMK2N1 (codes for an inhibitor of CaMKII, a synaptic protein pivotal in learning and memory) shows decreased expression between RES/AD and RES/CTRL. In contrast, in inhibitory neurons we identified 759 DEGs between RES/AD, and 46 DEGs in RES/CTRL. CRLF3 (encodes a cytokine receptor‐like factor thought to negatively regulate cell cycle progression, involved in neuronal morphology and synaptic vesicle biogenesis) exhibits increased expression in RES compared to AD and CTRL. For in silico cross‐validation, we determined if features identified as ‘markers of resilience’ were good predictors by comparing to the original diagnostic group. Our results suggest that oligodendrocytes are important drivers of AD resilience.

Conclusion

We have identified cell‐specific gene expression signatures of AD resilience, suggesting inhibitory neurons and oligodendrocytes as critical drivers of AD resilience.
Subjective cognitive decline and clinical progression in the memory clinic: The value of longitudinal self‐ and informant‐report in the SCIENCe project
Authors: Dubbelman Mark A. , Sikkes Sietske A.M. , Ebenau Jarith L. , van Leeuwenstijn Mardou , Kroeze Lior A. , van Berckel Bart NM , Teunissen Charlotte E. , van Harten Argonde C. , van der Flier Wiesje M.
Published: December 2022

Background

Among memory clinic patients who report the experience of subjective cognitive decline (SCD), only a small percentage are in a preclinical stage of Alzheimer’s disease (AD). We aimed to investigate how longitudinal self‐ and informant report of SCD relate to AD biomarkers and clinical progression.

Method

We followed 409 individuals with SCD (63±9 years, n = 180 (44%) female, MMSE 27.7±4.6) from the SCIENCe project over time, with yearly visits (n observations = 1,436, 2.7±1.7 years follow‐up). At baseline, amyloid was measured in cerebrospinal fluid or using amyloid positron emission tomography scans (n = 328, 80%) and dichotomized into positive (n = 100, 30%) or negative for AD (n = 228). We assessed degree of subjective complaints using both self and informant‐reported Cognitive Change Index (CCI). Using linear mixed models with random intercepts and slopes, CCI‐self and CCI‐informant were related to time and amyloid. In Cox regressions, we investigated the association between dichotomized baseline CCI and clinical progression to MCI or dementia (progressors n = 25). Models were adjusted for age, sex and education.

Result

At baseline, CCI‐self (intercept [95% confidence interval (95%CI)] = 45.20 [33.94, 56.43]) were higher than CCI‐informant scores (intercept [95%CI] = 45.39 [32.59, 58.15]). CCI‐informant scores of amyloid positive participants increased over time (estimate [95%CI] = 1.8 [0.5, 3.1]) whereas they did not in amyloid negative participants (estimate [95%CI] = ‐0.6 [‐1.3, 0.2]; Table 1). CCI‐self scores decreased in amyloid negative, but not in amyloid positive participants, although the rates of change did not differ significantly from each other (amyloid‐time interaction = 1.0, 95% confidence interval (95%CI) = [‐0.3, 2.2]; Figure 1, Table 1). High baseline CCI‐informant (hazard ratio (HR) = 4.8, 95%CI = [1.1, 21.4]), but not CCI‐self (HR = 5.3, 95%CI = [0.7, 40.5]), was associated with a higher risk of clinical progression.

Conclusion

Our results highlight the value of longitudinal self and informant‐report in the measurement of SCD. We found an effect of amyloid positivity on change in informant‐reported CCI and informant report also predicted clinical progression. Rates of change in self‐reported CCI scores did not differ significantly between amyloid positive and negative participants, which may hint at a waning awareness among those individuals with SCD due to AD pathology. Our work implies that informant‐report may be especially valuable in longitudinal studies.
Contributions of remote, unsupervised dyadic subjective measures to identify older adults with Mild Cognitive Impairment
Authors: Nosheny Rachel L , Jin Chengshi , Knight Krissy N , Banh Timothy , Howell Taylor , Truran‐Sacrey Diana , Fockler Juliet , Bui Chau L , Gummadi Shilpa L , Santhakumar Jess , Ashford Miriam T. , Camacho Monica R , Flenniken Derek , Roberson Erik D , Morris John C. , Moulder Krista L. , Li Yan , Petersen Ronald C. , Stricker Nikki H. , Rabinovici Gil D. , Carrillo Maria C. , Neuhaus John , Mackin R Scott , Weiner Michael W.
Published: December 2022

Background

Dyadic (self and study partner) subjective reports of an individual’s recent cognitive and functional decline are an efficient approach to facilitate identification of older adults with, and at risk for, Mild Cognitive Impairment (MCI). Such methods can be easily adapted for remote administration, but few studies have investigated the ability of remotely‐collected, unsupervised dyadic subjective reports to accurately detect MCI and cognitive decline.

Methods

In 289 older adults enrolled in the Brain health Registry (BHR), with clinically‐confirmed diagnoses of Cognitively‐unimpaired (CU) or MCI, we identified the optimal combination of remote measures to accurately distinguish CU from MCI. We then externally validated our predictive model in 217 participants enrolled in a separate cohort, Validation of Online Methods to Predict Cognitive Decline (eVAL). Predictors included Cogstate Brief Battery One Card Learning (OCL) accuracy; self‐ and study partner‐reported memory concern (SMCs); performance on online adaptations of Everyday Cognition Scale (ECog, self‐ and study partner‐report versions), Geriatric Depression Scale Short Form (GDS); family history of AD, age, gender, and education. We calculated 10‐fold cross validated area under the ROC curves (cvAUC), 95% confidence intervals (CI), and the percentage of participants correctly classified (accuracy) for all models. Likelihood ratio (LR) tests were used to compare model fits.

Results

In the BHR cohort, models including dyad‐report ECog, family history of AD, GDS, and Cogstate OCL scores distinguished CU from MCI with the highest accuracy (cvAUC = 0.90; 95% CI = 0.83, 0.92; accuracy = 85.5%). Models excluding study partner‐report ECog distinguished diagnostic groups with moderate accuracy (cvAUC = 0.83; 95% CI = 0.78, 0.85; accuracy = 75.9%) When applied to the validation cohort, the optimal training model including dyadic report performed with moderate accuracy (
Table 2
). In the validation cohort, inclusion of study partner (but not self) report SMC, in addition to dyadic‐report ECog, improved model fit (LR test p<0.01).

Conclusions

Remotely‐collected dyadic subjective measures, along with other remote measures, accurately distinguish CU from MCI. Subjective cognitive and functional decline and concerns about memory problems independently contribute to diagnostic discrimination. Results support future utilization of remote dyadic subjective measures to efficiently identify older adults with MCI for prodromal AD clinical trials, and in clinical care settings.
Importance of accounting for regional differences in modifiable risk factors for Alzheimer’s disease and related dementias: The case for tailored interventions in California
Authors: Hoffmann Coles M , Nianogo Roch A , Rosenwohl‐Mack Amy , Yaffe Kristine , Carrasco Anna , Barnes Deborah E
Published: December 2022

Background

We previously estimated that 37% of Alzheimer’s disease and related dementias (ADRD) cases in the U.S. may be attributable to modifiable risk factors, and that the most important risk factors differ based on race/ethnicity, but it’s not known whether national estimates generalize to specific states or regions. The aim of the present study was to (1) compare the proportion of ADRD cases that are potentially attributable to modifiable risk factors in California, to the U.S., overall and by sex and race/ethnicity, and (2) to estimate how many cases are potentially preventable by reducing the prevalence of key modifiable risk factors by 25%.

Method

Participants included adults ≥18 years from the California (n = 9,836) and the U.S. (n = 378,615). We calculated population attributable risks (PARs) using prevalence data from the national and California Behavioral Risk Factor Surveillance Survey (BRFSS) and relative risks from recent meta‐analyses. We estimated individual and combined PARs for ADRD in California and compared them to our U.S. estimates.

Results

In California, overall, 29% of ADRD cases were potentially attributable to the combination of 8 modifiable risk factors evaluated in this study, compared to 37% in the U.S. The top 3 ADRD risk factors were the same in California and the U.S., but their relative importance differed (low education [CA:15%; U.S.:12%], midlife obesity [CA:15%; U.S.:17.7%], and physical inactivity (CA:10%; U.S.:12%). The combined PAR was lower in California compared to the U.S. in men (CA:28%; U.S.:36%) and Blacks (CA: 30%; U.S.:40%), but was similar in women and other race/ethnic groups. This was primarily due to lower risk factor prevalence within these groups. Low education was especially important in the Hispanic population (CA:30%; U.S.:26%). The total number of ADRD cases currently attributable to combined risk factors was 199,246 in California and 2,287,683 in the U.S. If the combined risk factors were reduced by 25%, we could potentially prevent approximately 40,665 cases in California and 445,737 in the U.S.

Conclusion

The potential impact of modifiable ADRD risk factors differed in California and the U.S., overall and within sex and race/ethnic groups, highlighting the importance of tailoring dementia risk reduction campaigns.
Using participatory approaches in the development of a digital care assessment for family caregivers of people with dementia
Authors: Klein Olga A. , Group DZNE GAIN Research
Published: December 2022

Background

Participatory approaches are increasingly used in technology development research to improve care and support for people with dementia and their caregivers. People with lived experience are able to provide valuable contributions and insights into their needs which can increase acceptance and use of interventions. Dementia family caregiving is associated with high burden. To increase time‐efficiency and to ensure prompt service provision, our aim was to develop a digitally supported unmet needs assessment to better identify and manage care and support needs of family dementia caregivers.

Method

Using a participatory approach with caregivers and clinicians, the assessment was piloted for its content and technical usability in a memory clinic with interviews, think‐aloud protocols and written feedback. Data were analysed thematically. The development of the assessment was embedded within a randomised controlled trial examining the effectiveness of a digitally supported care management intervention for family caregivers.

Result

Regarding the assessment’s content, caregivers (n = 18) commented on the simplification of questions and answer options and suggested that they preferred direct questions whether care or support is needed in specific areas. Professional clinicians (n = 9) suggested that a focus on caregivers' care responsibilities was important. They commented on the order of instruments as well as the importance of avoiding duplicate questions. Reduction of completion time was named by both groups as important. Regarding the assessment’s tablet usability, caregivers provided information on the handling of the tablet, the ease of manual clicking and simple navigation. Professional clinicians commented primarily on the assessment’s layout and suggested one question at a time as well as adding an assessment progression bar. The final unmet needs assessment comprised several validated questionnaires with 57 questions examining a person’s self‐reported unmet needs, health‐related quality of life, caregiver burden, social support and the use of medical and non‐medical services and resource utilisation.

Conclusion

The participatory approach allowed us to incorporate aspects into the development of the digital assessment that we would have missed otherwise. The input of people with lived experience has supported the development of the assessment ensuring a higher degree of acceptability. For future projects, a higher level of involvement is sought.
Skin advanced glycation end products and the risk of dementia
Authors: Mooldijk Sanne S. , Lu Tianqi , Waqas Komal , Chen Jinluan , Vernooij Meike W. , Ikram M. Kamran , Zillikens M. Carola , Ikram M. Arfan
Published: December 2022

Background

Conditions such as hyperglycemia and oxidative stress lead to the formation of advanced glycation end products (AGEs), which have also been implicated in neurodegeneration including dementia. Previous studies have shown a link between these AGEs and the occurrence of Alzheimer’s neuropathology and worse cognitive functioning. However, no study examined the association between AGE levels and the risk of dementia. Therefore, we used skin AGE levels, reflecting accumulation of AGEs in long‐lived tissues, to determine the association with the risk of dementia and brain MRI measures.

Method

Within the Rotterdam Study, we determined skin AGEs using skin autofluorescence (SAF [arbitrary units]) measured at the forearm, between 2013 and 2016 in 2938 participants without dementia. Of them, 1515 also underwent brain MRI. All participants were followed for the incidence of dementia until 2020. The associations of SAF with incident dementia and with brain MRI measures were assessed, adjusting for potential confounders, namely age, sex, education, APOE ε4 carriership, smoking, estimated glomerular filtration rate, fasting glucose level and use of antidiabetic medication.

Result

Of 2938 participants (mean age 72.6 years, 57% women), 124 developed dementia during a median follow‐up of 4.3 years. Higher SAF was associated with an increased risk of dementia (hazard ratio (HR) 1.22 per standard deviation increase of SAF [95% confidence interval 1.03‐1.45]) and of Alzheimer’s disease (HR 1.21 [1.00‐1.48]). Stronger effects were seen in APOE ε4 carriers with HRs of 1.38 [1.03‐1.84] for all‐cause dementia and 1.51 [1.10‐2.09] for Alzheimer’s disease. Participants with higher SAF also had lower total brain volumes on MRI (difference per standard deviation increase: ‐2.71 mL [‐4.54; ‐0.89]), lower grey matter volumes (‐1.77 mL [‐3.45; ‐0.08]) and lower hippocampus volumes (‐0.04 [‐0.07; ‐0.01]). In addition, they tended to more often have lacunar infarcts and microbleeds (odds ratios: 1.22 [0.99‐1.50] and 1.09 [0.96‐1.25]).

Conclusion

Higher levels of AGEs in the skin are associated with an increased risk of dementia, especially in APOE ε4 carriers, and with lower brain volumes. These results suggest that AGEs are involved in dementia pathophysiology and may provide potential for prevention.
Needs Assessment Study in a Dementia Colombian Population
Authors: Romero‐Vanegas Sara Julieta , Vargas‐González Juan Camilo , Pardo Rodrigo , Moreno‐Angarita Marisol
Published: December 2022

Background

Dementia is a public health problem. In Colombia, there is no policy for dementia patients or their caregivers. Patients with dementia have unidentified needs and this lack of knowledge has contributed that a formal policy has not been raised. The recognition and identification of the needs facilitate the planning, provision, and evaluation of health services, and constitutes the first stage for the implementation of services or care plans. If the Colombian State wants to formulate policies that protect the population with dementia it should conduct studies that contemplate all dimensions and guarantee the social inclusion and equity of the affected population. A needs assessment study is required that includes the identification and analysis of physical, social, patrimonial, legal, access and psychological needs of patients with early stages of dementia and their caregivers.

Objective

To identify and analyze the needs of Colombian patients with mild dementia and their relatives with the purpose of contributing to the design of the health policy strategy for dementia, from a perspective of social justice and equity.

Method

Exploratory sequential mixed methods design. We will include Colombian adults with a mild dementia diagnosis, their caregivers and health professionals. We will employ a structured interview, an assessment of quality of life, psychiatric and medical comorbidities and we will employ case studies and focus groups to identify categories and interactions of the study problem. In the second stage, we propose to employ a needs assessment methodology and a mixed method using triangulation to evaluate the burden of known and unknown needs. Then, a theoretical analysis of inequities will be carried out stratifying by the insurance regime and city.

Result

The results will be analyzed in light of the theory of recognition as social justice.

Conclusion

We will recommend a proposal for the design of the strategy in health for this population.
A genetically informed examination of posttraumatic stress disorder and traumatic brain injury’s impact on dementia risk in US Veterans
Authors: Logue Mark W. , Sherva Richard , Zhang Rui , Harrington Kelly , Fonda Jennifer , Merritt Victoria , Panizzon Matthew S. , Hauger Richard L. , Wolf Erika , Miller Mark
Published: December 2022

Background

The US Veteran population is aging, and Veterans have higher rates of dementia risk factors such posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI). Moreover, some studies have indicated that APOE:ε4 (the largest Alzheimer’s disease genetic risk factor) x TBI interactions could further elevate dementia risk.

Method

Alzheimer’s disease and related dementia (ADRD) risk was examined using the electronic medical record and survey‐based phenotypes in the VA Million Veteran Program (MVP) cohort. We examined the impact of TBI (survey‐based), PTSD (medical record and survey‐based), and APOE:ε4 on ADRD risk in a European‐descent cohort (EUR, n=11,112 ADRD cases; 170,361 controls) and an African American cohort (AA, n=1,443 ADRD cases; 16,191 controls).

Result

PTSD, TBI, and ε4 were associated with ADRD in both cohorts (p<10‐9). In EUR, logistic models indicated dementia risk associated with TBI (OR=1.96) was approximately that of ε4 (OR=2.05), while the PTSD‐associated risk was slightly higher (OR=2.18). In AA, the effect of PTSD and ε4 were similar (OR=1.73 and 1.69 respectively), while the effect of TBI was higher (OR=2.69). GxE analyses yielded a modest but significant PTSD x ε4 interaction term in EUR (OR=0.84, p=0.0046). As multiplicative (logistic) interactions can be difficult to interpret, we calculated the risk curves predicted by the models (Figure 1) and relative excess risk due to interaction (RERI), which measures additive‐scale interactions. Modest but significant positive RERIs were observed for PTSD x APOE (EUR, RERI=1.28) and TBI x APOE (EUR and AA, RERI=0.86 and 1.45 respectively), indicating that risk of ADRD in terms of raw percentage associated with PTSD/TBI case status increases as ε4 dosage increases. For example, age 80 risk of ADRD associated with PTSD (PTSD case ADRD% – control ADRD%) in EUR is predicted to be 5.70% for those with one copy of ε4 and 11.19% for two copies of ε4.

Conclusion

Although the mechanisms have yet to be elucidated, PTSD, TBI, and genetic risk are strongly associated with dementia in Veterans. Veterans with PTSD and TBI have increased risk for ADRD and require monitoring for early detection of cognitive decline which can precede dementia onset.
Cognitive impairment is associated with cardiovascular remodeling in the mouse model of Alzheimer’s disease
Authors: Haghkar Mahdi , Grigorova Yulia N , Cezayirli Defne , Morrell Christopher H , Camandola Simonetta , Petrashevskaya Natalia , McDevitt Ross A , Zernetkina Valentina , Juhasz Ondrej , Wei Wen , Mattson Mark P , Lakatta Edward G , Fedorova Olga V
Published: December 2022

Background

Double‐mutant mice (APPswe/PS1dE9; 2xTg‐AD) represent a model of Alzheimer’s disease (AD). 2xTg‐AD mice develop progressive accumulation of amyloid plaques and cognitive impairment (CI) with age in >12 months old animals. The aim of the present study was to investigate the associations of CI and cardiovascular function in 2xTg‐AD mice.

Methods

Aortic pulse wave velocity (aPWV), an estimation of aortic stiffness, and cardiac parameters were measured by echocardiography in 16‐mo old male 2xTg‐AD (n=11) and wild type (WT; n=17) mice. Spatial memory (using Morris water maze; MWM) and the anxiety level (using open field test; OFT) were assessed. The relationship between cardiovascular and behavioral parameters were modeled using a linear regression analysis (LRA) with a backward elimination. P‐values <0.05 were considered significant, and 0.05≤P<0.1 were considered near significant and were included in the models.

Results

2xTg‐AD mice exhibited an increase in aPWV and had a thicker left ventricle (LV) posterior wall in diastole (LVPWd) and narrower LV internal diameter (LVIDd) vs. WT mice (Table 1). 2xTg‐AD mice spent less time in the center of OF vs. WT mice (Table 1). LRA revealed a negative association between time spent in the center of OF and LVPWd, and a positive association with LV volume in diastole (LVvold) in 2xTg‐AD mice (Table 2). In MWM, 2xTg‐AD mice exhibited impaired spatial memory estimated as prolonged average escape latency during their training vs. WT counterparts (Table 1). Although there was no difference between performance in the MWM probe trial, LRA showed a negative association between LVPWd and the mean distance from the platform in the probe trial in 2xTg‐AD mice, and a positive association of LVPWd with number of entries to the platform zone (Table 2). There was a positive association between aPWV and mean distance from the platform in the probe trial in both 2xTg‐AD and WT mice.

Conclusions

LRA results indicate that LV remodeling is associated with anxiety‐like behavior in 2xTg‐AD mice, but not with spatial memory impairment. Positive association of aPWV with spatial memory impairment in both groups suggests that aortic stiffness contributes to the age‐associated CI.

Supported by the NIH/NIA IRP.
Exploration of Multidimensional Needs in a Dementia Colombian Population: Preliminary Qualitative Results
Authors: Romero‐Vanegas Sara Julieta , Vargas‐González Juan Camilo , Pardo Rodrigo , Moreno‐Angarita Marisol
Published: December 2022

Background

World population is ageing, and as a result, dementias are becoming one of the major challenges for societies. Dementia involves patients, caregivers, professionals and the health system; for this reason, in Colombia, we need inplemented a diffent health policy models with a social justice approach. To contribute as input to a national strategy on dementia, our first step is multidimensional needs information gathering. To evaluate the perceived needs of a group of Colombian patients with dementia and their caregivers under a Social Justice framework using the Needs Assessment Methodology.

Method

We designed an information‐gathering program consisting of the first phase of a semi‐structured interview and the second phase of focal groups. We will triangulate both results using mixed methods. Nevertheless, this abstract only addresses the first phase. Due to social distancing, we designed a computerized interview using google forms that could be self‐answered through the internet or assisted through telephone. We obtained a telephonic approved informed consent before we enrolled any participant. In this interview, we evaluated the seven aspects of the need assessment methodology regarding the caregiving of dementia or the experience of suffering dementia.

Result

We conducted the interviews between September 2021 to December 2021. We included a total of 68 caregivers and fifteen dementia patients. Most caregivers were women, with ages between 27 to 72 years. Two‐thirds were familiar unpaid caregivers. We found that caregivers identified a lack of adequate resources provided by the health system. However, the burden of caregiving appears to be low in our context, and the results suggest that informal agreements within the families allow to distribute of the responsibilities.

Conclusion

caregivers in Colombia appear to present high resiliency and be assumed as an extended family responsibility even under the perception of neglected provision of resources by the health system.
The direct NLRP3 inhibitor and Phase 3 small molecule anticancer agent, RRx‐001, protects aged triple transgenic Alzheimer’s disease model mice from CNS degeneration and cognitive decline
Authors: Reid Tony , Oronsky Bryan , Caroen Scott , Cabrales Pedro
Published: December 2022

Background

RRx‐001 is an aerospace‐derived, intravenously administered NLRP3‐specific inhibitor with confirmed CNS‐penetrant properties and a favorable safety profile in a Phase 3 clinical trial. It is under investigation as an anticancer agent, a chemoradioprotector for oral mucositis and a prophylactic for acute graft vs. host disease (aGVHD). RRx‐001 has been shown to reduce interleukin‐1β (IL‐1β) production in vivo and to attenuate the severity both of experimental autoimmune encephalomyelitis (EAE), a disease model of multiple sclerosis, and dextran sulfate sodium (DSS)‐induced colitis.

Method

In the present study, the neuroprotective effects of 2mg/kg RRx‐001 administration on Alzheimer’s Disease (AD), which has been linked to aberrant NLRP3 activation, were evaluated via i.p. injection once weekly for 3 months on aged (21‐24 months old) triple transgenic AD model (3xTg‐AD) mice and control non‐transgenic (NonTg) mice.

Result

This sub‐chronic administration of RRx‐001 improved performance on learning and spatial memory tasks and greater risk assessment behavior based on the elevated plus maze test. A significant increase in reduced glutathione and a decrease in lipid peroxidation and amyloid plaque density were also observed in the 3xTg‐AD mice.

Conclusion

Together, these findings suggest that RRx‐001 reverses histological hallmarks of AD and protects cognitive and emotional function in aged 3xTg‐AD mice
Adherence to in‐person vs. virtual delivery of a multi‐domain behavioral intervention to prevent cognitive decline: The US POINTER Study
Authors: Katula Jeffrey A. , Ventrelle Jennifer , King Katelyn , Garcia Katelyn R , Graef Sarah , Lovato Laura , Wilmoth Sharon , Woolard Nancy , Espeland Mark A. , Snyder Heather M. , Kivipelto Miia , Carrillo Maria C. , Whitmer Rachel A. , Baker Laura D. ,   US POINTER
Published: December 2022

Background

In response to the global pandemic, U.S. POINTER procedures were adapted to include virtual intervention delivery. Here we describe the impact of this adaptation on adherence in a large community‐based lifestyle intervention trial.

Method

U.S. POINTER is conducted through a partnership between the Alzheimer’s Association (AA) and five clinical sites. A total of 2000 older adults at risk for cognitive decline are assigned to one of two 24‐month multi‐domain lifestyle interventions. The Self‐Guided (SG) group works toward lifestyle goals that best meet their individual needs and schedules. The Structured (STR) group follows a coordinated program with specific goals for physical activity, diet, cognitive/social challenge, and health monitoring. Both groups meet in teams of 12‐15 participants throughout the study for support and guidance, which are led by trained staff. SG teams meet six times over 24 months, and STR teams meet weekly for the first 4 months, then 2x/month for 2 months, and then monthly. Although Team Meetings for both intervention groups were planned as in‐person events, the global pandemic necessitated a pivot to virtual delivery.

Result

From January through December 2021, N = 2103 Team Meetings were conducted in‐person and N = 4663 Team Meetings were conducted virtually for 824 participants. For both intervention groups, in‐person and virtual Team Meeting attendance was the same, at 90%. When Team Meetings were held in‐person, STR participants completed a median of 93 very active Fitbit minutes/week (IQR = 38,185) and reported a median MIND Diet score of 11.0 (IQR = 9.5,12.0). When Team Meetings were virtual, adherence metrics were comparable with median values of 101 very active Fitbit minutes/week (IQR = 43,192) and a MIND Diet score of 11.0 (IQR = 9.8,12.0). Blood pressure monitoring and cognitive training metrics were also comparable without regard to Team Meeting delivery format.

Conclusion

Our findings demonstrate that a shift to virtual participant contact during the pandemic did not compromise adherence to a complex multi‐domain lifestyle intervention in older adults. These findings have high relevance for other ongoing lifestyle intervention studies within and outside of WW‐FINGERS, and highlight the importance of adaptability in clinical trial design and implementation to foster sustainability under challenging life circumstances.
Identifying and Prioritizing Research to Improve Emergency Care of Persons Living With Dementia: A Geriatric Emergency care Applied Research 2.0 Network ‐ Advancing Dementia Care (GEAR 2.0‐ADC) Scoping Review
Authors: Gifford Angela , Shah Manish N , Carpenter Christopher R , Dresden Scott M , Dussetschleger Jeffrey , Leggett Jesseca , Taylor Zachary , Hwang Ula
Published: December 2022

Background

Persons living with dementia (PLWD) frequently access emergency departments (EDs) for care, but current research surrounding their unique care needs is limited. The Geriatric Emergency care Applied Research 2.0 Network–Advancing Dementia Care (GEAR 2.0‐ADC) aims to identify and prioritize research gaps surrounding the most important needs for PLWD to advance their emergency care.

Method

A Task Force of 61 stakeholders including ED‐ and non‐ED‐based clinicians, PLWD, care partners, and advocacy organizations was established. Task Force members voted to choose the top four topics for investigation. Two Patient‐Intervention‐Comparison‐Outcome (PICO) questions were developed per topic. Following the PRISMA‐ScR guidelines and working with medical librarians, systematic literature searches and scoping reviews were completed by Task Force members. Findings were presented at the GEAR 2.0‐ADC Consensus Conference to the full Task Force. After discussion, they developed research questions for each topic area and voted to prioritize the questions within each topic area for future investigations.

Results

Task Force voting identified four critical topics for investigation and two unique PICO questions for each topic. The literature search and abstraction process comprehensively summarized the research to date for dementia detection (3,651 identified, 132 abstracted), communication and decision‐making (8,138 identified, 24 abstracted), ED clinical practices (6,348 identified, 23 abstracted), and care transitions from the ED to the community (3,484 identified, 10 abstracted). General themes that emerged from the abstraction process included a need for effective patient‐centered care interventions in the ED and when transitioning back to the community following care, identification of communication barriers between care partners and medical staff, measurement of dementia in the ED setting that is both efficient and operational, a need to decrease stimulation, and for increased PLWD and care partner engagement. The stakeholders rank‐voted the research questions developed for each topic, resulting in a framework for GEAR 2.0‐ADC’s support for future research.

Conclusion

Transdisciplinary stakeholders, PLWD, and care partners identified critical research topics and performed four scoping reviews, leading to refinement of the research gaps and prioritization for future research. These gaps will be addressed in upcoming GEAR 2.0‐ADC funding opportunities.
Polygenic score is associated with accelerated tau pathology accumulation in Alzheimer’s disease
Authors: Rubinski Anna , Frerich Simon , Malik Rainer , Franzmeier Nicolai , Ramirez Alfredo , Dichgans Martin , Ewers Michael ,   Disease Neuroimaging Initiative
Published: December 2022

Background

Progression of fibrillar tau is a key driver of neurodegeneration and cognitive decline in Alzheimer’s disease (AD), however which factors predict the rate of tau accumulation at the patient‐level is unclear. Here we propose to employ a polygenic score (PGS) for the prediction of tau accumulation and cognitive changes in AD, which could be useful for selection of individuals with faster tau progression in clinical trials.

Methods

We included 231 ADNI participants with longitudinal measurements of tau‐PET, amyloid‐PET, cognitive data and genotype data. We computed a PGS based on 85 independent lead SNPs from two recent large GWAS (DOI:10.1101/2020.10.01.20200659; DOI:10.1038/s41588‐021‐00921‐z), excluding all APOE variants. Using linear mixed effect models, we computed the individual rates of change in each of the biomarkers. In linear regression models we tested whether PGS can predict the rate of tau‐PET changes in Braak‐stage ROIs (Figure 1A) and cognitive changes. In order to assess whether amyloid mediates the effect of PGS on tau accumulation we performed sensitivity analyses in subgroups categorized by amyloid status as well as tested the interaction between the PGS and global amyloid‐PET. We further estimated sample size required for detection of hypothetical treatment effect on the rate tau accumulation using power analysis.

Results

Higher PGS was associated with higher accumulation rates of tau‐PET in cortical regions (Braak 3+4:β=0.306, pFDR<0.001; Braak 5+6:β=0.262, pFDR<0.001; Figure 1B). A higher PGS was further associated with faster decline in episodic memory (β=‐0.223, pFDR<0.001; Figure 1C) and global cognition (β=0.280, pFDR<0.001; Figure 1C). The observed effects of PGS on cognitive changes were mediated by higher tau‐PET accumulation (Figure 2). We found a synergistic effect between PGS and elevated amyloid‐PET levels on the rate of tau‐PET accumulation such that the PGS effects on tau‐PET accumulation were stronger particularly at elevated amyloid levels (Figure 3). Selection of individuals with highest PGS yielded a 32‐33% saving in required sample size to detect a treatment effect on tau accumulation.

Conclusion

Higher polygenic score is associated with faster tau accumulation and may be a useful tool for risk stratification in disease‐modifying treatments on tau.