bluuebunny/crossref_metadata_2025 huggingface dataset:
The role of subcortical grey matter structures in neuropsychiatric symptoms from cognitively healthy tot mild cognitive impairment: a population‐based study
Authors: vom Hofe Ilse , Luik Annemarie I. , Vernooij Meike W. , Ikram M. Arfan , Wolters Frank J.
Published: January 2025

Background

Neuropsychiatric symptoms are common in the prodromal phase of dementia, and may be related to altered structure and function of subcortical grey matter involved in emotion regulation. We aimed to determine the association between subcortical grey matter volume and occurrence of neuropsychiatric symptoms in a population‐based study.

Method

Between 2009‐2015 dementia‐free participants from the population‐based Rotterdam Study underwent 1.5T brain MRI. Volumes of the accumbens, amygdala, caudate, hippocampus, pallidum, putamen and thalamus were determined using FreeSurfer 6.1. Symptoms of depression and anxiety were assessed using the Center for Epidemiologic Studies Depression (CES‐D) scale and the anxiety subscale of the Hospital Anxiety and Depression scale (HADS‐A). We determined cross‐sectional associations between subcortical volumes (per 1 standard deviation [SD] decrease) and continuous CES‐D and HADS‐A scores using linear regression, and with clinically significant symptoms (CES‐D≥16;HADS‐A≥8) using logistic regression. Models were adjusted for demographics, lifestyle factors, comorbidities and co‐medication use. We repeated analyses stratifying on cognitive status (healthy/subjective complaints/MCI).

Result

Of 3452 participants (mean age 69.3 years, 55.2% women), 284 (8.2%) scored positive for clinical depressive symptoms, and 270 (7.8%) for clinical anxiety symptoms. Smaller hippocampal volume was associated with higher odds of clinical depressive symptoms (odds ratio [95%CI]: 1.27[1.05‐1.52], p = 0.01). In contrast, smaller volumes of the caudate were associated with less depressive symptoms (mean difference in log‐transformed score [95%CI] for caudate: ‐0.06[‐0.10;‐0.02], p<0.01, and pallidum: ‐0.04[‐0.08;0.00], p = 0.05). Smaller volumes of the caudate and pallidum were also associated with less anxiety (caudate: ‐0.04[‐0.07;‐0.01], p<0.01, pallidum: ‐0.05[‐0.09;‐0.02], p<0.01), accompanied for the caudate by a lower odds of clinical anxiety symptoms (OR[95%CI]: 0.84[0.72;0.98], p = 0.03). No associations were observed with the accumbens, amygdala, putamen, or thalamus. Associations were observed in cognitively healthy participants, as well as in those with subjective cognitive complaints or MCI.

Conclusion

In community‐dwelling older adults, volumes of the hippocampus, caudate, and pallidum are associated with neuropsychiatric symptoms, which do not differ by neurodegenerative disease stage. These findings support a complex role of subcortical volumes in the occurrence of neuropsychiatric symptoms in the older population.
Association of plasma glial fibrillary acidic protein (GFAP) and Mediterranean diet
Authors: Bandara E.M.S. , Gardener Samantha L , Pedrini Steve , Hone Eugene , Smith Stephanie Rainey , Martins Ralph N , Fernando Warnakulasuriya Mary Ann Dipika Binosha
Published: January 2025

Background

Evidence suggests that diet may play a modifiable role in reducing Alzheimer’s disease (AD) risk. Higher adherence to the Mediterranean diet (MeDi) is linked to a lower incidence of mild cognitive impairment (MCI) and AD. Increasing evidence indicates the potential utility of a cytoskeletal protein found in astrocytes, plasma Glial Fibrillary Acidic Protein (GFAP), as a marker specific for AD pathogenesis. However, the relationship between plasma GFAP level and the MeDi has not been fully determined. This cross‐sectional study examined whether MeDi diet as a whole or the individual components, were associated with plasma GFAP levels in an Australian older adult cohort drawn from the larger Australian Imaging, Biomarkers and Lifestyle (AIBL) study of ageing.

Methods

Cognitively unimpaired participants (n = 116) and individuals with MCI (n = 47) (mean age 75.37 ± 6.31; 44% male) completed a self‐reported food frequency questionnaire and had plasma GFAP levels measured using SIMOA platform. A score for the MeDi was generated for each individual. Linear regression models evaluated the association between plasma GFAP and the MeDi score, as well as individual MeDi components, including sex and age as covariates.

Results

MeDi score was not associated with plasma GFAP level. However, for individual MeDi components, dairy intake was positively associated with GFAP level (β = 0.107±0.039, p = 0.007).

Conclusions

This study is one of the first to report an association of plasma GFAP level with dietary components in an older adult cohort. The results suggest that dairy intake influences astrocyte reactivity. Further studies will include evaluation of plasma GFAP levels with additional dietary patterns, and individual dietary components to fully investigate the modifiable effect of diet on AD process.
Cerebrospinal fluid glial fibrillary acidic protein provides differential diagnostic value in some forms of dementias
Authors: Eriksson Pontus , Skillback Tobias , Kern Silke , Jönsson Linus , Blennow Kaj , Eriksdotter Maria , Zetterberg Henrik
Published: January 2025

Background

Glial fibrillary acidic protein (GFAP) is a marker of cerebral astrogliosis and occasionally elevated in patients with dementia. GFAP in cerebrospinal fluid (CSF), is routinely requested in referrals to neurochemistry laboratories; however, its ability to differentiate dementias and diagnostic capability is unclear. Our aim was to elucidate this, using two large datasets.

Method

First, GFAP data measured since 2015 was retrieved from the database of the Clinical Neurochemistry Laboratory at the Sahlgrenska University hospital. We then cross‐referenced with the Swedish dementia registry (SveDem). Here, information on ten different diagnoses such as early onset AD (EAD [<65 years]), late onset AD (LAD [≥65 years]), Parkinson disease with dementia (PDD), vascular dementia (VaD) and frontotemporal dementia (FTD), each with specific diagnostic criteria, were retrieved.

The GFAP data was log10‐transformed, followed by an analysis of covariance (ANCOVA) and a subsequent post‐hoc Tukey’s test, with GFAP as dependent variable, diagnosis as independent variable and sex and age as covariates.

Result

In total, 1912 individuals (mean [SD] age, 71.9 [8.2] years; 52% male), were included. Lower log10‐transformed GFAP concentrations were seen in PDD (mean [SD], 2.68, [0.28] pg/mL), than in EAD, LAD, VaD and FTD; here, mean concentrations of 2.76 (0.24), 2.89 (0.23), 2.89 (0.32) and 2.76 (0.25) pg/mL were observed, respectively.

In the post hoc analysis, GFAP differentiated VaD from EAD (p<0.001). PDD concentrations were significantly different from VaD (p<0.001) and LAD (p<0.001). Further, it also differentiated FTD from VaD (p=0.006) and LAD (p=0.001).

Conclusion

CSF GFAP could on a group level help differentiate VaD from EAD, FTD and PDD. Also, it could differentiate PDD from LAD. These results bear potential clinical relevance, where clinicians in some uncertain cases could use this marker as a differential tool.
The Effects of Single Instance Transcutaneous Vagus Nerve Stimulation on Cognition in MCI: A Randomized, Double‐Blind, Placebo‐Controlled Crossover Trial
Authors: Ho Brian D. , Velez Xavier A. , Waters Abigail B. , O'Neal Alexandria G. , Lamb Damon G. , DeKosky Steven T. , Porges Eric S. , Cohen Ronald A. , Williamson John B.
Published: January 2025

Background

Transcutaneous stimulation of the auricular branch of the vagus nerve (tVNS) was administered to participants diagnosed with mild cognitive impairment (MCI) to improve word‐list memory (primary outcome) and other cognitive skills.

Method

A randomized, double‐blind, placebo‐controlled crossover design was used for this trial. Participants with MCI (n = 59) were sorted into one of two sequences: Sham‐tVNS or tVNS‐Sham. In the Sham condition, electrodes were placed on opposite sides of participants’ left earlobes; the return electrode was placed on the mesial face of the earlobe. In the tVNS condition, electrodes were placed over the left auricular branch of the vagus nerve with the return electrode placed anterior to the tragus and one placed on the posterior face of the tragus to the interface of the auditory canal. In both conditions, stimulation parameters were set to 20Hz, 100 µs pulse width of alternating polarity, and intensity ramped from 0 to the threshold of discomfort and then reduced by 20%. During stimulation, participants simultaneously underwent comprehensive neuropsychological testing to assess various cognitive abilities. Test batteries were identical at both study visits, which were separated by at least 72 hours to avoid carryover effects, except where alternative forms were available. Structural brain MRI was also acquired.

Result

Performance on the immediate and delayed recall trials of the Rey Auditory Verbal Learning Test (RAVLT) did not significantly differ by treatment condition (p = 0.072 and p = 0.279, respectively). Likewise, performance on other cognitive tests did not significantly differ between treatment conditions (p = 0.101 to 0.958).

Conclusion

A single bout of tVNS does not appear effective for improving cognition in individuals with MCI.
Sex/Gender Differences in the Pattern of Comorbid Depressive Symptoms, Pain, and Sleep Problems among Older Mexican Americans With and Without Probable Dementia
Authors: Milani Sadaf Arefi , Brigham Trinity , Fang Kuo Yong‐ , Downer Brian , Markides Kyriakos S. , Raji Mukaila A
Published: January 2025

Background

Depression, pain, and sleep problems commonly co‐occur (overlap) among older adults. Data are lacking on the extent, pattern and sex/gender differences of overlap of these symptoms in adults aged ≥80 and living with dementia. Our objective was to examine patterns and sex/gender differences in overlapping depression‐pain‐sleep symptoms among older Mexican Americans with and without probable dementia.

Method

We used data from Wave 7 (2010/2011) of the Hispanic Established Population for the Epidemiologic Study of the Elderly, a study of Mexican Americans aged ≥75, residing in the Southwestern US. Participants were considered to have probable dementia if they scored <21 on the Mini‐Mental State Examination and had ≥1 activity of daily living limitation. Pain was defined as pain on weight‐bearing. Depressive symptoms were defined as having scores of 16 or more on the Center for Epidemiologic Studies Depression Scale. Clinically relevant sleep problems were defined as having trouble falling asleep, waking up several times per night, trouble staying asleep, or waking up feeling tired for at least 15 days in the past month. We used descriptive statistics to describe the prevalence and overlap in these three symptoms, by dementia status and sex/gender.

Result

Our sample was 85.7 years old on average and 65% were women (n = 974). Almost one‐third of participants (32.4%) had dementia. About 16% of participants with probable dementia reported overlapping depression‐pain‐sleep symptoms, compared to 5.5% of those without dementia (Figure 1). When stratified by cognitive status and sex/gender, 14.3% of men and 17.0% of women with probable dementia reported all three symptoms, compared to 2.0% of men and 7.6% of women without dementia.

Conclusion

Participants with probable dementia reported three times the frequency of co‐occurrence of clinically relevant depressive symptoms, pain, and sleep problems compared to those without dementia. Women, regardless of cognitive status, more frequently reported depression‐pain‐sleep symptom overlap, compared to men, but the gender disparity was smaller for those with probable dementia. The presence of one symptom should alert clinicians to screen for, treat, and manage the other two. Evidence supports common underlying mechanisms for these three highly co‐occurring conditions, potentially informing therapeutic decision‐making in patients with dementia.
Phase 1 Single and Multiple Dose Clinical Trials (ASCENT‐1 and ASCENT‐2) for Dose‐Finding of PRX012 in Participants with Biologically Confirmed Alzheimer’s Disease
Authors: Swanson Chad , Martényi Ferenc , Tooker Ryan E. , Campbell Brian M. , Johnson Ann , Li Lingnan , Quiceno Mary E. , Zago Wagner M. , Kinney Gene G. , Garren Hideki
Published: January 2025

Background

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder marked by the presence of brain amyloid beta (Aβ) plaques and stages of memory loss, cognitive decline, psychological and psychiatric changes, inability to perform activities of daily living, dementia, and eventually death. Recent evidence demonstrates the slowing of clinical decline with plaque‐clearing, anti‐Aβ monoclonal antibodies. PRX012 is a humanized monoclonal antibody that targets and clears known pathogenic forms of Aβ in development for subcutaneous (SC) use. Ongoing phase 1 clinical trials are evaluating the optimal dose of PRX012 in participants with AD.

Method

PRX012‐101 (ASCENT‐1) is a phase 1, randomized, double‐blind, placebo‐controlled, single ascending dose clinical trial to evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of PRX012 in healthy volunteers and participants with biologically confirmed AD (via amyloid PET). Subjects are given a single SC injection of PRX012, from 70 mg up to 400 mg, or placebo and followed for 85 days.

PRX012‐102 (ASCENT‐2) is a phase 1, randomized, double‐blind, sponsor‐open, placebo‐controlled, multiple dose clinical trial to evaluate the safety, tolerability, immunogenicity, pharmacokinetics, and pharmacodynamics of PRX012 in participants with biologically confirmed AD. Participants are assigned to one of two groups based on APOE genotype: Group A subjects with AD who are heterozygous‐ or non‐carriers of APOE4 alleles, and Group B subjects with AD who are homozygous for APOE4. Cohorts of APOE4 homozygous subjects were incorporated to allow for better representation and more complete characterization of the profile of PRX012 in homozygous carriers, as these individuals make up a small proportion of typical Alzheimer’s study populations. Subjects are given a series of 6 monthly SC injections of PRX012, from 45 mg up to 400 mg, or placebo.

Result

Data from both ASCENT‐1 and ASCENT‐2 will support dose‐finding for PRX012 through generation of a robust dataset.

Conclusion

Phase 1 development of PRX012 will support future late‐stage clinical trials that have the potential to position PRX012 as a best‐in‐class, next‐generation once‐monthly subcutaneous antibody for the treatment of AD.
Principal Factors Contributing to Cognitive Impairment in Homebound and Bedridden Frail Elderly Individuals from Low‐Resource Communities in Brazil
Authors: REAL ANA PAULA BERNARDES , MORAES FLAVIA LANNA DE , MORAES EDGAR NUNES DE , MACHADO CARLA JORGE
Published: January 2025

Background

Cognitive impairment (CI) is a major geriatric syndrome, leading to the loss of an individual’s decision‐making autonomy and representing a significant caregiving burden for families. It is commonly encountered in clinical practice and can be caused by dementia (major neurocognitive disorder), depression, delirium, or mental illness.

Methods

To assess the prevalence and primary causes of cognitive impairment (CI), as well as its correlation with other clinical conditions among bed‐bound or home‐bound elderly individuals from low‐resource communities in Brazil, we carried out a cross‐sectional study. This study involved patients from a public health system’s home care service, who received care from specialized geriatric‐gerontological teams in the low‐income communities of Belo Horizonte/MG, from 2011 to 2022. Statistical analyses were performed using Stata/SE for Macintosh 12.0.

Results

The study evaluated 1,391 elderly individuals, of which 67.8% were female, with an average age of 81.0 years (range 60 – 105). The prevalence of CI was 73.5%. The following probable etiologies were observed: dementia (82%), depression (40%), delirium (8.3%), and “mental illness” (15%), which were not mutually exclusive. The likelihood of CI among patients with delirium and mental illness was, respectively, 4.9 times (OR = 4.9; 95% CI 1.9‐12.8; p<0.001) and 7.6 times (OR = 7.6; 95% CI 4.1‐14.1; p<0.001) the likelihood of CI among patients without these conditions, indicating a significant and positive association. Age 80 years or older (OR = 1.6; 95% CI 1.2‐2.1; p = 0.003) and the presence of a high degree of frailty (OR = 2.2; 95% CI 2‐2.4) were also positively associated with CI. Polypharmacy was negatively associated with cognitive impairment (OR = 0.61; 95% CI 0.45; 0.82; p = 0.001).

Conclusions

The prevalence of CI was quite high in the population evaluated, present in nearly three‐quarters of the elderly. Dementia was the primary cause, followed by depression, mental illness and delirium. The association between dementia and depression was significant, complicating differential diagnosis while delirium constitutes the least frequent cause of CI in community‐dwelling elderly individuals.
Demographic, clinical and Alzheimer’s disease risk characteristics associated with interest in APOE disclosure amongst middle‐aged Australian adults
Authors: Rosenich Emily , Olver Hannah , Perin Stephanie , Haeusler Ruby , Foreman Tamar , Karlawish Jason , Lim Yen Ying
Published: January 2025

Background

Clinical guidelines in Australia discourage disclosure of apolipoprotein E (APOE) genotypes but advances in Alzheimer’s disease (AD) therapeutics will likely change this. Limited work has assessed interest in APOE disclosure in Australian adults, and it remains unclear which characteristics are associated with interest within this sample. In a large group of middle‐aged adults, this study aimed to describe interest in APOE disclosure and investigate differences in demographic and clinical characteristics and AD risk perceptions among groups with varying interest in disclosure.

Method

Cognitively unimpaired middle‐aged adults aged 40‐70 (N = 460) enrolled in the Healthy Brain Project or BetterBrains Trial completed the Knowledge, Interest and Preferences for APOE Testing and Disclosure questionnaire. Online assessments measured demographics (age, sex, education, ethnicity, dementia family history), anxiety and depressive symptoms, subjective cognition, perceived risk of developing AD, and knowledge of AD. Participants were categorized into groups based on self‐reported interest in disclosure (interested/want more information/not interested). Frequencies described interest in APOE disclosure and perceived benefits and concerns. Kruskal‐Wallis and chi‐square tests assessed whether demographic and clinical characteristics and AD risk perceptions differed between groups.

Result

Only 6% of participants were not interested, with most either interested (51%) or wanting more information about APOE (43%). Compared to participants who were not interested, interested participants were younger, more knowledgeable about AD, more likely to report any family history of dementia, had stronger beliefs in negative aging stereotypes and about the benefits of engaging in protective health behaviors to modify AD risk, had greater hope for an AD cure, and greater perceived risk of AD‐related mortality (Table 1). Amongst interested participants, motivation to change behaviors to reduce AD risk was the most common perceived benefit of disclosure (82%), whereas worry about attributing subtle memory changes to impending AD dementia was the most common concern (23%).

Conclusion

Most middle‐aged Australian adults sampled expressed an interest in APOE disclosure in a research setting. Contrary to previous findings, greater subjective cognitive concerns did not influence interest. Instead, results highlight that an array of biopsychosocial factors influence interest in APOE disclosure. Findings will inform the development of disclosure protocols for Australian populations.
Association of Multimorbidity and Plasma Biomarkers of Alzheimer’s Disease: The HABS‐HD Study
Authors: Jiang Xiaqing , O'Bryant Sid E. , Rissman Robert A , Johnson Leigh A. , Peltz Carrie B. , Yaffe Kristine
Published: January 2025

Background

Multimorbidity, known as the coexistence of two or more chronic conditions in the same individual, is prevalent among older adults and has been linked to an increased risk of dementia. Yet, little is known about its relationship with plasma Alzheimer’s disease (AD) biomarkers, especially in diverse populations. In the Health and Aging Brain Study: Health Disparities (HABS‐HD), we investigated the association of multimorbidity burden and plasma AD biomarkers.

Method

We cross‐sectionally studied a diverse cohort of 2,110 dementia‐free participants (63% women, 43% Mexican Americans [MA], 44% non‐Hispanic Whites [NHW], and 13% Blacks) aged ≥50 years (mean age 65.6±8.5) at baseline (2017‐2023). Plasma AD biomarkers, including β‐amyloid (Aβ)42/40, total and phosphorylated tau (t‐tau and p‐tau181), and neurofilament light (NfL), were assayed using ultra‐sensitive Simoa. Multimorbidity burden was measured by the total number of 16 chronic conditions, defined based on laboratory values, medical history, objective measures, and self‐report. We conducted linear regression to assess the associations of multimorbidity burden with plasma AD biomarkers and effect modification by race/ethnicity.

Result

Median multimorbidity burden was 3 (interquartile range 2‐4), with 86% of the participants having ≥2 chronic conditions: 14% with 0‐1, 41% with 2‐3, and 45% with ≥4 chronic conditions. After adjusting for age, sex, and race/ethnicity, multimorbidity burden was significantly associated with a lower level of Aβ42/40 and higher levels of t‐tau, p‐tau181, and NfL (Table 1). The associations remained significant after further adjustment for education, physical activity, and serum creatinine, except for Aβ42/40, in which the association was attenuated. We found significant interactions by race/ethnicity (p<0.05, Figure 1), with the associations of multimorbidity with p‐tau181 and NfL being stronger among MAs and Blacks than among NHWs.

Conclusion

Greater multimorbidity burden is associated with elevated p‐tau and NfL, particularly among race/ethnic minorities. This suggests that multimorbidity may be involved in tau‐related and neurodegenerative pathways of AD, as well as other peripheral clearance mechanisms. Efforts to interpret plasma biomarkers for screening purposes could benefit from considering multimorbidity and potentially tailored approaches in diverse populations.
Baseline demographic, risk and cognitive characteristics of the final randomized sample enrolled in a decentralised multi‐domain lifestyle intervention trial (BetterBrains) to delay cognitive decline
Authors: Rosenich Emily , Pirotta Stephanie , Cummins Hannah , Norfolk Maya , Da Costa Gabrielle , Yassi Nawaf , Churilov Leonid , Sinnott Richard O. , Brodtmann Amy , Pase Matthew P. , Barton Chris , Bush Ashley I. , Maruff Paul , Ayton Darshini , Lim Yen Ying ,   BetterBrains Research Group
Published: January 2025

Background

The BetterBrains Trial is a prospective behavior‐modification blinded endpoint randomized controlled trial to delay cognitive decline in middle‐aged adults (aged 40‐70) with a family history of dementia. The primary outcome is absence of decline on at‐least one out of four cognitive tests at 24‐months. We present trial recruitment and current participant completion statistics and baseline demographic, modifiable dementia risk factor (MDRF) and cognitive characteristics of the randomized sample, blinded to intervention arm.

Method

Participants completed online assessments (betterbrains.org.au), including assessment of vascular, sleep, mood, and social/cognitive engagement MDRFs. Participants with ≥1 MDRF were eligible. Participants also completed assessments of cognition, general health, medical history, and lifestyle factors at baseline, 12‐ and 24‐months. Unsupervised cognitive testing was conducted using the Cogstate Brief Battery (see Figure 2 for details). Subjective cognition was assessed using a modified Cognitive Function Instrument.

Result

From August 2021 to July 2023, 1830 participants enrolled and 1053 (57%) were randomized (Figure 1). Randomized participants were on average 59.7 (±6.8) years, 83% women, 90% highly educated (≥12 years of education), 93% White, and 86% reported a first‐degree family history of dementia (Table 1). Importantly, 27% resided in regional or rural Australia (Table 1). Participants reported an average of 6.5 MDRFs (max = 18) and a mean Cardiovascular Risk Factors, Aging and Incidence of Dementia risk score (without APOE) of 6.3 (max = 15) (Table 1). Baseline cognitive performance scores are presented in Table 1 and Figure 2. Randomized participants required, on average, 19.2 days to complete baseline assessment. To date, 61% and 70% of randomized participants have completed the 12‐ and 24‐month assessments (respectively), with study attrition at 3% (Figure 1).

Conclusion

Compared to the general population, participants in this decentralised trial exhibit some increased risk of dementia, indicated by high prevalence of first‐degree dementia family history, female gender, and prevalent MDRFs. Participant characteristics are similar to those observed within other lifestyle intervention trials. The finding that 27% of the sample resides in a regional or rural area highlights that the BetterBrains methodology facilitates inclusion of hard‐to‐reach populations. Low attrition and high follow‐up rates suggest that the BetterBrains program is acceptable and feasible.
Hypothetical Midlife Lifestyle Interventions and Dementia Risk in US Older Adults: A Comparative Effectiveness Microsimulation Study
Authors: Nianogo Roch A , Churchill Nicola A , Barnes Deborah E
Published: January 2025

Background

Lifestyle and metabolic multi‐domain approaches targeting several risk factors at a time are increasingly being recognized as critical for dementia prevention since single‐factor approaches and one‐size‐fits‐all interventions often fall short in substantially reducing the dementia burden. Therefore, we compared the effectiveness of several hypothetical midlife lifestyle interventions considered singly and in combination across two health approaches: high‐risk subpopulations (targeted) and general population (untargeted).

Method

Data came from the combined 2006 and 2008 biomarker samples of the Health and Retirement Study (HRS, N = 12,219). High‐risk populations (47%) were defined as individuals who: i) were APOEe4 carrier, ii) had high allostatic load (i.e., being in the top decile of the sum of z‐scores for biomarkers including C‐reactive Protein, HbA1c, systolic blood pressure), or iii) had metabolic syndrome (defined according to the Joint Interim Statement specification for metabolic syndrome based on measured criteria). We used the parametric, simulation‐based g‐formula to project the risk of dementia among older adults under different scenarios compared to the natural course of no‐intervention. We simulated three hypothetical lifestyle interventions based on being the top three lifestyle risk factors from the literature and the availability of the variables in HRS.

Result

For single‐factor, untargeted interventions, only exercise was associated with significant reduction in dementia risk of 13% (95% CI: 2% to 21%) reduction. Increasing social support alone reduced the risk of dementia by 9% (95% CI: ‐4% to 20%) and smoking cessation alone by 8% (95% CI: ‐3% to 18%). When exercise was combined with smoking cessation and social support, there was a 32% (95% CI: 15% to 44%) reduction in dementia risk using the general population approach (untargeted) and a 23% (95% CI: 10% to 37%) reduction in dementia risk in the general population when targeting high‐risk individuals (targeted).

Conclusion

Microsimulations suggest that midlife lifestyle interventions are likely to be marginally effective at reducing dementia risk when implemented individually with exercise being the most effective. Combined, multi‐domain approaches targeting several lifestyle factors at a time and targeting the general population regardless of risk factor distribution yielded a greater reduction in dementia risk than single lifestyle interventions or targeting only high‐risk individuals.
Predicting PET‐Based Amyloid and Tau Pathology Stages With Plasma Biomarkers in Alzheimer's disease
Authors: Kim Han‐Kyeol , Lee Jae Hoon , Chun Joong‐Hyun , Lee Jeong‐Ha , West Tim , Kirmess Kristopher M. , Verghese Philip B. , Braunstein Joel B. , Connell Daniel , Ryu Young Hoon , Lyoo Chul Hyoung , Cho Hanna
Published: January 2025

Background

We aimed to investigate whether the quantitative analysis of plasma biomarkers could distinguish the pathology stages indicated by positron emission tomography (PET)‐based Thal phase of amyloid and Braak stage of tau.

Method

A total of 232 participants were enrolled, all of whom underwent 18F‐florbetaben (FBB), 18F‐flortaucipir (FTP) PET, plasma p‐tau217/np‐tau217 ratio, p‐tau217, and Aβ42/40 ratio. To differentiate between image‐based Thal phases and Braak stages, region‐of‐interests (ROIs) were constructed, and cut‐off points were established at each stage using Gaussian mixture modeling. Consequently, FBB PET was classified into Thal phase 0, I‐II, and ≥III groups, while FTP PET was categorized into Braak stage 0, I‐II, III‐IV, and V‐VI.

Result

The plasma biomarker that most accurately reflected both the PET‐based Thal phase and the PET‐based Braak stage was the p‐tau217/np‐tau217 ratio. P‐tau 217 was superior in reflecting the Braak stage, but inferior to the p‐tau217/np‐tau217 ratio in the Thal phase. The Aβ42/40 ratio exhibited a difference between Thal phase 0 and I‐II, ≥III, but failed to distinguish between I‐II and ≥III, and did not correlate with the Braak stage. The AUC for predicting Thal phase I‐II and Thal phase ≥III using the p‐tau217/np‐tau217 ratio was 0.965 and 0.848, respectively. The AUC for predicting Braak I‐II, Braak III‐IV, and Braak V‐VI using the p‐tau217/np‐tau217 ratio was 0.864, 0.925, and 0.889, respectively.

Conclusion

The p‐tau217/np‐tau217 ratio demonstrates a strong correlation with the pathological stages based on amyloid and tau PET and exhibits the ability to predict the pathological stages of Alzheimer's disease through quantitative values, particularly reflecting the earlier stages more accurately.
Cardiovascular‐Kidney‐Metabolic Syndrome and Incidence of Dementia among Older Adults
Authors: Jiang Xiaqing , Bahorik Amber L , Dintica Christina S. , Yaffe Kristine
Published: January 2025

Background

Cardiovascular‐Kidney‐Metabolic Syndrome (CKM), a systemic interplay among metabolic risk factors, chronic kidney disease (CKD), and cardiovascular disease (CVD), has profound impacts on cardiovascular events and mortality, yet its association with dementia risk remains poorly understood. With data from the Health, Aging, and Body Composition study, we investigated the association between CKM and dementia risk among older adults.

Method

We studied 2,722 participants (mean age 74 ± 2.8, 53% female, 37% Blacks) who had measurements for CKM and were free of cognitive impairment at baseline (1997‐98). We defined incidence dementia over 15 years based on hospital records, prescription for dementia medication, or a decline ≥1.5 standard deviations below the mean on the Modified Mini‐Mental State (3MS) score. CKM staging, as defined by the American Heart Association, was based on constructs comprising dysfunctional adiposity, metabolic risk factors, CKD, and CVD. We used cause‐specific hazards models to assess the association between CKM, both as a linear term and dichotomously (CKM stage 3‐4 vs. 0‐2), and time to dementia diagnosis, treating death as censored. Models were adjusted for age, sex, race, education, and baseline 3MS.

Result

Participants with advanced CKM stages (3‐4) were prevalent at baseline: 3% stage 0 (no CKM risk factors), 4% stage 1 (excess or dysfunctional adiposity), 34% stage 2 (metabolic risk factors), 17% stage 3 (subclinical CVD in CKM), and 43% stage 4 (CVD in CKM). When modeled as a linear term, a greater CKM stage is significantly associated with an 11% increase in the risk of incident dementia (hazard ratio [HR] 1.11, 95% CI 1.02 to 1.21) after multivariable adjustment. Compared to participants with CKM stages 0‐2, those with CKM stages 3‐4 had a significant 24% increase in the risk of incident dementia (HR 1.24, 95% CI 1.03 to 1.50) after multivariable adjustment. Sensitivity analyses indicated no significant interaction between CKM and race, sex, or APOE ε4 (p‐values>0.05).

Conclusion

Among community‐dwelling older adults, CKM is associated with increased risk of developing dementia. Older adults with CKM may need to be followed closely for adverse cognitive outcomes, and modifiable risk factors for CKM need to be managed adequately.
KLOTHO‐VS heterozygosity ameliorates the effects of APOE ε4 on longitudinal hippocampal atrophy
Authors: Zhang Linda , Alfayate Eva , Calero Miguel , Medina Miguel , Grothe Michel J. , Sanchez‐Juan Pascual , Strange Bryan A.
Published: January 2025

Background

KLOTHO‐VS heterozygosity (KL‐VShet+) has been posited to be a protective factor against age‐related disease and cognitive decline, having been associated with increased cortical volumes and brain connectivity, as well as improved cognition in healthy elderly individuals. Conversely, the APOE‐ε4 allele is a primary risk factor for the development of Alzheimer’s disease (AD), with ε4 carriers more likely to have greater β‐amyloid burden, earlier age of AD onset, and accelerated rates of cognitive decline. Relatively few studies have investigated the interaction between these two genetic factors, with those that have presenting conflicting findings.

Methods

720 cognitively normal elderly participants (mean age: 74.7 years, range: 69‐87) with 3T T1‐weighted MRI, APOE and KL‐VS genotyping were selected for cross‐sectional analyses from the Vallecas Project cohort, a single‐centre 12‐year longitudinal study with annual follow‐ups. Of these participants, 443 had at least two visits and were included in longitudinal analyses (average follow‐up 4.7 years). Linear regression models were conducted to study the interaction between KL‐VS heterozygosity (KL‐VShet‐ vs. KL‐VShet+: n = 539 and 181, respectively) and APOE‐ε4 (carrier vs. non‐carrier: n = 135 and 585, respectively) on FreeSurfer‐derived hippocampal volumes, neuropsychological test scores, and plasma AD biomarkers (available for a subset, n=186), controlling for age, sex, education (in models with neuropsychological outcomes), and total intracranial volume (when considering hippocampal volume). Linear mixed‐effects models were used for longitudinal analyses of the same variables.

Results

No significant interactions between genotypes were found for any cross‐sectional comparisons. A significant KL‐VShet+ by APOE‐ε4 interaction was observed in longitudinal right hippocampal volumes, where KL‐VShet+ ε4‐carriers had similar rates of hippocampal atrophy compared to ε4‐noncarriers, and slower rates compared to KL‐VShet‐ ε4‐carriers (β=52.94, SE=25.03, p=0.03). No significant interactions were found for neuropsychological scores or biomarker levels.

Conclusion

Our study provides additional evidence to suggest that KL‐VS heterozygosity attenuates the detrimental effects of APOE‐ε4 on brain structure in healthy elderly adults, although the effects are not apparent in cognitive performance. Plasma AD biomarker levels did not vary significantly as a function of genotype, although this may be due to the smaller sample size. Further analyses will be conducted as more samples continue to be processed.
Stavros Niarchos Park Walk for people with dementia: Memory and Senses
Authors: Blekou Patra , Zoi Panagiota , Leonti Antigoni Athina , Kalimniou Meropi , Sakka Paraskevi
Published: January 2025

There are 160.000 people living with dementia and 280.000 with Mild Cognitive Impairment (MCI) in Greece. Accordingly, more than 1.500.000 family carers are involved their care. COVID‐19 pandemic and social distancing measures caused significant decline, both in an overall aspect of the people with dementia and their carers, and in specific domains (mostly communication, mood and socialization).

Rapidly aging global population increases the demand for programs activating elderly people in general and people with cognitive disorders in particular. Museums and cultural centers are well placed to provide such interventions. Many studies indicate that activities such as visiting museums and cultural centers, engaging in visual and performing arts, enjoying music, dancing etc., have positive impact on people with dementia and lead to alleviation of depression symptoms and improvement of cognitive functions.

In order to dismantle barriers and provide equal opportunities to people with dementia in engaging in cultural activities in Greece, Alzheimer Athens with the support of the Stavros Niarchos Foundation Cultural Center (SNFCC) has designed a guided walking tour in the Stavros Niarchos Park, where the largest public Mediterranean garden in the world is located. On a monthly basis, during an 1,5 hour tour, people with MCI and dementia are acquainted with a rich variety of flora, trees, shrubs, as well as an extensive selection of indigenous Greek aromatic plants accompanied by two health professionals from Alzheimer Athens. Later on, they visit a temporary art exhibition located at the SNFCC Esplanade. The walk ends with specially designed dual task activities using the information provided in the tour. With an average of 25 participants per tour, more than 300 people with cognitive deficits have participated since January 2023.

Overall, this intervention aims to combine physical and mental activation using the senses (touch, smell, sight and hearing), to improve mood and to promote socialization of elderly participants through an interactive, educational and relaxing journey.
Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia
Authors: Zelek Wioleta M , Bevan Ryan J , Morgan Bryan Paul
Published: January 2025

Background

Neuroinflammation is a critical factor of Alzheimer’s Disease (AD). Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in the brain where inflammation is poorly tolerated and brain cells are vulnerable to direct damage by complement. Membrane attack complex (MAC) is highly pro‐inflammatory product of the complement cascade killing cells by lysis and/or causing ‘bystander’ damage initiating NLRP3 inflammasome activation and provoking other immune damaging responses leading to death of the vulnerable nerve cells.

Method

The role of MAC in AD was investigated in MAC‐deficient animals and by using a newly developed anti‐C7 monoclonal antibody (mAb) that efficiently inhibits formation of the MAC in vitro and in vivo. Impact of C7 deficiency on brain complement dysregulation, synapse loss, amyloid load and cognitive decline was examined by comparing APPNL‐G‐F mice back‐crossed to C7 deficiency (APPNL‐G‐FxC7) with unmodified APPNL‐G‐F mice. To assess the effect of therapeutic C7 blockade, unmodified APPNL‐G‐F mice were treated systemically (for four weeks) with anti‐C7 mAb or control IgG and the same set of parameters of complement dysregulation, pathology and cognition measured.

Result

C7 deficiency in AppNL−G−F mice reduced levels of complement activation markers, reduced amyloid load and increased synapse density with a commensurate improvement in cognitive test performance. Systemic treatment of AppNL−G−F mice with a blocking anti‐C7 mAb reduced brain levels of complement activation markers, amyloid load and increased neuronal spine density in treated mice in peri‐plaque areas when compared to controls. in AppNL−G−F mice. APPNL‐G‐FxC7 performed significanlty better in behavioural cognitive tests.

Conclusion

We demonstrate that complement dysregulation occurs in brain in mouse models of AD. C7 deficiency reduced brain complement dysregulation, improved pathological parameters and cognitive function; systemic anti‐C7 therapy reduced complement dysregulation and protected from synapse loss in the model. Modification for brain delivery of the anti‐C7 mAb will enhance efficacy in the model. The findings highlight the potential for complement inhibition at the level of MAC as a therapy in AD.
Targeting novel anti‐complement drugs to the brain reduces complement activation and synapse loss, and improves cognition in a mouse model of dementia
Authors: Zelek Wioleta M , Bevan Ryan J , Nimo Jacqui M , Dewilde Maarten , De Strooper Bart , Morgan Bryan Paul
Published: January 2025

Background

In the brain as in other organs, complement contributes to immune defence and housekeeping to maintain homeostasis. Sources of complement may include local production by brain cells and influx from the periphery, the latter severely restricted by the blood brain barrier (BBB) in healthy brain. Dysregulation of complement leads to excessive inflammation, direct damage to self‐cells and propagation of injury. This is likely of particular relevance in the brain where inflammation is poorly tolerated and brain cells are vulnerable to direct damage by complement.

Method

We have developed novel anti‐C7 antibodies (mAb) that efficiently inhibit formation of the pro‐inflammatory membrane attack complex (MAC) in vitro and in vivo. Here we describe recombinant fusion proteins (FP) that replicate the MAC‐blocking action of the mAb, and are designed to access the brain utilising “Trojan horse” shuttles. The Alzheimer model APPNL‐G‐F mice were treated systemically with native mAb to swamp peripheral C7 followed by the FP. Immunohistochemistry and ELISA were used to demonstrate FP entry into brain and show impact on the disease pathology.

Result

The recombinant FP showed complement inhibitory activity in vitro equivalent to their parent mAb and were able to cross an artificial BBB in transwells. The presence of the FP in brain homogenates of peripherally dosed animals was confirmed by ELISA. Treatment with the FP caused reduced levels of complement activation products C3b and terminal complement complex (TCC) in brain. Diolistics analysis showed significant increased neuronal spine density in treated mice compared to controls, demonstrating a protective effect of the FP on synaptic function. Mice treated with the drug showed significant improvements in cognition.

Conclusion

The FP described are able to cross BBB and are potent inhibitors of complement in brain; impact on brain pathology was detected after just one week of treatment. The findings highlight the potential for complement inhibition as a therapy in Alzheimer’s disease.
Aging and ADRD social media programs for outreach and recruitment: Longitudinal outcomes
Authors: Teano Anthony L. , Scott Ashley , Gipson Cassandra , Albert Marilyn S. , Pettigrew Corinne
Published: January 2025

Background

Social media may be a useful method for research centers to deliver health messaging, increase their visibility in the local community, and recruit study participants. There are, however, few studies evaluating the outcomes of social media in this setting. The objective of this study was to describe one Alzheimer’s Disease Research Center’s social media activities for community education on topics related to aging, memory loss, and dementia, and evaluate their impact on recruitment into clinical research studies.

Method

Several social media platforms were used, including: Facebook, Twitter/X, and YouTube. Objective assessments quantified monthly, based on each platform’s native dashboard, included: number of posts, number of followers, post reach and engagement, and post impressions. The number of participants volunteering for research during this period was also tracked using a RedCap database, with many entries reflecting individuals who indicated that they learned about Center research through social media when completing a “Participate in Research” webform. Educational material posted to social media most frequently included content developed by Center staff, content from partner organizations, and news articles/resources featuring Center researchers. Multiple educational programs were developed, including social media series, virtual talks, Twitter chats, and webinars. Facebook content was occasionally boosted to increase visibility in the local geographical region.

Result

Metrics over four years demonstrate growth in reaching social media audiences, as indicated by increases over time in the numbers of likes/followers on Facebook and Twitter and video views on YouTube (growth trajectories). Overall, Facebook reach rates and Twitter impression rates were respectable, although Facebook engagement rates were more modest (Table 1). Months that included boosted Facebook posts resulted in a greater change in page Followers and page Likes, and higher reach and engagement rates (all p£.002). Recruitment of participants into Center‐affiliated research studies increased during this time frame, particularly when Facebook posts were boosted.

Conclusion

These data demonstrate that social media activities can provide increased educational opportunities focused on Alzheimer’s disease and related dementias and have a measurable impact on recruitment of participants into research studies. Additionally, this study highlights the importance of tracking outcomes to maximize return on investment.
Higher plasma antioxidant nutrient levels associated with slower cognitive decline among individuals with APOE‐e4: an investigation of the MIND trial
Authors: Liu Xiaoran , Rajan Kumar B , Beck Todd , Tangney Christy C , Dhana Klodian , Willett Walter C. , Aggarwal Neelum T. , Sacks Frank , Barnes Lisa L.
Published: January 2025

Background

Observational studies have shown a protective association between antioxidant nutrients and lower risk of Alzheimer’s disease. Results from dietary intervention trials remain inconclusive. The effect of APOE‐e4, the strongest risk factor for AD, on responsiveness to dietary interventions remains largely uninvestigated. We examined whether the association of plasma nutrient levels and changes in global cognition over three years differed by the APOE‐e4 allele among MIND trial participants.

Method

The study included 601 participants from the MIND trial with APOE‐e4 genotype. Plasma nutrients were analyzed using HPLC at Harvard School of Public Health. Cognitive function was evaluated with a 12‐test battery from which a composite of global cognition was derived. Mixed‐effect regression model was used to examine the association of plasma nutrient levels, the APOE‐e4 allele and cognitive decline.

Result

The mean age was 70.4 years for the 428 APOE‐e4 non‐carriers and 69.8 years for the 174 carriers (p = 0.08) (Table 1). Among APOE‐e4 carriers, individuals in the highest tertile of lutein and zeaxanthin, alpha‐carotene, and beta‐carotene had a significantly slower cognitive decline by 0.16 standardized unit (SU) [SE = 0.07, p = 0.03], 0.16 SU [SE = 0.07, p = 0.02], and 0.18 SU [SE = 0.07, p = 0.01], respectively, when compared with the lowest tertile (Figure 1). Among APOE‐e4 carriers, individuals in both the moderate and the highest tertiles of lycopene (0.24 ± 0.07, p = 0.001, 0.19 ± 0.07, p = 0.01) and beta‐cryptoxanthin (0.26 ± 0.07, p = 0.000, 0.20 ± 0.07, p = 0.01) had slower cognitive decline than those in the lowest tertile

Among APOE‐e4 non‐carriers, there was no association, except individuals in the moderate tertile of lutein and zeaxanthin which showed slower declines (0.08 ± 0.04, p = 0.04) compared to the lowest tertile.

When comparing APOE‐e4 carriers and non‐carriers at high plasma levels (75th percentile) of alpha‐tocopherol, lutein and zeaxanthin, beta‐carotene, lycopene, and beta‐cryptoxanthin, APOE‐e4 carriers had slower global cognitive decline ranging from 4.7% to 21% (p<0.05 for all).

Conclusion

Higher plasma antioxidant nutrients were associated with significantly slower cognitive decline among APOE‐e4 carriers in the MIND trial participants, suggesting the potential effects of antioxidant nutrients in mitigating the genetic risk posed by APOE‐e4.