bluuebunny/crossref_metadata_2025 huggingface dataset:
Dyadic patterns of subjective cognitive reports as predictors of incident dementia
Authors: Numbers Katya T. , Lam Ben C. P. , Crawford John D. , Kochan Nicole A. , Sachdev Perminder S. , Brodaty Henry
Published: December 2022

Background

Subjective cognitive decline (SCD), in the absence of impaired clinical testing, may be a clinical indicator of early Alzheimer’s disease (AD) and other dementias. However, not all individuals with SCD have cognitive decline. Corroboration of decline by an informant (i.e., close friend or family member) is one feature of SCD thought to increase the likelihood of preclinical AD. Few studies have examined whether different patterns of SCD in individuals and their informants are related to risk of dementia over time.

Method

Data from 628 dyads comprising participants (M = 78.65 years, 56.1% female) and their informants from the Sydney Memory and Ageing Study were analysed to determine whether different dyadic patterns of SCD recorded at baseline were associated with differential risk of incident dementia ten years later. Four groups were formed by categorizing participants’ and informants’ responses on a binary SCD measure at baseline: [1] both participant and informant NO (n = 180, 28.7%); [2] participant YES, informant NO (n = 232; 36.9%); [3] participant NO, informant YES (n = 41; 6.5%); [4] Both YES (n = 175; 27.9%). We compared incident dementia risk across these groups and conducted Cox regression adjusting for demographics, APOE4 status, mood, and personality.

Result

Figure 1 shows the incidence dementia risk of the four groups. After controlling for covariates in the Cox regression, compared to Group 1, participants in Group 3 were at higher risk of incident dementia over 10 years (HR = 2.35, p = .020) as were participants in Group 4 (HR = 2.24, p = .004). Participants in Group 4 were at greater risk of incident dementia than participants in Group 2 (HR = 1.61 p = .034; see Table 1).

Conclusion

Participants from dyads where both individuals endorsed SCD at baseline, and where the informant, but not the participant endorsed SCD, had a more than two‐fold increased risk of progressing to dementia over 10 years. Our results, though preliminary, highlight the value of collecting both self‐ and informant SCD ratings in research and clinical contexts and suggest that informant reports of SCD may be especially important for identifying pre‐clinical AD.
Sex and Race/Ethnic Differences in Risk Factors for Alzheimer’s Disease and Related Dementias: Implications for Prevention
Authors: Nianogo Roch A , Rosenwohl‐Mack Amy , Yaffe Kristine , Carrasco Anna , Hoffmann Coles M , Barnes Deborah E
Published: December 2022

Background

We previously estimated that 1 in 3 cases of Alzheimer’s disease and related dementias (ADRD) in the U.S. may be attributable to modifiable risk factors, the most important being physical inactivity, depression, and smoking. However, these estimates do not account for changes in risk factor prevalence over the past decade and do not consider potential differences based on sex or race/ethnicity. The objective of this study was to update and estimate the proportion of ADRD in the U.S. that are potentially attributable to modifiable risk factors and to assess for differences by sex and race/ethnicity.

Method

We estimated individual and combined population attributable risks (PARs) for ADRD for the following risk factors: physical inactivity, current smoking, depression, low education, diabetes, midlife obesity, midlife hypertension, and hearing loss. To account for non‐independence of the risk factors, we estimated their communality and uniqueness via principal component analysis. Risk factor prevalence and communality were determined using data from the nationally‐representative Behavioral Risk Factor Surveillance Survey (BRFSS) and relative risks for each risk factor were extracted from recent meta‐analyses. Respondents included 378,615 noninstitutionalized adults in the U.S., older than 18 years.

Result

Approximately 1 in 3 (37%) cases of ADRD in the U.S. are potentially attributable to 8 modifiable risk factors, the most important of which are midlife obesity (17.7%, 95% CI: 17.5,18.0) physical inactivity (11.8%, 95% CI: 11.7, 11.9), and low educational attainment (11.7%, 95% CI: 11.5, 12.0). Combined PARs were higher for men (36%) than women (30%) and differed by race/ethnicity: Black (40%), Native Americans/Alaska Natives (39%), Hispanic (any race, 34%), White (29%), and Asian (16%). The most important modifiable risk factors, regardless of sex, were midlife obesity for Whites, Native Americans/Alaska Natives and Blacks; low education for Hispanics; and physical inactivity for Asians.

Conclusion

Our findings suggested that the major contributors to ADRD have changed over the past decade and differ based on sex and race/ethnicity. Therefore, Alzheimer’s disease risk reduction strategies may be more effective if they target higher‐risk groups and consider current risk factor profiles.
The Study of Neuronal Hyperactivity in the Early Stage of Alzheimer’s Disease
Authors: Yook Yeeun
Published: December 2022

Background

Alzheimer’s disease (AD) is a neurodegenerative disease, characterized by memory loss and cognitive impairment. The pathology of AD includes the accumulation of beta‐amyloid (Aβ) in the extracellular space and hyper‐phosphorylation of tau in neurons. Aβ pathology has been shown to begin approximately 20 years before tau pathology and mild cognitive impairment develop in AD patients. Aβ deposits cause alterations in brain function, leading to the loss of neurons in the cerebral cortex and hippocampus in the later stages of AD. However, the cellular mechanisms by which Aβ induces AD pathology remain largely elusive. Traditionally, lower neuronal activity has been thought to contribute to the synaptic failure and cognitive impairments observed in AD. However, recent studies suggest that Aβ triggers neuronal hyperactivity during the early stages of AD. Consistent with this observation, epileptic seizures have been detected in both mouse models of AD and human patients with Alzheimer’s. Uncontrolled or severe seizures can lead to further brain damage and exacerbate the cognitive decline seen in AD. Thus, neuronal hyperactivity could be one of the contributing factors to the neuronal loss induced by Aβ. However, it is unclear how Aβ can induce neuronal hyperactivity and seizures.

Method

To evaluate seizure susceptibility, we employed kainic acid‐induced seizures in a well‐established AD mouse model, the APP/PS1 mice. To measure neuronal activity, we employed primary cortical neuron cultures treated with a scrambled or Aβ 1‐42 peptide and recorded with a multi‐electrode array (MEA) recording system. Biochemistry and molecular biology assays were performed to study molecular players associated with Aβ‐induced neuronal hyperactivity.

Result

Our data showed that acute Aβ treatment induces hyperexcitability in wild‐type (WT) cortical neurons. We also confirmed a higher susceptibility to seizures in APP/PS1 mice. Lastly, we identified a postsynaptic protein that is up‐regulated and potential involved in Aβ‐triggered neuronal hyperexcitability.

Conclusion

In summary, our data are expected to provide insights into the etiology of AD‐associated brain hyperactivity and potentially suggest therapeutic targets for reducing seizures during early stage of AD.
Boosting Hippocampal Neurogenesis Rescues Cognitive Impairments in 3xTgAD Mouse Model of Alzheimer’s Disease
Authors: Lee Chi‐Chieh , Calegari Federico
Published: December 2022

Background

Alzheimer’s disease (AD) is an irreversible neurodegenerative disease with no treatment to date. Symptoms of AD include emotional disorders and memory impairments mainly resulting from dysfunction of the hippocampus, a brain area involved in learning, memory, navigation and regulation of mood. To attempt a rescue of hippocampal function in the disease, hippocampal neurogenesis was boosted in the Alzheimer’s mouse model.

Method

3xTgAD mice were injected with lentiviruses encoding for Cdk4/cyclinD1 (lenti‐4D) as a means developed by our group to enhance neurogenesis in the dentate gyrus. 3xTgAD mice with increased levels of adult‐born granule cells were then examined for behavioral and cognitive performance.

Result

The genetic manipulation by lenti‐4D system increased the number of neural stem cells and adult hippocampal neurogenesis (two‐fold) in dentate gyrus of 10‐month‐old 3xTgAD mice. The increased neurogenesis rescued some of the behavioral effects observed in 3xTgAD mice. In the open‐field test, the mice with new‐born neurons showed decrease of behavioural inhibition. In the Morris water maze, the same group of mice performed less anxiety behaviours and more perseverance, which indicates better memory.

Conclusion

Increased neurogenesis by lenti‐4D system rescued some cognitive impairments in 3xTgAD mouse model of Alzheimer’s disease.
From Plan to Impact ‐ progress towards targets of the WHO Global action plan on dementia
Authors: Arthurton Lewis , Lynch Chris , Weidner Wendy S
Published: December 2022

Background

The WHO Global action plan on the public health response to dementia 2017‐2025 was universally adopted by Member States in 2017. Every year since, Alzheimer’s Disease International (ADI) has produced the report ‘From Plan to Impact’ reviewing progress and barriers towards the goals of the plan, including the development of national dementia plans worldwide and shining a light on the challenges, responses and innovation around the COVID‐19 pandemic.

Method

ADI will conduct desk‐based research, distributing a survey to its 120 member associations. For non‐ADI Member states, further desk‐based research will be conducted by contacting associations, officials and ministries in those countries. The survey will predominantly seek to determine the status of a national dementia plan, or dementia integrated into another health plan (global action area 1), with further questions seeking to illuminate the remaining six action areas, including diagnosis, treatment, care, support, research, risk reduction and support for carers, and continuing to discover the impact, disruption and response to COVID‐19.

Result

Habitual monitoring of the global national dementia plan environment has shown that new plans have been approved in Iran and Czech Republic. Armenia and Brazil appear to be making advances towards the implementation of their own national dementia plans. Preliminary findings suggest that Member States are likely to miss the target of 75% of countries (146) having a national dementia plan by 2025, findings mirrored by the WHO Global status report on the public health response to dementia, unless a concerted effort is made to rectify this. COVID‐19 has exposed inadequacies in the preparedness of governments to care for and support those living with dementia and their carers. We expect further granularity of data to become available throughout the development of the report.

Conclusion

Only with robust national dementia plans can governments prepare their health and care systems to meet the needs of their population. This research and report will focus attention on those governments and areas where an acceleration to progress is required, identifying gaps and shining a light on best practice in other countries and regions that can act as a stimulus and motivation for others.
The Clinical Features of Patients with Alzheimer’s Disease and a History of Traumatic Brain Injury
Authors: van Amerongen Suzan , Caton Dewi , Pijnenburg Yolande A.L. , Scheltens Philip , Vijverberg Everard G.B.
Published: December 2022

Background

Traumatic brain injury (TBI) has been associated with a greater risk of developing Alzheimer’s disease (AD). Previous studies have argued that AD patients with TBI history have a differences in age of disease onset, cognitive features and neuropsychiatric symptoms (NPS), but current evidence is still limited and did not always take into account injury characteristics, such as age at injury, TBI frequency, and severity. The primary objective of this study is to examine whether a history of TBI and specific injury characteristics are associated with differences in age of disease onset, cognitive features and NPS in biomarker proven AD patients.

Method

Biomarker proven AD patients (CSF or amyloid PET, stage MCI or dementia) were selected from the Amsterdam Dementia Cohort. TBI events were classified by severity, frequency and age at injury (TBI <25 or ≥25 years). Cognitive composite scores were calculated from results of a neuropsychological test battery. Neuropsychiatric symptoms (NPS) were assessed with the Neuropsychiatric Inventory Questionnaire (NPI‐Q). Linear regression analyses were utilized to examine the association between TBI, injury characteristics and clinical outcome measures.

Result

Among the 1755 selected AD patients (mean age 65.2), 166 patients (9.5%) reported ≥1 TBI in their history. Overall, a history of TBI was not related to differences in age at AD, but age at injury <25 years old was associated with a 2.3 years earlier age at diagnosis (β = ‐2.34 P = 0.031), which was independent of APOE e4 status. No significant associations were found between TBI history or age at injury and differences in cognitive functioning or NPS.

Conclusion

The findings of our study indicate that TBI during childhood, adolescence or early adulthood may influence age of disease onset in AD patients. This underscores previous findings on vulnerability of the brain during critical development and maturation phases and suggest that an early TBI may contribute to lower resilience or higher vulnerability to neurodegenerative changes. TBI history does not seem to affect cognitive characteristics and NPS profiles in AD patients.
Real‐world sleep in Parkinson’s disease predicts cognitive dysfunction.
Authors: Chang Jun Ha , Bhatti Danish , Mieth Teagan , Tartaglia Adam , Rizzo Matthew , Bertoni John M , Merickel Jennifer
Published: December 2022

Background

Sleep dysfunction is signature of Alzheimer’s disease and Parkinson’s disease (PD), and can signify incipient disease, disease risk, and worsen symptoms over time. How real‐world sleep dysfunction relates to patient self‐report of sleep and clinical cognitive dysfunction is poorly understood, partly because self ‐report is impaired in patients with cognitive decline. We monitored real‐world sleep with wearable actigraphy devices in patients with PD to test the hypothesis that objective patterns of sleep dysfunction are associated with worse cognitive performance.

Method

Twenty‐nine participants with idiopathic PD (age = 67.44 ± 5.79, 20 males) completed the Montreal Cognitive Assessment (MoCA) and Epworth Sleepiness Scale (ESS) to capture clinical cognitive decline and self‐reported daytime sleepiness. Sleep was monitored for 4‐weeks using wrist‐worn ActiGraphs. Sub‐scores and total scores of MoCA were compared with Total Sleep Time (TST), Sleep Efficiency (SE), Wakefulness After Sleep Onset (WASO), and Sleep Fragmentation Index (SFI) measured by actigraphy, as well as ESS total using a Pearson correlation.

Result

Worse sleep fragmentation (SFI), the percentage of awakenings and movements during sleep, predicted worse cognitive impairment overall (MoCA score: r = ‐0.38, p < .05) and delayed recall (r = ‐0.44, p < .05). Reduced sleep time (TST) and worse sleep quality (SE, WASO) did not worsen patient cognitive impairment. Patient self‐report of sleepiness (ESS) did not associate with worse cognitive outcomes.

Conclusion

This pilot analysis identifies sleep fragmentation as a key risk factor for cognitive dysfunction in PD. Patient self‐report of sleep may not reliably reflect chronic sleep disruption and related cognitive dysfunction. Results underscore that objective measures of real‐world dysfunction can help inform clinical care and intervention for patients at risk for cognitive decline and dementia.
Metabolic and Cerebrovascular Perturbations in the 5xFAD Mouse Model of Alzheimer’s Disease
Authors: Jullienne Amandine , Szu Jenny , Quan Ryan , Silvola Rebecca , Bedwell Amanda A , Eldridge Kierra , Speedy Rachael , Persohn Scott C , Obenaus Andre , Territo Paul R ,   MODEL AD
Published: December 2022

Background

The Model Organism Development and Evaluation for Late‐Onset Alzheimer’s Disease (MODEL‐AD) Consortium seeks to develop the next generation of AD models based on human data. A popular model of familial AD is the 5xFAD mouse. It is characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic aspects over its lifespan.

Method

Males and females 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. Brains were analyzed for vascular characteristics such as vessel and junction density, vessel length, network complexity, number and diameter of collaterals.

Result

Our analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but interestingly their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was significantly decreased at 8 and 12 months in 5xFAD mice compared to WT; primarily driven by males. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.

Conclusion

The 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.
Feasibility and Satisfaction with Online, Livestreaming, Interactive, Group Movement Classes for People with Mild Cognitive Impairment or Mild Dementia and Care Partners
Authors: Nicosia Francesca M , Lee Amanda , Chesney Margaret A , Lee Jennifer Ann , Benjamin Cynthia , Mehling Wolf , Sudore Rebecca L , Barnes Deborah E
Published: December 2022

Background

Preventing Loss of Independence through Exercise (PLIÉ) is a gentle, in‐person, mind‐body, group movement program for people with dementia (PWD) or mild cognitive impairment (MCI); Paired PLIÉ includes dyads of PWD and care partners (CPs). We previously found that PLIÉ and Paired PLIÉ improve physical, cognitive, social, and emotional well‐being. This study assessed feasibility and satisfaction with an online version called Moving Together.

Method

Study participants were recruited through previous in‐person PLIÉ/Paired PLIÉ classes, caregiver support groups, social media, and word‐of‐mouth. Inclusion criteria were: ≥18 years old, live in U.S., be a PWD (typically with a CP) or have MCI (with or without CP), and be willing and able to participate in online Moving Together classes for 1 hour, 2 days/week for 12 weeks during the study period. We assessed feasibility based on program completion and class attendance and satisfaction using a post‐program evaluation survey with quantitative and open‐ended questions.

Result

A total of 39 people (18 PWD, 7 MCI, 14 CP) participated in 4 classes. PWD/MCI were 78 ± 16 years old, 56% female and 73% non‐Hispanic white. CPs were 66 ± 16 years old, 80% women, and 61% non‐Hispanic white. Nearly half (44%) had previously participated in‐person. Thirty participants (77%) completed the 12‐week program, of whom 24 (80%) completed the evaluation survey. Participants attended 75% ± 29% of classes. Ninety‐six percent (n = 23) rated the program as excellent (n = 19) or good (n = 4), and 88% (n = 21) were highly likely to recommend the program to others (scores of 8‐10 on 10‐point scale). Qualitative analyses revealed participant‐reported benefits for PWD, MCI and CPs in the domains of social connection (“camaraderie,” “like a family”), emotional well‐being (“happier,” “less stressed”), physical function/state (“balance has improved,” “more range‐of‐motion,” “stronger,” “energized,” “relaxed”), cognitive function (“more focus,” “learning new things”) and present‐centered body awareness (“more conscious of breathing patterns”). In addition, PWD/MCI experienced improvements in self‐concept/acceptance (“less immediate shame and more confidence”), and CPs reported improvements in caregiving efficacy (“greater purpose,” “more comfortable”).

Conclusion

The online Moving Together program is feasible for people with dementia or mild cognitive impairment and care partners. Participants report high satisfaction and positive outcomes.
Validation of the ki:e SB‐C a Novel Digital Speech Biomarker for Cognition in a Dutch Memory Clinic Population
Authors: Linz Nicklas , Mallick Elisa , Mina Mario , Possemis Nina , König Alexandra , Huurne Daphne B.G. ter , Ramakers Inez H.G.B. , Tröger Johannes
Published: December 2022

Background

Progressive cognitive decline is the cardinal behavioral symptom in most dementia‐causing diseases such as Alzheimer’s disease. Whereas classic neuropsychological tests often have excellent psychometric properties to measure cognitive decline in dementia, there are scenarios in which they are less suitable. Speech‐based digital biomarkers can be deployed remotely and extracted in a highly automated fashion allowing solutions to scale. We present the validation of a novel digital Speech Biomarker for Cognition (SB‐C) in a Dutch memory clinic population containing patients with Mild Cognitive Impairment (MCI) and age‐ as well as education‐matched participants with Subjective Cognitive Decline (SCD).

Method

The ki:e SB‐C is a novel speech‐based cognitive composite score. The presented validation results are based on a sample that was not used when developing the SB‐C. Validation data has been collected from two age‐ and education‐matched groups: Normal Cognition but subjective cognitive decline (SCD; n = 48, 15 F), MCI (n = 48, 18 F). We automatically extract the SB‐C from SVF and AVLT speech recordings using our proprietary speech analysis pipeline including automatic speech recognition and feature extraction. Recordings were collected from a Dutch memory clinic population containing MCI and SCD participants. We performed (1) analytical and (2) clinical validation. For (1) we performed Spearman rank correlation between SB‐C score and anchor score Mini Mental State Examination (MMSE) to show that the algorithm is correctly measuring the concept of interest cognition. For (2) we performed a non‐parametric Kruskal‐Wallis test to compare SB‐C scores of both NC and MCI groups.

Result

The biomarker score SB‐C and MMSE were strongly correlated (r = 0.61, p < 0.001), such that lower MMSE scores are reflected in lower biomarker scores (compare also figure 1). Additionally, there was a very significant group difference for the SB‐C biomarker score between the NC and MCI group (NC > MCI; χ2 = 26.461 (1), p < 0.001).

Conclusion

The ki:e SB‐C is a reliable score for cognition, showing convergent validity with the MMSE and separating well between MCI and SCD populations. The availability of valid digital speech biomarkers for cognition has great potential for decentralized clinical trials in dementia aetiologies and beyond.
Amyloid‐associated increases in soluble tau is a key driver in accumulation of tau aggregates and cognitive decline in early Alzheimer
Authors: Binette Alexa Pichet , Franzmeier Nicolai , Spotorno Nicola , Ewers Michael , Brendel Matthias , Biel Davina , Strandberg Olof , Janelidze Shorena , Palmqvist Sebastian , Mattsson‐Carlgren Niklas , Smith Ruben , Stomrud Erik , Ossenkoppele Rik , Hansson Oskar
Published: December 2022

Background

For optimal design of anti‐amyloid‐β (Aβ) and anti‐tau clinical trials, it is important to understand how Aβ and soluble phosphorylated tau (p‐tau) relate to the accumulation of tau aggregates assessed with positron emission tomography (PET) and subsequent cognitive decline across the Alzheimer's disease (AD) continuum.

Method

We included 327 participants from the Swedish BioFINDER‐2 cohort with cerebrospinal fluid (CSF) p‐tau217, Aβ‐PET, longitudinal tau‐PET, and longitudinal cognition. The main groups of interest were Aβ‐positive non‐demented participants and AD dementia patients (Table 1 and Figure 1), and analyses were conducted separately in each group. First, we investigated how soluble p‐tau217 and regional Aβ‐PET were associated with tau‐PET rate of change across the 200 brain parcels from the Schaefer atlas. We also tested the mediating effect of p‐tau217 between Aβ‐PET and tau‐PET change. Second, we investigated how soluble p‐tau217 and tau‐PET change related to change in cognition, and mediation between these variables.

Result

In early AD stages (non‐demented participants), increased concentration of soluble p‐tau217 was the main driver of accumulation of insoluble tau aggregates across the brain (measured as tau‐PET rate of change), beyond the effect of regional Aβ‐PET and baseline tau‐PET (Figure 2A‐C). Further, averaged across all regions, soluble p‐tau217 mediated 54% of the association between Aβ and tau aggregation (Figure 2D). Higher soluble p‐tau217 concentrations were also associated with cognitive decline, which was mediated by faster increase of tau aggregates (Figure 3). Repeating the same analyses in the AD dementia group, results were different. In late stage of AD, when Aβ fibrils and soluble p‐tau levels have plateaued, soluble p‐tau217 was not associated with accumulation of tau aggregates beyond baseline tau‐PET (Figure 4A), and cognitive decline was driven by the accumulation rate of insoluble tau aggregates and not soluble p‐tau217 (Figure 4B‐C).

Conclusion

Soluble p‐tau is a main driver of tau aggregation and future cognitive decline in earlier stages of AD, whereas tau aggregation accumulation is more likely an important driver of disease in later stages. Overall, our data suggest that therapeutic approaches reducing soluble p‐tau levels might be most favorable in early AD.
Functional networks underlying the association between tau pathology and memory
Authors: Ziontz Jacob , Harrison Theresa M. , Adams Jenna N. , Chen Xi , Cassady Kaitlin , Zhuang Kailin , Jagust William J.
Published: December 2022

Background

Tau pathology is associated with impaired episodic memory (EM) in both aging and Alzheimer’s disease (AD), but the mechanisms by which tau and memory are linked remain unclear. We hypothesized that strength of an EM‐defined functional brain network would mediate the relationship between tau and memory performance.

Method

Resting state fMRI was collected in 120 cognitively normal older adults from the Berkeley Aging Cohort Study (77.6 ± 6.4 years, 57.5% female), with a subset of 94 individuals receiving tau‐PET with 18F‐Flortaucipir and Aβ‐PET with 11C‐PiB. Functional connectivity (FC) for each ROI‐ROI pair of a 246‐region whole brain atlas was computed, yielding 30,000+ unique connections. LASSO regression of each of these values against an EM composite measure was used to select a sparse subset of connections related to greater EM performance. Overall strength of this network was computed as the sum of FC values for all selected ROI‐ROI pairs. Linear regression and causal mediation analyses were used to assess relationships between network strength and AD pathology.

Result

The EM‐defined network of 51 ROI‐ROI connections comprised limbic, temporal, and frontal regions (Figure 1). Adjusting for age and sex, reduced overall network strength was associated with an interaction between greater global Aβ and tau, both in an inferomedial temporal cortex meta‐ROI (b=‐26.97,p=.013; Figure 2a), and entorhinal cortex (b=‐14.01, p=.034; Figure 2b). For control analyses using an executive function‐defined network, overall network strength was not related to an Aβ‐tau interaction in the meta‐ROI (b=‐9.894, p=.415) or entorhinal cortex (b=‐6.206, p=.403; Figure 2c‐d). Causal mediation analysis revealed the effect of meta‐ROI tau on EM performance was mediated by the overall strength of the EM‐defined network (b=‐0.802, p=.017; Figure 3a), but not the executive function‐defined control network (b=‐0.098, p=.424; Figure 3b).

Conclusion

Using LASSO regression to select a sparse subset of functional connections related to EM in older adults, we found that reduced strength of this network was associated with the coincidence of greater tau and Aβ pathology. Alterations in behaviorally‐defined networks thus are reflective of AD pathology and appear to be a key factor in understanding its link to cognitive function.
Neuropathological evidence that the association between APOE‐e4 genotype and higher medial temporal lobe tau burden is mediated by higher local amyloid‐β levels
Authors: Salvadó Gemma , Vogel Jacob W , Beach Thomas G , Serrano Geidy E , Schneider Julie A , Ossenkoppele Rik , Hansson Oskar
Published: December 2022

Background

Evidence from previous PET imaging studies suggests that increased neocortical tau seen in APOE‐ε4 carriers can be explained by the higher levels of neocortical amyloid‐β (Aβ) pathology also seen in this group. However, these studies also suggest an amyloid‐independent association between APOE‐ε4 and medial temporal lobe (MTL) tau. Using neuropathological data, we investigated whether amyloid‐β in the MTL, which is difficult to accurately measure with PET, may fully mediate the association between APOE‐ε4 carriership and MTL tau burden.

Method

Amyloid‐β and tau pathology in MTL and neocortical areas have been measured in a total of 2,704 individuals from two independent neuropathological datasets (Arizona Study of Aging and Neurodegenerative Disorders, Brain and Body Donation Program, n=1,117 and ROSMAP, n=1,587; Table 1). Regression models were used to investigate the associations between APOE‐ε4 carriership and neocortical and local (MTL) amyloid‐β on MTL tau, adjusting for age, sex and presence of co‐pathologies. Based on these results, we also tested whether local (MTL) amyloid‐β mediated the association between APOE‐ε4 carriership and MTL tau.

Result

Supporting results from previous studies, APOE‐e4 carriers showed higher tau burden in the MTL (p<0.001) when amyloid‐β was not included in the model in both datasets. In independent models, both local and neocortical amyloid‐β were associated with MTL tau, with local amyloid‐β showing a stronger association with MTL tau in both datasets (Arizona: βMTL=0.93 vs. βneoc=0.76; ROSMAP: βMTL=0.42 vs. βneoc=0.40). When both measures were included in the model, local amyloid‐β also showed a stronger association with MTL tau in ROSMAP (βMTL=0.28 vs. βneoc=0.19). In the Arizona dataset, neocortical amyloid‐β effect became non‐significant (p=0.252) when local amyloid‐β was also included in the model. Finally, with mediation analyses we observed that MTL amyloid‐β fully mediated the APOE‐ε4 effect on MTL tau in both datasets (Figure 1). All statistics are reported in Table 2.

Conclusion

In two large neuropathological datasets, we showed that the association between APOE‐ε4 genotype and higher medial temporal lobe tau burden is mediated by higher local amyloid‐β levels. This finding contradicts some previous imaging literature, where only global amyloid‐β burden was considered.
Effect of diet on cognitive function and gut microbiota
Authors: Solch Rebecca J , Engler‐Chiurazzi Elizabeth , Harper Colin , Wasson Savannah , Ogbonna Sharon , Ouvrier Blake , McDonald Katherine , Wang Hanyun , Biose Ifechukwude Joachim , Bix Gregory J , Maraganore Demetrius M
Published: December 2022

Background

Alterations in the gut microbiota have been observed in patients with mild cognitive impairment and Alzheimer’s disease. Dietary consumption directly modulates gut microbiota; therefore, the quality of a diet may impact cognitive function and susceptibility to dementia. We hypothesized that consumption of the nutrient dense Mediterranean diet (MeDi) would improve cognitive function through beneficial changes to the gut microbiota as compared to the diet primarily consumed by Americans, the Western diet (WD).

Method

Ten‐week‐old Sprague Dawley male rats were assigned a MeDi (n = 10) or WD (n = 9). After three months, Morris water maze (MWM) was used to assess spatial reference memory cognition. MWM data were analyzed with two‐way RM ANOVA. Fecal samples were collected prior to the MWM. Microbial composition was determined by 16S rRNA sequencing, and analyses included Mann‐Whitney with false discovery rate.

Result

The MeDi group also spent significantly more time in the target quadrant during probe testing (p = 0.03) and was quicker to reach the platform on reversal testing (p = 0.004), indicative of improved cognitive flexibility. Microbiota α‐diversity indices, Shannon (p = 0.053), Simpson (p = 0.054), and Chao1 (p = 0.056), had a trend to be increased in the MeDi. Microbiota β‐diversity was dissimilar between diets (p<0.001). At the phylum level, Actinobacteria decreased and Patescibacteria increased with consumption of the MeDi as compared to the WD. Actinobacteria relative abundance correlated with MWM time in target quadrant (r = ‐0.58, p = 0.009). Further, relative abundance of Actinobacteria and Patescibacteria correlated with MWM reversal distance to reach platform (Actinobacteria, r = 0.77, p = 0.0001; Patescibacteria, r = ‐0.59, p = 0.007).

Conclusion

The MeDi maintained long‐term spatial memory, as measured by the MWM, compared to the WD. Additionally, diet‐modulated gut microbiota at the phylum level and these changes were correlated with cognitive function. Modulation of the gut microbiota through a neuroprotective diet, such as the MeDi, may serve as a method to improve cognitive function.
Effectiveness of a digitally supported care management program for family and other informal dementia caregivers: baseline data from the GAIN randomized controlled trial
Authors: Kilimann Ingo , Klein Olga A. , Thyrian Jochen René , Boekholt Melanie , Teipel Stefan , Hoffmann Wolfgang
Published: December 2022

Background

Almost two‐thirds of people with dementia (PwD) living at home receive care from a family or other informal caregiver. For the caregiver this can result in a work load comparable or above a full‐time employment position. Evidence shows that family caregivers have a higher risk for psychiatric and non‐psychiatric diseases like depression, anxiety, and arterial hypertension compared to non‐caregivers. A dyadic approach on disease management and the assessment of unmet needs can help to reduce the burden of care and increase the quality of life of caregivers and PwD. The cluster randomized “Gesund Angehörige Pflegen” (GAIN) trial conducted in general practitioner (GP) practices and memory clinics in Northern Germany aims to evaluate the effectiveness of a digitally supported care management programme to reduce unmet needs of informal caregivers of PwD.

Method

The recruitment for the GAIN trial began in October 2020 and will end in January 2022 with an estimated sample size of n = 200 caregiver. The GAIN baseline assesses the caregiver’s self‐reported unmet needs (Camberwell Assessment of Need for the Elderly, CANE), health‐related quality of life (EQ‐5D‐5L), caregiver burden (Zarit Burden Interview, ZBI), social support (Lubben Social Network Scale, LSNS), the use of medical and non‐medical services and resource utilisation.

Result

A blinded interims data quality control analysis (n = 86) documented 10.45 unmet needs on average, 4.55 unmet needs for the caregivers and 5.9 unmet needs connected to the PwD triggering a maxium of 8 suggested interventions per unmet need. These results are higher compared to the previous studies on unmet needs of dementia caregivers. The recruitment for the trial is currently still ongoing. Complete baseline results will be presented at the conference.

Conclusion

The use of a tablet‐based expert assessment system in memory clinics or GP praxis to identify unmet needs is well feasible. Caregivers of PwD recruited at GPs or memory clinics for the GAIN trial report a high number of unmet needs indicating the importance of a structured and in‐depth assessment to allow a personalized and dyadic treatment of family caregivers and PwD.
Improved risk prediction of all‐cause dementia, Alzheimer’s disease, and vascular dementia by inflammation‐related biomarkers
Authors: Trares Kira , Schöttker Ben
Published: December 2022

Background

Dementia risk prediction models, such as the widely used Cardiovascular Risk Factors, Aging and Dementia (CAIDE) model, combining factors from the fields of demographic, cognition, physical and health, have proven themselves. However, it is of interest whether inflammatory biomarkers additionally improve such dementia risk prediction models.

Methods

The Olink Target 96 Inflammation panel was assessed in serum samples of a large German, population‐based cohort study. In a nested case‐cohort design (n=1688), the CAIDE model was used for dementia risk prediction and aimed to improve by adding 72 inflammation‐related biomarkers of the Olink panel. Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression and bootstrapping were utilized to select relevant biomarkers and determine areas under the curve (AUCs) for all‐cause dementia, Alzheimer’s disease (AD) and vascular dementia (VD) in the total cohort, as well as in mid‐life and late‐life sub‐samples.

Results

Over 17 years of follow‐up, 440 participants developed dementia. Of those, 147 were diagnosed with AD and 195 with VD. The prediction model including APOE ε4 carrier status (CAIDE model 2) had a better discriminative ability for all‐cause dementia, AD, and VD than the model without APOE ε4 (CAIDE model 1) with AUCs of 0.751, 0.767, and 0.725, respectively. Adding 16 inflammation‐related biomarkers selected by LASSO regression to the CAIDE model significantly increased the AUC for all‐cause dementia risk prediction by 0.025 (95%CI: 0.001–0.045). The AUC increases for AD (0.024) and VD (0.019) were of similar magnitude but not statistically significant due to lower case numbers. Moreover, the CAIDE model generally performed better in mid‐life (50‐64 years) than in late‐life (65‐75 years) sub‐samples, and all increases in the AUC caused by inflammation‐related biomarkers were larger in the mid‐life sub‐sample.

Conclusion

Inflammation‐related biomarkers significantly improved the CAIDE model for all‐cause dementia prediction. Especially the predictive abilities of these blood‐based biomarkers in mid‐life are of clinical relevance to guide early preventive measures.
Value of plasma biomarkers to predict memory change in cognitively unimpaired individuals
Authors: den Braber Anouk , Verberk Inge M.W. , Tomassen Jori , Coomans Emma M , van der Landen Sophie M , Boonkamp Lynn , Dage Jeffrey L. , Stoops Erik , Willemsen Gonneke , Nivard Michel G. , van Berckel Bart NM , Scheltens Philip , Visser Pieter Jelle , de Geus Eco J.C. , Teunissen Charlotte E.
Published: December 2022

Background

Plasma levels of amyloid‐β1‐42/1‐40, phosphorylated‐tau (P‐tau) and glial fibrillary acidic protein (GFAP) can be used to predict amyloid‐β pathology in elderly cognitively unimpaired individuals, but their prognostic value in early Alzheimer’s Disease (AD) stages in the normal aging population needs further study. We aimed to investigate the value of these plasma biomarkers for predicting memory change in cognitively unimpaired individuals in a population‐based cohort.

Method

From the EMIF‐AD PreclinAD study we selected 188 individuals with normal cognition, who had plasma samples, amyloid‐β status and at least one cognitive follow‐up available (total follow‐up years (mean(SD) = 4.3(.42)) (Table 1). Amyloid‐β status was defined using visual read of dynamic [18F]flutemetamol‐PET images or CSF amyloid‐β1‐42/1‐40<0.066 (Euroimmun). Simoa assays were used to measure plasma amyloid‐β1‐42/1‐40 (AMYBLOOD), P‐tau181 (Eli Lilly) and GFAP (Quanterix) levels. Linear mixed models, adjusted for age, sex and years of education, were applied to test associations of baseline plasma biomarker levels with subsequent change in memory (plasma*time), and its interaction with amyloid‐β status (plasma*time*amyloid‐β status).

Result

From the total cohort tested, 31 subjects (16.5%) were amyloid‐positive. These individuals were older, showed worse baseline memory performance, lower plasma amyloid‐β1‐42/1‐40, and higher plasma P‐tau181 and GFAP levels compared to amyloid‐negative individuals (Table 1). Higher plasma GFAP levels at baseline were significantly associated with worse memory performance over time (GFAP*time: β=‐.03, p=.01). Interestingly, this relation was significantly stronger in amyloid‐positive compared to amyloid‐negative individuals (GFAP*time*amyloid‐β status: β=‐.07, p=.001) (Table 2, Figure 1). No significant associations were observed for baseline plasma amyloid‐β1‐42/1‐40 and P‐tau181 levels with change in memory over time (P‐tau181*time: β=‐.02, p=.07; amyloid‐β1‐42/1‐40
*time: β=.02, p=.12) (Table 2).

Conclusion

Our data suggest plasma GFAP can be used as a predictor of future memory decline in cognitively unimpaired, amyloid‐positive, individuals in the normal aging population. This supports the use of plasma GFAP as a prognostic marker for disease and treatment‐effect monitoring in the early stages of AD development.
Allowing “rescue therapy” in preclinical Alzheimer’s trials
Authors: Donohue Michael C. , Insel Philip S. , Aisen Paul , Delmar Paul , Giacobino Caroline , Ostrowitzki Susanne , Fontoura Paulo , Doody Rachelle S.
Published: December 2022

Background

Aduhelm’s recent approval, and the potential approval of additional effective therapies in early (prodromal‐to‐mild) Alzheimer’s disease (AD), will impact the conduct of clinical trials, including trials designed to delay or prevent cognitively unimpaired participants from progressing to mild cognitive impairment (MCI) or AD dementia. Allowing “rescue therapy” with these approved therapies during preclinical AD trials (“treatment policy design”) is expected to increase participation and improve adherence in these very large and long clinical trials. Our goal was to evaluate the impact of allowing “rescue therapy” on the study power using simulation.

Method

In the simulated study, cognitively unimpaired elderly adults with elevated levels of beta‐amyloid were randomized 1:1 to the control arm (starting on placebo and initiating “rescue therapy” upon progression to Clinical Dementia Rating [CDR] scale score > 0) or to the experimental arm (same experimental treatment throughout the study).

Key simulation parameters (placebo decline and variance) were based on the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and other cohort data. The continuous endpoint was Preclinical Alzheimer’s Cognitive Composite (PACC) scores. The triggering event to allow the start of “rescue therapy” was progression to CDR > 0. A range of different study design parameters (study duration, magnitude and timing of treatment effect, and continuous outcome vs time to event) were explored.

Result

Preliminary simulation results indicated that allowing “rescue therapy” had limited impact on the study power/sample size. They also suggested that continuous endpoints provided more power compared with a time‐to‐event endpoint in this setting.

Conclusion

This initial simulation study suggests that clinical trials of subjects in preclinical or at‐risk stages of AD that allow rescue medications during the trial may retain adequate power, with a limited impact on sample size, when analyzed with a primary treatment policy estimand. The potential benefit of the “treatment policy” approach in terms of recruitment and adherence/engagement cannot yet be quantified but could be substantial.
An examination of the usability of the Mayo Test Drive remote cognitive testing platform in older adults with and without cognitive impairment
Authors: Patel Jay S , Christianson Teresa J. , Karstens Aimee J , Stricker John L , Kremers Walter K. , Jack Clifford R. , Knopman David S. , Mielke Michelle M. , Petersen Ronald C. , Stricker Nikki H.
Published: December 2022

Background

Mayo Test Drive (MTD): Test Development through Rapid Iteration, Validation and Expansion, is a web‐based platform for self‐administered assessment for novel (Stricker Learning Span) and open access (Symbols Test) cognitive measures with previously demonstrated validity and reliability. Our study aim was to examine the usability of MTD, defined as the extent to which MTD was used to achieve the desired study goal of completing a testing session among participants willing to engage in an all‐remote study.

Methods

248 Mayo Clinic Study of Aging and Mayo Alzheimer’s Disease Research Center participants were invited to participate in this ancillary, uncompensated remote pilot study via email. To examine 1) willingness to participate in a remote cognitive assessment study and 2) usability of MTD, the initiation and completion rates of MTD were examined by cognitively unimpaired (CU; n = 142) and cognitively impaired (CI; n = 106) groups (see Figure 1). These rates and other factors associated with MTD feasibility were further explored across age in CU (i.e., 50–69, 70–79, and 80+ years) and specific diagnostic groups in CI (i.e., individuals with dementia, mild cognitive impairment (MCI), and possible MCI).

Results

Session completion rate (usability) was 98% across all participants who chose to participate, and, surprisingly, completion rates did not vary by age or diagnostic groups (p = .69; see Table 1). As expected, more individuals chose to participate in the CU (77%) versus CI (52%) group (p < .001). In terms of feasibility, individuals over 80 and with CI were more likely to have some contact with the study coordinator. Use of smartphones decreased with age, with most CU individuals over 70 using a personal computer (69‐73%; Table 2).

Conclusions

Though the CI group was less likely to choose to participate than the CU group, out of those that did choose to participate the rate of completion was 98%. This demonstrates high usability of MTD. Study coordinator support and a flexible testing platform is critical for facilitating participation in remote testing across the aging population, and more supports and incentives may be needed for individuals with cognitive impairment to improve participation rates.