bluuebunny/crossref_metadata_2025 huggingface dataset:
The Effects of Sex and APOE4 Genotype on Longitudinal Changes in White Matter Integrity Differ by Diagnostic Group Along the Spectrum of Alzheimer’s Disease
Authors: Blujus Jenna K , Oh Hwamee
Published: December 2023

Background

Sex and APOE ε4 (APOE4) are well‐established risk factors for Alzheimer’s disease (AD), with female ε4‐carriers at greatest risk. Uncovering the neurobiological substrates of sex and genetic effects in AD is critical to improve prevention, intervention, and treatment monitoring. While changes to white matter (WM) integrity are commonly noted in the progression of AD, it is unclear if these changes are further modulated by sex and APOE4 status. In the current study, we examined the effects of sex and APOE4 carrier status on WM integrity, both cross‐sectionally and longitudinally, across the AD continuum.

Method

A total of 457 participants (233 cognitively normal (CN), 167 mild cognitive impairment (MCI), and 57 AD; 223 females; 187 APOE ε4‐carriers) was selected from the ADNI database, based on the availability two diffusion MRI (dMRI) sessions. The dMRI data were processed using FSL’s TBSS pipeline to quantify the degree of fractional anisotropy (FA). Annualized FA change maps were created to measure voxel‐wise WM change over time. The effect of sex, APOE4‐carrier status, diagnosis, and their interactions, on cross‐sectional and longitudinal WM integrity were assessed by FSL’s randomise and cluster‐level correction, controlling for age.

Result

At baseline, females exhibited greater FA than males in the fornix, right inferior fronto‐occipital fasciculus, left inferior and superior longitudinal fasciculus, while males showed greater FA in the left corticospinal tract. Additionally, there were widespread differences across the skeleton by diagnosis, with FA decreasing stepwise across the continuum (CN>MCI>AD). There were no APOE4‐related differences in baseline WM integrity. Longitudinally, a three‐way interaction between diagnosis, APOE4, and sex emerged within the corpus collasum, left anterior thalamic radiation, left corticospinal tract, left uncinate fasciculus, and left inferior and superior longitudinal fasciculus. Posthoc analyses revealed that within the AD group, but not CN or MCI groups, females underwent greater WM degeneration than males among nonε4‐carriers, while males showed greater WM degeneration than females among ε4‐carriers.

Conclusion

These findings suggest that increased risk associated with sex and APOE4 genotype may change and interact with the progression of AD. Future studies are warranted to examine the contribution of cerebrovascular risk factors to AD progression in male ε4‐carriers.
Does parity and risk of dementia follow a U‐shaped relationship? Findings from the Cache County Study of Memory and Aging
Authors: Schliep Karen Cecilia , Bigler Erin Daniel , Meeks Huong , Fraser Alison , Smith Ken Robert , Ostbye Truls , Tschanz JoAnn T
Published: December 2023

Background

Recent evidence from the UK Biobank of over 273,000 women indicates a U‐shaped relationship between parity and risk of dementia, with nulliparity and grand multiparity showing increased risk of dementia compared to women having 1‐3 births after adjustment for important sociodemographic and health history factors, but not Apolipoprotein E (ApoE) polymorphism. ApoE4 genotype, a known risk factor for Alzheimer’s disease and Alzheimer’s disease related dementia (AD/ADRD), has been shown to be related to higher potential female fertility due to increased concentrations of progesterone. Our objective was to determine whether a similar U‐shaped relationship is present in the population based Cache County Study of Memory in Aging (CCSMA) cohort, after controlling for important confounding factors including ApoE genotype.

Methods

CCSMA was a longitudinal study that investigated risk factors contributing to AD/ADRD and other dementias. CCSMA enrolled 90% (N = 5,092, n = 2928 women) of the Cache County, Utah permanent resident population aged 65 and older as of January 1, 1995. Participants were followed for four triennial waves for AD/ADRD ascertainment. Prior number of live births for CCSMA women was assessed via self‐report and validated via linked Utah Population Database records (99% successful linkage). Adjusted risk ratios using Poisson regression with robust variance were calculated to assess whether parity was associated with later dementia risk, adjusting for important sociodemographic and health history factors (Table 1).

Results

Among the total sample, 5.6% were nulliparous, 18.4% had 1‐2 births, 54% had 3‐5 births, and 22% had 6+ births. Over the course of the study, 12% were diagnosed with AD and 7% with ADRD. Compared to women with 3‐5 births, women with zero, 1‐2, and ≥6 live births had an aRR of 1.16 (95% CI: 0.80, 1.69), 1.00 (95% CI: 0.76, 1.32), and 1.21 (95% CI: 0.96, 1.53) (Figure 1), respectively. Results were similar for ADRD.

Conclusion

Our results support a U‐shaped relationship between parity and dementia risk. Whether the relationship between parity and dementia risk is being driven by social and behavioral factors involved in parenting or biological factors associated with childbearing (e.g., total endogenous estrogen exposure) warrants further investigation.
Creation of a brain homeostatic model, digital twin, and digital population for functional assessment of lipidomics
Authors: Funk Cory C , Rohrs Jennifer , Paterson Tom
Published: December 2023

Background

AD is a complex, multifactorial disease, with ∼60% of variance attributed to genetics. Many studies have identified various biomarkers and lifestyle risk factors in the form of hazard ratios, relating biological mechanisms to cognitive decline. Numerous multiomic datasets (ADNI, ADSP, AMP‐AD) exist in the hopes of weaving an integrated understanding of AD pathophysiology. Traditional systems biology analyses of these datasets has demonstrated limited gains in assembling a cumulative understanding of how diverse molecular and clinical data fit together. Analyses of these proteomic, lipidomic, metabolomic datasets reveal a wealth of correlated molecular networks. Unfortunately, the functional significance of these networks is challenging to discern.

Method

We created a model of brain homeostasis and age‐driven cognitive decline, curating over 1,000 publications, and mathematically representing an array of Alzheimer’s‐related biological sub‐systems with 232 functional processes. Starting with a Digital Population of over 10 million hypotheses on the model’s foundation, we used ADNI non‐lipidomic data (APOE4 status, Abeta, Tau, MMSE, hippocampal atrophy) to create Digital Twins of 20 ADNI patients over four time points, spanning from cognitively normal to end‐stage disease. Using the ADNI lipid data from these same 20 patients, we identified 75 lipid networks, and looked for correlations between the those networks and synthetic data on the 232 functional processes from the patient’s Digital Twins.

Result

11 of the 75 ADNI lipidomic modules were highly correlated with 11 of the 273 functional processes in the digital twin synthetic data. These 11 functional processes were in the domains of microglia lipid droplet metabolism, reverse cholesterol transport, and neuron energy balance. Subsequent systems biology analyses of each of these lipid networks was consistent with the functional processes linked via the digital twin synthetic data. Principal component analyses of each lipidomic network yielded a quantitative assessment of the functional process that can serve as a “translator” to use those lipid data for even more accurate digital twins.

Conclusion

We have created a model of brain homeostasis that can be used to create a digital population to understand the non‐linear relationships of a diversity of omics data, bridging the gap between omics, intermediate functional processes and clinical outcomes.
The structural integrity of anterior‐temporal and posterior‐medial brain regions in Alzheimer’s disease and Parkinson’s disease: Effects of APOEε4, p‐tau181 and Aβ42
Authors: Coughlan Gillian T , Zhukovsky Peter , Sanchez Erlan , McLaughlin Paula , Grady Cheryl , Black Sandra E. , Munoz Douglas , Buckley Rachel F. , Masellis Mario
Published: December 2023

Background

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are two distinct neurodegenerative brain conditions associated with varying degrees of cognitive impairment, including an overlapping amnestic phenotype. At autopsy, APOEε4 and AD proteinopathies are associated with dementia severity in both AD and PD. The extent to which in‐vivo AD biomarkers are associated with memory and underlying regional brain volume in AD and PD patients is under‐investigation. Here, we focused on plasma biomarker associations with anterior‐temporal and posterior‐medial regions that are known to accumulate tau and Aβ in AD.

Method

Neuroimaging, biomarker, genetic and cognitive data were collected from 244 patients through the Ontario Neurodegenerative Disease Research Initiative (MeanAge = 68.96; 41% women; 35%APOE‐ε4‐carriers). Based on clinical diagnostic criteria, three groups were formed: i)AD with mild cognitive impairment or dementia(ADMCI/ADD;N = 120), ii)PD with MCI or dementia(PDMCI/PDD;N = 76) and iii)PD with normal cognition(PD‐NC;N = 48). Linear regressions assessed clinical diagnosis differences in the volumetric integrity of a priori regions: anterior‐temporal(ATN; including amygdala, fusiform gyrus, and ITG) and posterior‐medial(PMN; including PCC, parahippocampal cortex and precuneus;Fig1). Differences on related item recognition memory and associative memory was examined via the FaceName Association Task. APOE(ε4‐/ε4+), p‐tau181‐UGOT and Aβ42 associations between ATN/PMN and item recognition/associative memory outcomes were estimated. Diagnostic*APOEε4*ptau181 interactions were tested. Age, sex, education and ICV were covaried.

Result

Background characteristics showed that the ADMCI/ADD group exhibited the oldest age and the highest frequency of female sex and ε4‐carriership. ADMCI/ADD and PDMCI/PDD, but not PD‐NC, exhibited elevated ptau181 and Aβ42 relative to a healthy control group. Both ADMCI/ADD and PDMCI/PDD groups exhibited PMN and ATN degradation, as well as memory impairment, relative to the PD‐NC(Fig2A‐B). Plasma p‐tau181 was associated with ATN and PMN, as well as associative memory(Fig3A). APOEε4 was associated with PMN only, as well as item recognition(Fig3B). Diagnostic*APOEε4*ptau181 interactions were not significant. Post‐hoc analysis showed significant p‐tau181xAPOEε4 interactions on item recognition and total white matter hyperintensity(WMH;Fig3C). Aβ42 was not associated with outcomes.

Conclusion

Volumes of the ATN and PMN are lower in cognitively impaired AD and PD patients with higher p‐tau and/or APOEε4‐carriership. P‐tau and APOEε4 may work synergistically to promote domain‐specific memory impairment and WMH burden in both AD and PD.
Drug repositioning for Alzheimer’s disease and related dementias: Network meta‐analysis using individual participant data
Authors: Liu Yu‐Lun , Kong Zifang , Tao Cui , Chen Yong
Published: December 2023

Background

Alzheimer’s disease and related dementias (AD/ADRD) are chronic neurodegenerative pathology and bring a growing public health concern worldwide; particularly, treatments for AD/ADRD remain limited. Drug repositioning has alternate potential to provide an opportunity to accelerate newly identified treatments for individuals with AD/ADRD. Like, some studies have investigated effects of antihypertensive medications on dementia risk, but inconsistent results are reported. In this study, we aim to determine whether existing or approved drugs, including antihypertensive drugs and hormone replacement therapy, enable to reduce the risk of dementia or cognitive impairment.

Method

We searched PubMed, MEDLINE and EMBASE for published trials up to December 31, 2020. The primary outcome of interest was incident dementia or incident cognitive decline. We examined the following candidate repurposed drugs, including hormone replacement therapy and antihypertensive drug classes: diuretics, beta blockers (BB), angiotensin‐converting enzyme inhibitors (ACE‐I), angiotensin II receptor blockers (ARB), calcium channel blockers (CCB), alpha blockers, central agonists, vasodilators, and aldosterone blockers. We conducted a random‐effects network meta‐analysis using individual participant data to identify both direct and indirect evidence from the include trials.

Result

Four trials, including 19,632 participants and 10 candidate repurposed drugs, met the eligibility criteria, as shown in Figure 1. The results of network meta‐analysis were presented as a league table in Figure 2. We found that aldosterone blockers (OR = 2.32; 95% CI: 1.41 to 3.81), ARB (OR = 1.31; 95% CI: 1.07 to 1.60) and hormone therapy (OR = 1.36; 95% CI: 1.08 to 1.71) were less effective in reducing dementia risk when compared with ACE‐I. Moreover, all the other drugs reduced dementia risk statistically significantly compared with aldosterone blockers (ORs ranging from 0.46 (95% CI: 0.27 to 0.79) for alpha blockers to 0.59 (95% CI: 0.35 to 0.99) for hormone replacement therapy).

Conclusion

Our findings showed some classes of antihypertensive drugs may have more potential to prevent the incidence of dementia or cognitive decline than the other classes. However, further research for validation of our results is needed.
Relation between cortical thickness and frontal lobe P50 response in neurotypical aging: MEG study
Authors: Gumenyuk Valentina , Peled Noam , Korzyukov Oleg , Murman Daniel L , Rizzo Matthew , Miller Nicholas
Published: December 2023

Background

The auditory Event Related Potential (ERP) with latency at peak at 50 ms is a potential biomarker of prodromal Alzheimer’s disease (AD). However, the relation between P50 ERP and the thickness of the gray matter over frontal brain regions in healthy individuals over 55 y.o is not well studied. We examined the relation between frontal lobe generator of auditory P50 and degree of the gray matter volume lost in healthy individuals. We hypothesized that reduced thickness in the cingulate cortex is associated with aberrant function of the frontal lobe generator of the P50 response.

Method

Seven healthy subjects (ages 58‐72 years, 4 women) participated in the ongoing study. P50 response was calculated from magnetoencephalographic and electroencephalographic data during presentation of 7 tones (30 ms duration) ranging from 500 to 986 Hz. Each tone was preceded by 850 ms period of silence. Free‐surfer computed the cortical thickness for each subject as the distance between the gray/white matter boundary and the pial surface for each pair of vertices. 110 T1‐MPRAGE scans of elderly healthy controls (over 65 yo) from a Neurocognitive aging dataset were used as an average‐control group. To calculate the difference in thickness between averaged control and individual subject, the z‐value was applied. The template of 110‐averaged data was transformed into the subject’s space, and for each vertices we subtracted the mean and divide by the standard deviation

Result

In this study we show, that in subjects with less thickness in the cingulate cortex the amplitude of P50 response was enhanced with respect to those subjects who had more cortical thickness (Z value >5 vs. Z value <2). The aberrant function of the frontal lobe generator of P50 response was associated with enchanted amplitude of the P50 in MEG and EEG data.

Conclusion

Our results suggest that age‐related deficiency in frontal lobe generators of auditory P50 in healthy aging participants is associated with a reduction of gray matter volume in cingulate cortex. Present results support the notion about age‐related changes in modulatory role of frontal lobe generator of auditory P50 that are located at the cingulate cortex.
Mobile Early Detection Memory Screening project with Older Adults in Armenia utilizing the Montreal Cognitive Assessment Test (MoCA) in cooperation with mobile eyecare hospital.
Authors: Mahakian Jane
Published: December 2023

Background

The aim of the project is to address this tremendous gap in care by developing a unique multidisciplinary in‐home mobile clinic to address the need for cognitive screening as well as provide overall healthcare for the person with Alzheimer’s and their families. The Brain Health Armenia Project is an innovative approach to addressing the need for comprehensive cognitive screening as well as the overall care of the person with dementia in Armenia. This country wide project will increase cognitive screening rates and proper diagnosis as well as visibility and awareness of Alzheimer’s disease which will help decrease myths and fears about the disease.

Method

cognitive screenings by partnering with the Armenian EyeCare Project by assessing patients for cognitive screenings. The Armenian EyeCare Project is a Mobile Eye Hospital that provides care for people throughout Armenia since 2002. They also have five Regional Eye Centers. The Brain Health Armenia Project will provide cognitive screenings to people who come to the mobile Eye Hospital as well as to their Regional Eye Centers. Once screened, people who show impairment twill be offered to be part of the Brain Health Armenia Project. The Brain Health Armenia Project’s multidisciplinary team will make in home visits where they will administer assessments, provide referrals to neurologists; provide cognitive rehabilitation, care management and follow‐up; palliative and end‐of‐life care. The team will provide caregiver education and counseling about the disease as well as best practices for caring for their loved one.The target population is vulnerable adults living in Armenia’s regions outside of main city.

Result

Currently, around 14.4% of Armenia’s population is already over the age of 60 (Ryan, 2018). By 2050, 31.5% of Armenia’s population will be over the age of 60 (Ryan, 2018). The number of people in Armenia with Alzheimer’s disease is expected to grow exponentially in the coming decades.

Conclusion

This Project, which the Ministry of Health endorses, will increase the importance of cognitive screening as well as care of the person with dementia and be a significant program for the country’s National Dementia Plan. This project has revealed the prevalence of dementia in Armenia.
Can exercise benefit cerebral white matter myelin? Findings from a 12‐month randomized controlled trial in older adults with vascular cognitive impairment
Authors: Silva Nárlon Cássio Boa Sorte , Dao Elizabeth , Hsu Chun Liang , Tam Roger , Lam Kevin , Alkeridy Walid Ahmed , Laule Cornelia , Vavasour Irene M , Stein Ryan G , Liu‐Ambrose Teresa
Published: December 2023

Background

Cerebral small vessel disease is a major underlying cause of subcortical ischemic vascular cognitive impairment (SIVCI). Myelin loss is a feature of cerebral small vessel disease, which may underly cognitive and functional decline in older adults living with SIVCI. Resistance training (RT) is a form of exercise associated with slower progression of white matter lesions, a cerebral small vessel disease marker. However, it remains to be determined whether RT can counteract myelin loss in individuals living with SIVCI. Thus, we examined the impact of a 12‐month, twice‐weekly progressive RT program on myelin content in those with SIVCI.

Method

This was a sub‐study of a 12‐month single‐blinded, randomized controlled trial. Participants (n = 91) were randomized to RT or an active control group (balance and tone exercises [BAT]). Study eligibility included: 1) age 55 years and older; 2) magnetic resonance imaging (MRI) evidence of cerebral small vessel disease; 3) mild cognitive impairment; and 4) the absence of dementia. Myelin was measured using a multi‐echo gradient and spin echo T2 relaxation MRI sequence, indexed as myelin water fraction (MWF). Differences between groups at 12 months were assessed via analysis of covariance adjusting for baseline MWF and estimated intracranial volume. MWF data from fifteen white matter tracts were analyzed. Post‐hoc regressions were conducted to determine if changes in MWF were associated with changes in mobility measured with the Short Physical Performance Battery (SPPB).

Result

Seventy‐three participants (RT = 36) aged 74.1 (SD = 5.7), 64% females with high‐quality MRI data were included in the analyses. At 12 months, RT showed lower MWF levels compared with BAT in the genu of the corpus callosum (estimated mean difference [RT – BAT]: ‐0.610, 95% CI: ‐1.041 to ‐0.178, p = 0.006), fornix (‐0.883, 95% CI: ‐1.570 to ‐0.197, p = 0.012), and combined white matter tracts (‐0.326, 95% CI: ‐0.643 to ‐0.009, p = 0.044). Changes in MWF in the combined white matter tracs were positively associated with changes in SPPB (Unstandardized B = 0.124, SE = 0.061, p = 0.047).

Conclusion

Contrary to our expectations, 12 months of balance and tone exercises, but not RT, showed positive changes in myelin. These improvements may result in better mobility in older adults with SIVCI.
Effective strategies to recruit rural family/friend caregivers of persons living with dementia in the United States into a national randomized controlled trial: preliminary results
Authors: Yank Veronica A. , Santoyo‐Olsson Jasmine , Luzanilla Maritza , Romo Elizabeth Macias , Ramirez Giselle Aguayo , Chesla Catherine , Lorig Kate , Cheng Jing , Covinsky Kenneth E , Gallagher‐Thompson Dolores , Karliner Leah
Published: December 2023

Background

Family/friend caregivers of persons living with dementia (PLWD) in rural areas of the United States (U.S.) are more isolated and under‐served than urban counterparts[1] and are under‐represented in randomized controlled trials (RCTs)[2,3]. Our objective was to identify effective strategies for recruiting rural caregivers into a national RCT and describe baseline characteristics of enrolled caregivers.

Methods

We recruited U.S. rural caregivers of PLWD into an ongoing RCT evaluating the impact of an online asynchronous 6‐week workshop (“Building Better Caregivers”) on caregiver psychological health (June 2020‐present)[4] using multiple strategies (Table, row 1). We prospectively recorded characteristics of recruitment efforts (e.g., strategy type, cost, date) and caregiver responses (tick‐box, free‐text) to the eligibility survey question “How did you hear about the Building Better Caregivers study?” We performed descriptive analyses to determine the level of recruitment success of each strategy.

Results

Of 669 eligible caregivers, 360 (54%) enrolled to date (enrollment ends April 2023). Caregivers had mean age of 62.0 years (range 23‐86); identified primarily as White (87%), female (83%), and straight/heterosexual (90%); were caring for a spouse (44%), parent (43%), other relative (7%), or friend/neighbor (6%); and lived in all U.S. Census regions (34% West, 25% Midwest, 24% South, and 18% Northeast). Recruitment efforts with advertisements on Facebook, Google, and large media outlets (e.g., daily newspapers) had low success and cost money, whereas efforts through websites of trusted community/government agencies or local media (e.g., weekly newspapers) had medium‐to‐high success and were free (Table, row 2). Efforts to recruit through national associations had limited (low‐medium) success. Efforts to recruit through community agencies and health systems achieved high success when they had robust, searchable databases of PLWD/caregivers, mailing lists, and online resources. Some frontline caregiver experts (e.g., rural caregiver support specialists) achieved high recruitment but were challenging to identify in individual states and regions.

Conclusions

We successfully recruited rural dementia caregivers into a national RCT. We found that recruitment efforts were most effective when they engaged community‐based media, organizations, and experts to reach rural caregivers who trusted them. Rural recruitment is possible and necessary to achieve equitable trial access for vulnerable rural caregivers.
[18F]AV45 standardized uptake value ratio harmonization using ComBat in multi‐center cross‐sectional Alzheimer’s studies
Authors: Nazneen Tahnia , Servaes Stijn , Hosseini Seyyed Ali , Tissot Cécile , Rahmouni Nesrine , Therriault Joseph , Macedo Arthur C. , Tudorascu Dana , Rosa‐Neto Pedro
Published: December 2023

Background

[18F]AV45 (florbetapir) based Positron emission tomography (PET) imaging of brain amyloid load is one of the core biomarkers for Alzheimer’s disease (AD). However, with the rise in the trend of combining data from multicenter studies, the need to correct substantial technical variability associated with image intensity scale due to multi‐center effect continues to rise. While smoothing methods remove small variability, data‐driven feature harmonization methods can adjust for scanner settings and patient motion without over‐blurring the scans. Here we aimed to investigate the effect of ComBat harmonization on multi‐site florbetapir studies to reduce variance across diagnosis groups.

Method

We assessed 163 scans from the Alzheimer’s disease Neuroimaging Initiative (ADNI3) database. These scans were acquired from 14 different sites. T1‐weighted MRI images were processed using the ADNI pipeline. PET images had 20 min (4×5min frames) acquisition at 50‐70 min post‐injection of 370 MBq (10.0 mCi) ± 10% florbetapir. Raw PET images from all sites were downloaded for quality control at the University of Michigan where the rest of the preprocessing took place using ADNI guidelines. These preprocessed scans were then used to extract SUVR maps using the cerebellar gray matter as the reference region. Based on the literature, the global SUVR for each subject was estimated from the averaged frontal, parietal, temporal, and cingulate cortices. ComBat harmonization was then performed using multicenter data, preserving diagnosis group as the covariate. A paired t‐test and logistic regression were performed to analyze the effect of the harmonization method on the SUVR.

Result

A paired t‐test confirms the significant difference between the pre‐and post‐ComBat SUVR, especially for AD samples. Although the variance only decreases by 7.1% for CN as opposed to 26.9% (MCI) and 55.4% (AD), this may be explained by the large variance in the age in the sample as well as the possibility of amyloid positive individuals in the CN population. The logistic regression shows an accuracy of 87.9% for AD.

Conclusion

Even though ComBat harmonization significantly reduces the variance in AD and MCI population, more studies need to be performed to check its use across all PET derived features.
Antagonistic Amyloid‐β and tau interactions with T1‐weighted/T2‐weighted magnetic resonance ratio in Alzheimer’s disesase continuum
Authors: Lim Hyeon‐Wu , Seong Joon‐Kyung , Lee Wha‐Jin
Published: December 2023

Background

Tau protein has been reported as a major cause of neurodegeneration in Alzheimer’s disease (AD) continuum. Decrease of T1‐weighted/T2‐weighted magnetic resonace (MR) ratio has been proposed as a measure of demyelination related to neurodegeneration, but some previous researches showed contradictory increase in several brain regions, which was considered as the effecs of other microstructures such as the amyloid‐related iron deposition. Therefore, amyloid β and tau proteins appear to affect the T1w/T2w ratio antagonistically, making their relationship need to be elucidated in order to unambiguously interpret the ratio.

Method

We obtained 221 individuals which include T1‐ and T2‐weighted MR images, and 18F‐florbetapir‐ and 18F‐flortaucipir‐PET images from ADNI. The subjects were then divided into four subgroups based on the status of global Aβ and tau accumulation amount: A‐T‐, A‐T+, A+T‐, and A+T+. We determined positive amyloid status(A+) as global Aβ PET SUVR > 1.11. When determining tau positivity, we used entorhinal cortex (EC) as the earliest tau accumulation region to selectively include tau‐negative individuals while amyloid is being presented. Group differences in regional T1w/T2w ratio values were evaluated.

Result

We found significant group differences in various cortical regions, but also observed distinct effects of Aβ and tau for the T1w/T2w difference. First of all, Aβ and tau affect the T1w/T2w ratio in an opposite direction. A+ individuals have greater T1w/T2w ratio values across wide cortical regions compared to A‐ individuals for both T‐ and T+ groups. However, A‐T+ groups have smaller T1w/T2w ratio values than A‐T‐ groups, while the significant group difference was observed across relatively few cortical regions. Second, Aβ has stronger effect on the T1w/T2w ratio than tau. Specifically, the group difference between A+T+ and A+T‐ shows that Aβ increase the ratio values more strongly than tau reduces the ratio values due to greater accumulation of Aβ in the A+T+ than A+T‐.

Conclusion

In this work, we observed the antagonistic interaction of Aβ and tau with T1w/T2w ratio, while more interestingly, we also found that Aβ causes high T1w/T2w ratio, more than tau causes demyelination, followed by lowering T1w/T2w ratio.
In vivo Braak staing using 18F‐MK‐6240 PET in Alzheimer’s disease
Authors: Kang Jae Myeong , Park Kee Hyung , Noh Young
Published: December 2023

Background

This study aimed to identify the distribution of [18F]MK‐6240 PET retention and classified according to Braak staging in Alzheimer’s disease (AD). We also evaluated the relationship between [18F]MK‐6240 PET retention and cognitive functions and neurodegeneration.

Method

We enrolled 194 participants including 70 CU (cognitively unimpaired elderly participants older than 60 years old), 56 MCI, 60 probable AD, and 8 patients who had dementia other than AD (subcortical vascular dementia (n = 3), semantic variant primary progressive aphasia (n = 2), frontotemporal dementia (n = 2), corticobasal syndrome (n = 1)). All participants underwent 3T MRI, [18F]MK‐6240, and [18F]Flutemetamol (FLUTE) PET scans, APOE genotyping, and detailed neuropsychological tests. Braak staging was defined as the stages where regional SUVR of ROIs composing each Braak stage > = 1.3. We assessed the Braak staging in the subjects. Correlation analyses between global retention of MK‐6240 PET and neuropsychological test results or neurodegeneration were performed using linear regression.

Result

The proportion of amyloid positivity was 11.4% in CU, 45.5% in MCI, and 83.3% in probable AD. Among probable AD (n = 60), 12 patients were classified to other dementia after amyloid PET and tau PET confirmation. Main Braak stage was Braak 0 in CU, Braak III/IV in amyloid (+) MCI, Braak V/VI in AD dementia. In CU an patents with AD spectrum, global retention of MK‐6240 PET was significantly correlated with MMSE, CDR SOB, language, visuospatial function, memory and frontal/executive functions. In addition, global retention of MK‐6240 PET was correlated with the MRI markers for neurodegeneration, that is, mean cortical thickness and hippocampal volumes.

Conclusion

[
18F]MK‐6240 PET successfully identified the Braak staging and associated with amyloid pathology and clinical phenotype in patients with AD. MK‐6240 PET also correlated with cognitive functions and neurodegeneration. MK6240 is a promising tau PET tracer with the potential to be sensitive surrogate markers of AD.
Neuronal SIRPα modulates disease pathology and progression in a mouse model of Alzheimer’s disease
Authors: Samuel Melanie , Iakova Polina , Abdulwahab Qudrat , Andrade Pilar , Jiang Danye
Published: December 2023

Background

Microglia are phagocytic cells that play multiple critical roles in Alzheimer’s disease susceptibility and progress. In parallel, they display remarkable diversity in their functional and molecular states in the context of disease. This suggests that a diverse portfolio of microglial subtypes modulates outcomes in AD, but the molecules that link microglia state to their function remain unknown. To address this question, we have probed whether microglia phagocytic states are regionally specified by brain neurons via a particular neuron‐derived receptor‐ligand pair – signal regulatory protein alpha (SIRPα) and CD47.

Methods

To investigate the role of SIRPα, we use cell‐specific loss‐ and gain‐of‐function genetic approaches together with murine AD models.

Results

Our data surprisingly show that neuron‐derived SIRPα is crucial for regulating microglial phagocytic function and phagocytic state in the context of AD. Neuronal SIRPα appears to achieve this by acting as a decoy receptor to prevent microglial CD47‐SIRPα signaling, thereby permitting microglia phagocytosis. In addition, we show that neuronal SIRPα alters microglia state by regulating microglia phagocytosis in a brain‐region specific manner. We have also identified AD pathology changes and cognitive dysfunction that are limited by neuronal SIRPα‐driven microglial phagocytosis.

Conclusion

We show that neuronal SIRPα is a permissive cue for microglial phagocytosis in AD and is required to restrict AD progression and cognitive decline. Identification of a neuron‐derived mechanism that dictates microglia state plasticity is unexpected and changes the way we understand how neurons program microglia outcomes in the context of disease. Results from this study also help lay the groundwork for new therapeutic options to regionally modify brain microglia state and function.
Memory focused cognitive training for older people with MCI: A CogTale Meta‐Analysis
Authors: Bahar‐Fuchs Alex , Chesser Courtney , Hampstead Benjamin M.
Published: December 2023

Background

Cognition‐oriented treatments (COTs) such as cognitive training (CT) are effective for improving cognition in people with MCI. Although multi‐domain CT has positive effects on global cognition, the extent to which memory‐focused CT impacts memory functions more specifically, and how process‐based, strategy‐based, and group‐based CT studies compare remains unknown.

Method

We conducted a systematic review using CogTale (Sabates et al. 2021), a novel evidence synthesis tool which automates aspects of the meta‐analysis pipeline. Embase, Medline and PsycINFO databases were searched from inception to 19/10/2022. Studies reporting the results of a controlled, memory‐oriented CT intervention for people with MCI, and that reported at least one cognitive outcome were eligible. Multi‐domain CT, multicomponent interventions were excluded. Data from eligible studies was extracted into the CogTale platform, and methodological quality scores were computed for each study. Random effects inverse variance meta‐analysis was performed for all outcomes reported by a minimum of three studies, and confidence in the effect estimates was computed based on heterogeneity, precision, and risk of bias.

Result

After removing duplicates, 653 studies were screened and 101 studies underwent full‐text review, of which 24 (17 reporting any strategy, 16 individually‐delivered) were eligible. Across studies, small to moderate effects were found for auditory‐verbal, visuospatial, and mixed memory outcomes, and for working memory. Findings were similar when only studies using any memory‐strategy were included (k = 17). However, when studies using only mnemonic strategy training (MST) were analysed (k = 8), effect estimates for the small number of outcomes that could be pooled did not reach significance, but the confidence in these findings was low.

Conclusion

Memory‐oriented CT studies are associated with gains in measures of memory and working memory but not on measures of global cognition in people with MCI. Although the analysis suggested that the use of any‐memory strategy (e.g., MST, errorless learning, spaced retrieval) were associated with similar effects, when examined in isolation, no evidence was found that MST‐based CT is associated with gains on any outcomes studied. More high‐quality studies of MST‐based CT are needed to determine whether this effortful approach to CT is beneficial relative to less effortful approaches such as rehearsal‐based CT.
A toolkit to study microglia states using stem cell‐derived models
Authors: Therrien Martine , Dolan Michael John , Jereb Sasa , Kamath Tushar , Meyer Daniel , Atkeson Trevor , Glass Christopher K. , Leinonen Ville , Blurton‐Jones Mathew , Macosko Evan , Stevens Beth
Published: December 2023

Background

Emerging genetic studies of late‐onset Alzheimer’s Disease (LOAD) implicate microglia, the brain’s resident macrophages. More than half the risk genes associated with LOAD are expressed in microglia, yet we know little about the underlying biology or how myeloid cells contribute to LOAD pathogenesis. Single‐cell transcriptomic studies reveal diverse microglial states in patients and mouse models; however, we lack tools to track these states and understand the impact of environmental challenges or genetic susceptibility.

Method

We used human embryonic and induced pluripotent stem cell models to gain insights into microglia. These cells can be differentiated into microglia, enabling the broad characterization of cells in vitro and understanding their impact on the other cell types in xenograft models, allowing us to gain biological insight into disease pathogenesis.

Result

Our lab has developed a novel human stem cell‐based platform1 which induces stem cell‐derived microglia (iMGLs) to take on diverse transcriptional signatures similar to those found in the human brain in response to exposure to brain‐relevant substrates. Moreover, we conceived a lentiviral protocol that allows for efficient genetic manipulation of microglia (>90% transduction). Building on these systems, we generated reporters of microglia state to track the expression of key microglial genes and adapted iPSC “villages”2, or pooled cultures, that combine iPSC cell lines in the same dish. Using these tools in vitro and in xenograft models3,4, we identified genetic regulators and functional changes of microglia states in LOAD.

Conclusion

Together, these tools represent a broad toolset that will allow us to answer some of the most pressing questions, such as when and how in disease these states are formed, what is their impact on disease progression, and how plastic they are. These tools will be invaluable to understanding the role of microglia in AD and the brain in general.

1. Dolan, M.‐J. et al. Biorxiv 2022.05.02.490100 (2022)

2. Wells, M. F. et al. Biorxiv 2021.11.08.467815 (2021)

3. Hasselmann, J. et al. Neuron
103, 1016‐1033.e10 (2019)

4. Mancuso, R. et al. Nature Neuroscience
22, 2111‐2116 (2019)
Multiomics of iPSC‐derived ApoE3‐ and ApoE4 astrocytes and microglia uncovers cell type specific dysregulation of immunometabolism
Authors: van der Kant Rik , Blomberg Niek , Erlebach Lena , Feringa Femke M , Heijneman Jorin , Koppes Sascha , Kruijff Iris Daphne , McQuade Amanda , Miramontes Ricardo , Olivier‐Jimenez Damien , Robert Aiko , Thompson Leslie M. , Ori Alessandro , Kronenberg‐Versteeg Deborah , Mohammed Yassene , Kampmann Martin , Giera Martin
Published: December 2023

Background

ApoE4 is the major genetic risk factor for Alzheimer’s disease and the main lipid transporter in brain. How ApoE4 drives AD pathogenesis, and how this is related to changes in lipid metabolism, is not well understood. This lack of mechanistic insight has hampered the development of interventions that can reverse the pathological effects of ApoE4.

Methods

Here we perform integrated multiomic analysis (lipidomics, metabolomics, transcriptomics and proteomics) on isogenic iPSC‐derived glia carrying an ApoE4/4, ApoE3/3 or ApoE‐knockout genotype. We employ pathway enrichment to identify candidate biological processes that contribute to AD pathogenesis and perform a number of biochemical‐ and intervention experiments to gain insight into the biological mechanism. We feed iPSC‐derived glia with different lipid species to better understand the interaction between lipids and immune dysfunction. Lastly, we generate a new open‐access resource (the Neurolipid atlas), to allow others in the field to interact with our lipid data.

Results

Our lipidomic analysis shows that ApoE4 has a major effect on lipid metabolism in human iPSC‐derived astrocytes and microglia. In both astrocytes and microglia, ApoE4 causes accumulation of cholesteryl esters (CE), triglycerides (TAG) as well changes in ceramide metabolism. Interestingly, transcriptomic and proteomic analysis in both cell types shows that ApoE4 glia have strongly upregulated cholesterol synthesis despite having already high levels of stored cholesterol (CE). Astrocytes and microglia show very distinct adaptations to ApoE4 in terms of energy production. Whereas ApoE4 astrocytes have higher levels of mitochondrial proteins, ApoE4 microglia downregulate mitochondrial proteins but have increased levels of key glycolytic proteins. Immune profiles, including DAM signatures in microglia, are changed in a similar direction in both ApoE4 astrocytes and microglia. Lipid feeding also directly affect these immune pathways.

Conclusion

Our data indicate that astrocytes and microglia display both common and distinct immunometabolic adaptations to the ApoE4 genotype. Interestingly, both ApoE4 microglia and astrocytes have increased stored cholesterol yet keep upregulating cholesterol synthesis, indicating a possibly pathogenic broken feedback loop. We also show that this altered lipid metabolism is tightly coupled to immune dysfunction and propose novel mechanisms and interventions that may normalize ApoE4 dysfunction in human glia in AD.
An agenda for addressing multimorbidity and racial and ethnic disparities
Authors: Quiñones Ana R.
Published: December 2023

Advancements in Alzheimer’s disease and related dementias (ADRD) research on the U.S. population acknowledge the importance of the high burden of ADRD on segments of the population and yet‐to‐be characterized risks attributable to the burden of multiple chronic diseases (multimorbidity). These realizations suggest successful strategies in caring for people with ADRD and their caregivers will rely not only on clinical treatments but also on more refined and comprehensive models of ADRD that take its broad effects on the whole‐person and the whole of society into consideration. To this end, it is critical to characterize and address the relationship between ADRD and multimorbidity combinations that complicate care and lead to poor outcomes, particularly with regard to racial and ethnic disparities in the occurrence, course, and effects of ADRD.
Observations on biomarkers in Roche Abeta‐targeting monoclonal antibody trials
Authors: Doody Rachelle S.
Published: December 2023

Background

One of the profound innovations in Alzheimer’s disease research has been the ability to image beta‐amyloid plaques in living patients with the use of amyloid PET imaging. This technology, coupled with advances in basic research that supported mechanisms of action targeting beta amyloid, and innovations in the clinical profiling of AD patients and in clinical trial designs have enabled the disease‐modification era for AD therapeutics.

Method

While identifying amyloid plaques in living patients has greatly helped to stratify populations for study and treatment, measured changes in plaque burden during treatment with anti‐beta amyloid drugs has not proven to be a simple outcome measure that directly quantifies clinical benefit. Dissociations between amyloid reduction and downstream markers of AD pathology, such as those seen in the crenezumab and gantenerumab Autosomal Dominant AD studies (NCT01998841 and NCT05552157) suggest that the brain processes associated with AD can improve without causing concurrent measurable benefits in people at risk for or affected by genetic forms of AD, with or without lowering plaque burden.

Result

Biomarker results in the phase III GRADUATE I and II (NCT03444870 and NCT03443973) trials with gantenerumab in early AD (sporadic) also suggest that even moderate reduction of beta‐amyloid plaques may not result in clinically meaningful benefits over a therapeutic time course that makes sense for patients, while the phase III CLARITY‐AD trial (NCT01767311) with lecanemab and phase III TRAILBLAZER‐ALZ 2 trial (NCT04437511) with donanemab suggest that enough reduction can cross the threshold for clinical efficacy. Taken together, these study data suggest that plaque depletion to a level near or below the amyloid PET positivity threshold may be necessary to see clinical benefit with this type of monotherapy.

Conclusion

This observation, if confirmed, would not rule out the use of beta amyloid lowering therapies that do not completely clear beta amyloid when used in combination approaches.
Lecanemab: Amyloid Reduction and Evidence of Downstream Biomarker Modification
Authors: Irizarry Michael C.
Published: December 2023

Background

Lecanemab is a humanized IgG1 monoclonal antibody that targets soluble aggregated Aβ species (protofibrils) which has demonstrated robust brain fibrillar amyloid reduction and slowing of clinical decline in a Phase 3 Study in early AD (Study 301). The objective of this analysis is to report biomarker results from Study 301.

Methods

Study 301 was a double‐blind, randomized, placebo‐controlled study of 1875 patients with early AD randomized to 10 mg/kg IV lecanemab or placebo for 18 months of treatment. Plasma, CSF, and imaging biomarkers of amyloid, tau, neurodegeneration, and gliosis were assessed.

Results

Lecanemab met all primary and key secondary clinical endpoints with a high degree of statistical significance. Lecanemab improved markers of amyloid with reduction of brain amyloid by PET in as early as 3 months and improvement in CSF Aß42 and plasma Aß42/40. Biomarkers of tau showed improvement in CSF and plasma p‐tau181, and slowing of tau accumulation relative to placebo in the medial temporal regions by tau PET. For biomarkers of neurodegeneration and gliosis, there was improvement in CSF t‐tau, CSF neurogranin, and plasma GFAP. There were no significant differences in CSF or plasma Nf‐L between lecanemab and placebo. Volumetric MRI results were inconsistent, with reduced hippocampal atrophy on lecanemab, but greater cortical volume loss relative to placebo, possibly “pseudoatrophy” related to amyloid mobilization.

Conclusions

Lecanemab treatment resulted in significant reduction in amyloid plaques and a slowing of clinical decline. Improvements in biomarkers of amyloid, tau, neurodegeneration, and gliosis provide a biological basis for the treatment effects consistent with disease modification.
Uncovering the burden of Dementia in the Middle East and North Africa (MENA) Region: current situation, opportunities, and challenges
Authors: Chaaya Monique
Published: December 2023

The increase in the aging population in the Arab countries of MENA is consistent with the global trend. Yet, several countries in the region have no to little information about dementia burden. Projections are dire but preparedness is limited. Dementia studies from the Arab region remain scarce and available ones suggest that the disease incidence in an Arab population is higher than a population with similar literacy and educational profile. The only published study reporting on dementia incidence in the Arab region is from Egypt. Unpublished data from Lebanon reported a rate falling in the high range of incidence, lower than Venezuela, Mexico, and China and close to European and North American countries’ estimates. Using standardized and validated tools, in collaboration with Danish research experts in dementia, and with funding from Fogarty, Lebanese researchers were able to measure the burden of dementia among community based older adults. (crude prevalence 7.4% and standardized is 9). A more recent research activity supported by an NIA R01 grant and in collaboration with US‐based researchers, will establish a cohort study of 3000 older adults to assess ADRD burden, risk factors and dementia. Lebanon have benefited from two NIH funding opportunities to establish collaboration, train scientists, and build the infrastructure to study Dementia.