bluuebunny/crossref_metadata_2025 huggingface dataset:
Neuropeptide Alterations in Alzheimer's Disease: A Meta‐Analysis of Cerebrospinal Fluid Concentrations
Authors: Muneer Muneeb Ahmad , Suresh Vinay , Bhonsale Aman Milind , Vasipalli Sonit Sai , Kumar Vignesh , Gowda Poorvikha , Javed Binish , Bardhan Mainak , Garg Ravindra Kumar , Malhotra Hardeep Singh
Published: January 2025

Background

Neuropeptides are crucial proteins in the central nervous system, which significantly influence neurophysiological processes. This analysis explores cerebrospinal fluid alterations in Alzheimer's disease, offering insights to better understand the condition and explore novel diagnostic and therapeutic avenues.

Method

We systematically searched MEDLINE (PubMed), EMBASE, Cochrane, and Scopus using specific search strategies. Following PRISMA guidelines, our screening and extraction included studies that investigated neuropeptide concentrations in Alzheimer's patients' cerebrospinal fluid (CSF). Utilizing the 'meta' R package, particularly the 'metacont' tool, we analyzed mean concentration levels and standard differences via the random effects model. Data pooling utilized inverse variance weighting, with I² and tau² assessing heterogeneity. The restricted maximum−likelihood estimator and Q−profile informed tau² and its confidence interval. The primary outcome was the mean difference in CSF neuropeptide levels between Alzheimer's patients and controls, considering reported units separately.

Result

In our analysis of neuropeptides across diverse studies involving Alzheimer's Disease (AD) patients and controls, we observed distinct neurochemical alterations. Somatostatin showed a significant mean difference of ‐15.48 pg/mL (95% CI: ‐20.95 to ‐10.01, I² = 89%) in 9 studies (141 AD, 203 controls), and ‐8.05 pmol/L difference (95% CI: ‐13.35 to ‐2.76, I² = 0%) in 2 studies (44 AD, 57 controls). Neuropeptide Y (NPY) showed ‐8.83 pg/mL difference (95% CI: ‐19.81 to 2.16, I² = 65%) in 5 studies (76 AD, 95 controls), and ‐16.85 pmol/L difference (95% CI: ‐35.21 to 1.52, I² = 71%) in 3 studies (87 AD, 62 controls). Orexin exhibited a difference of 8.03 pg/mL (8 studies: 235 AD, 177 controls; ‐2.60; 18.67, I² = 27%, p‐value: 0.14). After excluding a study that significantly reduced heterogeneity, the adjusted result was 12.77 (95% CI: 1.16 ‐ 24.39, p‐value: 0.03). Substance P also showed a reduction in mean difference by ‐16.52 pg/mL (2 studies: 45 AD, 35 controls; ‐67.47; 34.42, I² = 87%) but was not statistically significant.

Conclusion

Somatostatin exhibited a consistent decrease in levels across studies, indicating potential relevance to AD pathophysiology. Additionally, orexin demonstrated a significant increase in levels in individuals diagnosed with Alzheimer's.
Markers of Interstitial Fluid Dynamics from Diffusion MRI Reveal Association with Amyloid Deposition in Cognitively Normal Older Adults
Authors: Chen Chang‐Le , Jin Hecheng , Schweitzer Noah , Minhas Davneet S , Villemagne Victor L , Yang Shaolin , Aizenstein Howard J , Wu Minjie
Published: January 2025

Background

Glymphatic clearance dysfunction within the perivascular space has been implicated in Alzheimer's Disease (AD) pathology. Diffusion MRI‐based techniques such as DTI‐ALPS can quantify perivascular interstitial fluid (ISF) dynamics, yet their links with other early AD markers in the cognitively normal elderly population remain underexplored. Here, we investigated associations between DTI‐ALPS and cerebral β‐amyloid (Aβ) burden measured with Pittsburgh Compound B (PiB)‐PET. We also evaluated an augmented version of DTI‐ALPS to enhance sensitivity and better reflect the ISF diffusivity potentially associated with glymphatic function.

Methods

Diffusion tensor images (DTI) and PiB‐PET images were collected from 40 cognitively normal older adults (age: 74.8 [5.8] years, sex: 18 males, mini‐mental state examination (MMSE): 28.8 [1.4], APOE‐e4%: 23%). Based on the DTI (acquired on a 3T MRI scanner with 12 diffusion directions, b‐value = 1000, and voxel size in 2 mm cubic), we estimated DTI‐ALPS index that evaluates the perivascular ISF movement along the medullary conduits and also developed an algorithm to generalize the definition of the traditional DTI‐ALPS by automatically localizing the periventricular space as the target area and calculating transverse tensor ratios as the primary measure (Figure 1). PiB‐PET analysis followed our previous validated approach, and the regional standardized uptake value ratios (SUVR) representing PiB retention relative to the cerebellar gray matter were averaged to determine global cerebral Aβ burden. Linear regression analysis was applied to investigate the relationship between DTI‐ALPS and global PiB‐PET SUVR.

Results

The baseline model with the predictors of age, sex, MMSE and APOE4 status significantly explained the logarithmic global SUVR of PiB‐PET (Figure 2). When incorporating DTI‐ALPS indices, the baseline models were significantly improved (Likelihood‐ratio test: both p < 0.01); the explained variance increased by 15.3% and 19.3% by adding traditional and proposed augmented DTI‐ALPS indices, respectively. The models indicated that the DTI‐ALPS indices were significantly negatively associated with the global Aβ burden after adjusting the covariates (Figure 2).

Conclusion

We observed that higher ISF diffusivity (likely better glymphatic clearance) corresponds to lower PiB‐PET retention (lower Aβ burden) in the cognitively normal older adults, suggesting the potential utility of ISF measures as a putative AD biomarker.
Sex Differences in Amyloid PET in a Large, Real‐Life Sample from the Imaging Dementia‐Evidence for Amyloid Scanning (IDEAS) Study
Authors: Raya Maison Abu , Zeltzer Ehud , Schonhaut Daniel R. , Allen Isabel Elaine , Carrillo Maria C. , Gatsonis Constantine , Hanna Lucy , Hillner Bruce E , Iaccarino Leo , March Andrew , Mundada Nidhi S , Mejía‐Perez Jhony Alejandro , Siegel Barry A. , Windon Charles , Whitmer Rachel A. , Joie Renaud La , Rabinovici Gil D.
Published: January 2025

Background

Previous studies on sex differences in amyloid burden have shown inconsistent findings. We examined the effect of sex on amyloid‐PET outcomes in a large, real‐world, cohort of individuals with cognitive impairment.

Method

The IDEAS study evaluated the clinical utility of amyloid‐PET in 18,295 Medicare beneficiaries age ≥65 years with MCI or dementia. All scans were visually interpreted as positive or negative at each site by a local radiologist or nuclear medicine physician. A subset of 10,361 scans were centrally processed and quantified in Centiloids. We used multivariate logistic regression to calculate odds ratios of amyloid‐PET positivity (based on visual read) for males and females, adjusting for demographic and clinical risk factors. We used linear regression to assess the association between sex and amyloid burden quantified in Centiloids.

Result

Of 10,361 included individuals, 51% were females. Compared to males, females were slightly younger (75 versus 76 median age, p=0.008) and had higher rates of dementia (39.3% versus 35.2%, p<0.001). Rates of vascular risk factors were significantly higher in males than females, whereas females had significantly higher rates of history of depression and family history of AD. Females had higher rates of amyloid‐PET positivity than males (63% versus 59%, p<.001) and higher Centiloid values (median=48.7 versus 36.9, p<.01); see Figure 1 and Table 1 model 1. Sex differences remained significant in models adjusted for demographics and clinical risk factors (Table 1, models 2‐3). In an analysis that included only individuals with visually positive amyloid‐PET, females exhibited higher Centiloid values than males (Table 1 multivariable linear models). In amyloid‐positive individuals, we found a significant interaction between sex and age, with greatest sex differences in amyloid burden found in the youngest females (Figure 2A). We also found a significant interaction between sex and race, with greatest differences found in Black females vs. males (Figure 2B).

Conclusion

Females with cognitive impairment exhibited a higher frequency of amyloid‐PET positivity and higher amyloid burden. Our findings shed light on sex‐specific biological and potential sociocultural differences in Alzheimer's disease pathology.
Mechanistic links of amyloid, atrophy, and cognition profiles for gait disturbance in Alzheimer's disease
Authors: Baek Min Seok , Seong Joon‐Kyung , Kim Sung‐Woo , Kim Dong Ho , Hong Jin Yong
Published: January 2025

Background

This study delves into the relationship between gait disturbances and the progression of Alzheimer's disease (AD), focusing on how these changes correlate with cognitive impairments and key neuropathological indicators.

Method

We prospectively enrolled 48 patients with AD dementia (ADD), 27 patients with prodromal AD (proAD), and 41 cognitively unimpaired (CU) individuals between January 2022 and May 2023. Participants underwent brain T1‐weighted MRI, 18F‐florbetaben PET, neuropsychiatric tests, and APOE genotyping, and quantified gait analysis was assessed using a 5.79‐m long pressure sensor embed walkway. To evaluate the relationships between gait parameters, cognitive scores, regional amyloid deposition, and regional cortical thickness, Pearson partial correlation coefficients were computed, adjusting for age, sex, education duration, and leg length. Path analysis was employed to test hypothetical models comprising cortical amyloid deposition, cortical thickness, cognition, and gait parameters. Our models hypothesized five main pathways: from amyloid deposition to cortical thickness, cognition, and gait parameters; and from cortical thickness to cognition and gait parameters.

Result

As AD progresses, a significant decline in velocity (p=0.0144 for comparing CU and proAD; p=0.0010 for comparing CU and ADD) and step length ( p=0.0033 for comparing CU and proAD; p= 0.0002 for comparing CU and ADD) was observed, indicative of a slower gait pace. The swing time percentage was reduced, and the double support time percentage was increased, showing a significant difference only in ADD patients ( p=0.0015 and p=0.0007 respectively). Gait variability, reflected in the standard deviations of step length and double support time, escalated with AD progression ( p=0.0173 and p=0.0143 for comparing CU and ADD, respectively) (Figure 1). Changes in gait pace, variability, and rhythm were found to be linked to neuroimaging markers of AD, including Aβ deposition in widespread areas and cortical atrophy in the inferior parietal and middle temporal gyri, precuneus, and insula (Figure 2). Path analysis revealed directed relationships between Aβ deposition and cognitive impairment, as well as cortical atrophy, collectively impacting gait disturbance in AD (Figure 3).

Conclusion

Our analysis indicates directed relationships between amyloid deposition and cognitive impairment, as well as cortical atrophy in these regions, collectively impacting gait disturbance in AD
Emerging role of serum biomarkers in neurodegenerative dementias in a diverse context
Authors: Arshad Faheem , Subramanian Sarada , Ramakrishnan Subasree , Alladi Suvarna
Published: January 2025

Background

The aetiology of Alzheimer’s Disease and Related dementias (ADRD) in a diverse context is complex, and clinical methods lack sensitivity and specificity due to overlapping symptoms. This underscores the need of novel serum biomarkers in diagnosis of dementia. Serum glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) are non‐amyloid blood‐based biomarkers indicative of ongoing inflammatory and neurodegenerative process. We aimed to assess and validate their diagnostic value in patients with Alzheimer’s dementia (AD) and Frontotemporal dementia (FTD) spectrum disorders in the Indian context.

Method

Ninety‐nine participants recruited in the study underwent detailed neurocognitive assessment along with basic brain imaging. Quantitative determination of serum Glial fibrillary acidic protein (GFAP), neurofilament light chain (NfL), total‐tau and ubiquitin C‐terminal hydrolase L1 (UCHL1) were assessed using Simoa platform following a 2‐step digital immunoassay method as per manufacturer’s instructions using HD‐X analyser. Healthy controls (n=29), and participants with AD (n=28) and FTD spectrum disorders (n=42) diagnosed as per standard criteria were recruited.

Result

Mean age of the participants and healthy controls was 61.26 years (10.31) and 55.69 years (8.97), respectively. GFAP and NfL were significantly higher in participants with dementia compared to healthy controls (p<0.001). Serum GFAP levels were higher in AD (p<0.001), while NfL levels were significantly elevated in AD and FTD compared to controls (p< 0.05). However, there was no difference in t‐tau and UCHL1 levels between dementia group and healthy controls. Higher biomarkers levels of serum GFAP, NfL, t‐tau and UCHL1 were significantly associated with increasing levels of severity of dementia (r=0.539, p=0.000; r=0.637, p=0.000; r=0.241, p=0.016; r=0.476, p=0.000; respectively).

Conclusion

Levels of GFAP and NfL in serum have an emerging role in differentiating ADRD (AD and FTD) from healthy controls. These biomarkers are valuable predictors of severity across the neurodegenerative dementias. Further prospective cohort studies are required to replicate these findings in a diverse context.
Coronary artery calcium and Alzheimer’s Disease biomarkers in cognitively unimpaired adults
Authors: Marcolini Sofia , Mondragon Jaime , Vliegenthart Rozemarijn , Teunissen Charlotte , Verberk Inge M.W. , Borra Ronald J.H. , Dierckx Rudi , Deyn Peter Paul De
Published: January 2025

Background

Atherosclerosis, the hardening of arterial walls resulting in atherosclerotic plaques, is linked to cognitive dysfunction and an increased risk of cognitive decline. Findings on the impact of high coronary artery calcium (CAC), a subclinical atherosclerosis biomarker, on cognition remain inconsistent. Additionally, its effect on Alzheimer’s Disease (AD) biomarkers has not been previously analysed. This study explores differences in cognitive measures and AD biomarkers in cognitively unimpaired adults with absent or elevated evidence of CAC.

Method

285 cognitively unimpaired adults over fifty were recruited through the Lifelines database, a Dutch population‐based cohort study. Participants underwent non‐enhanced third‐generation dual‐source cardiac computerised tomography to derive total CAC using the Agatston score. They were categorized into two groups: participants with no evidence of CAC (all with a score=0; n=154) and participants with high CAC (with score>300; n=131). Subsequently, participants underwent a neuropsychological assessment and blood was sampled. Domain scores were created for memory, executive functioning, information processing, manual dexterity, and general cognition. Serum AD biomarkers (Aβ40, Aβ42, pTau181, NfL, GFAP) were analysed using a single‐molecule array assay technology. Group differences between the two groups were analysed using ANCOVA models adjusting for main confounders for normally distributed variables, and Mann–Whitney U otherwise.

Result

After excluding participants with MMSE<25, 278 participants (68±9 years, 59% males) remained. CAC scores of participants in the high CAC group had median=667.5 and interquartile range=638.95. These participants, older and with more males, exhibited worse overall cognition [adjusted mean difference=‐0.28 (95% CI=‐0.48,‐0.08)], worse executive functioning [adjusted mean difference= ‐0.21(95% CI=‐0.38,‐0.04)] and higher pTau181 levels (z=‐2.50, p=0.01) compared to the group with absent CAC. No differences were found for all other determined AD biomarkers.

Conclusion

Our results suggest that individuals with high evidence of CAC might be at higher risk of cognitive decline, as evidenced by poorer cognitive function and elevated pTau181 levels. Ongoing investigations aim to validate early cognitive decline imaging markers, including advanced measures of cerebral perfusion and small vessel disease, and explore the relationship between cerebrovascular and AD markers in this population. Additionally, how these relationships vary at different levels of CAC severity is being examined.
Elevated levels of CSF p‐tau212 in FTLD‐Tau
Authors: Kac Przemyslaw Radoslaw , Cousins Katheryn A Q , Shaw Leslie M. , Irwin David J , Karikari Thomas K , Turton Michael , Deerlin Vivianna M Van , Harrison Peter , McMillan Corey T , Wolk David A , Lee Eddie B , Blennow Kaj , Zetterberg Henrik
Published: January 2025

Background

Phosphorylated‐tau (p‐tau) biomarkers are typically specific for Alzheimer’s disease (AD) and are less elevated in the cerebrospinal fluid (CSF) of frontotemporal lobar degeneration (FTLD) type tau (FTLD‐tau). FTLD is a pathologically and clinically heterogenous neurodegenerative disorder, and we currently lack biomarkers to differentiate the two major pathological subtypes 1) FTLD‐tau, where pathological tau aggregation is observed or 2) FTLD‐TDP, where TAR‐DNA binding protein 43 (TDP‐43) is linked with the disease development and progression. Because FTD clinical phenotype does not predict pathology, biomarkers sensitive to FTLD‐tau are needed to provide a biological diagnosis in life. In this study, we test CSF p‐tau212 in patients with autopsy‐ or mutation‐confirmed FTLD‐tau and FTLD‐TDP without AD pathology; clinically healthy individuals without cognitive impairment and autopsy‐confirmed Lewy body disease with alpha‐synuclein (αSyn) were included as reference groups.

Method

Autopsies were performed at the University of Pennsylvania in the Center for Neurodegenerative Disease Research. Definite diagnosis was based on autopsy results or determined genetically. Using SIMOA technology, we tested p‐tau212 in 51 healthy controls, 33 FTLD‐Tau, 36 FTLD‐TDP and 13 αSyn (Figure 1). For further analysis we excluded individuals with evidence of AD pathology: intermediate/high AD neuropathologic change (ADNC), Thal phase ≥2, or CSF β‐amyloid 1‐42 ≤192. Wilcoxon test was used to compare groups. In brain regions sampled at autopsy, pathological tau burden was rated using a semi‐quantitative 5‐point scale; Spearman correlations tested associations between p‐tau212 and tau burden by region.

Result

CSF p‐tau212 was significantly increased in FTLD‐Tau when compared to healthy controls, people with FTLD‐TDP and people with αSyn pathology (Figure 2). Results remained significant when people with evidence of AD pathology were excluded. P‐tau212 measurements strongly correlated with tau burden across multiple brain regions (Figure 3). Average correlation was r=0.57, p<0.0001.

Conclusion

CSF p‐tau212 is strong candidate biomarker to differentiate FTLD‐tau from FTLD‐TDP and αSyn.
Inflammation and cytoskeleton pathway gene expression relates to rate of clinical progression in individuals with Alzheimers disease
Authors: Bebek Gurkan , Kim Hyun Jo , Benchek Penelope , Bekris Lynn M. , Leverenz James B , Bush William S. , Pillai Jagan A.
Published: January 2025

Background

Inflammatory changes are a key element of Alzheimer’s disease (AD)pathophysiology. However, there is lack of clarity regarding key gene drivers of the cytokines identified as playing a role in clinical AD progression and their relationship to AD biomarkers to understand their clinical role.

Method

We investigated transcriptomic datasets from Alzheimer’s Disease Neuroimaging Initiative (ADNI) and Harvard Brain Tissue Resource Center (HBTRC) to evaluate regulatory gene networks in human AD. We hypothesized that key inflammatory genes are differentially upregulated in AD, predicting clinical progression. ADNI peripheral blood transcriptomic data with cerebrospinal fluid (CSF) AD biomarker confirmed diagnosis was available for 30 AD dementia, 95 MCI, and 41 controls. This was next compared against HBTRC dorsolateral pre‐frontal cortex tissue gene expression data from 376 AD dementia and 173 controls with neuropathology confirmed diagnosis. The association between differentially expressed genes (DEGs) and change in cognition from baseline in ADNI, measured by clinical dementia rating scale ‐sum of boxes (CDR‐SB) at baseline 6, 12, 24 and 36 months using a linear mixed model (LMM) with random intercepts.

Result

We identified 170 DEGs between AD and controls common to ADNI and HBTRC. Among the DEGs, canonical inflammation signaling pathway genes were enriched. Using an FDR cutoff of 0.15, five genes (DUSP13, ANK1, SPTB, SLC6A and DMTN) were associated with significant CDR‐SB change from baseline in MCI and AD. Four of these genes were highly correlated (r2 > 0.8) and were involved in the Spectrin‐associated cytoskeleton pathway (GO:0014731). Among them, increased expression of DUSP13 in AD compared to controls (log2FC = 0.17) was associated with an increased decline in cognition (P = 0.001). An increased expression of ANK1 was related to reduced decline in cognition (P = 0.002) and ANK1 expression was lower in AD compared to MCI (log2FC = ‐0.16). CDR‐SB models incorporating gene expression for these significant genes were equivalent to or better than models incorporating CSF pTau, Aβ42, or MRI hippocampal volume when evaluated by Akaike information criterion.

Conclusion

Key peripheral inflammation and cytoskeletal gene expression relates to clinical progression in human AD. Validation of these results is an important future direction.
Association of synaptic density and neurofibrillary tau in preclinical and clinical Alzheimer’s disease
Authors: DiFilippo Alexandra H , Christian Bradley T. , Jonaitis Erin M. , McLachlan Max , McVea Andrew K , Bettcher Brecca , Schulz Nicholas R , Pasquesi Mary‐Elizabeth , Davenport‐Sis Nancy J , Thor Yer , Grover Ethan , Barnhart Todd E , Engle Jonathan W , Betthauser Tobey J. , Johnson Sterling C. , Bendlin Barbara B.
Published: January 2025

Background

Synaptic density loss is a major correlate of cognitive functioning in adults with and without significant impairment. It is also a feature of clinical Alzheimer’s disease (AD) and suspected to co‐occur with neurofibrillary tau (NFT) accumulation. Previous studies using [11C]UCB‐J for in‐vivo analysis of synaptic density have been restricted to unimpaired (CU) A‐ and impaired (CI) AD (A+) participants where within group analyses have shown no association between synaptic density and NFT. There is also little known about the relationship between synaptic density and NFT in AD without cognitive impairment. Here we evaluated the association between synaptic density and NFT in CU and CI AD.

Method

Participants were recruited from ongoing AD‐related studies (Wisconsin Registry for Alzheimer’s Prevention, ADRC) at UW and from the community and underwent comprehensive clinical and cognitive evaluation to determine cognitive status. Pearson’s r was used to determine associations between synaptic density ([11C]UCB‐J DVR) and neurofibrillary tau ([18F]MK‐6240 SUVR) across all participants and within amyloid and cognitive groups.

Result

Participant demographics are reported in Table 1. Across all participants, synaptic density and ERC, Hp NFT were well correlated (ERC NFT: r = ‐.46, p < .001; Hp NFT: r = ‐.49, p < .001). Within groups, only the CU A+ correlation between synaptic density and NFT remained significant (ERC NFT: r = ‐.49, p = .02; Hp NFT: r = ‐.59, p = .003) with CI A+ showing only a moderate (insignificant) relationship with Hp NFT (ERC NFT: r = ‐.16, p = .44; Hp NFT: r = ‐.31, p = .14) (Figure 1).

Conclusion

In agreement with previous work, CI AD has lower Hp synaptic density than CU A‐, and no significant relationship between Hp synaptic density and NFT. However, CU AD participants showed a significant relationship between NFT and synaptic density. This may be explained by a floor effect of Hp synaptic density that is reached by participants with clinical AD, but not yet in preclinical AD, or the existence of non‐AD pathologies contributing to synapse loss. These results can help better understand the process of neurodegeneration in AD as participants progress from preclinical to clinical AD.
Sex‐specific topological structure associated with dementia identified via latent space network analysis
Authors: Wang Selena , Wang Yiting , Xu Fredericks , Shen Li , Zhao Yize
Published: January 2025

Background

Statistical network analysis has transformed neuroimaging research in recent years by enabling flexible and intuitive integration of multiple data types and preserving the topological brain connectivity structure while uncovering mechanism of degenerative aging. In this study, we apply a novel latent space joint network model to perform a case‐control comparison using the functional connectivity data together with region‐specific cortical volume, cortical thickness, surface area and PET information. By preserving complex network structures during imaging biomarker detection, we find sex‐specific topological structures associated with dementia.

Method

We used resting state functional neuroimaging data from the ADNI study collected from 406 subjects, 208 males and 198 females. Of these, 198 subjects are healthy; 158 subjects show mild cognitive impairment; and 55 subjects show symptoms of dementia. To capture the group‐level functional connectivity information, the proposed method extends the latent space model to accommodate multiplex brain network structure and identify significant imaging biomarkers by comparing group‐level connectivity between healthy, MCI and dementia patients.

Result

For female subjects, areas of connectivity edges that are impacted by dementia and MCI tend to following the organizational topological structure of the brain (Figure 1). In contrast, areas of connectivity edges that are impacted by dementia and MCI for the male subjects do not follow such structures (Figure 2). Furthermore, we found that, among the female subjects, the difference between healthy and patient population tends to be larger for central actors of the network, brain regions of high node strength (Figure 3A and B). In Figure 3C, we see that, for females, there seem to be differences in brain connectivity among different types of imaging biomarkers, but not for males. For females, strong connectivity edges tend to indicate the development of dementia; whereas, for males, there is no such trend.

Conclusion

The proposed latent space joint network model is designed to capture brain topological structure while performing statistical inference. This initial AD functional connectivity study demonstrates the promise of uncovering the topological structure associated with degenerative aging and foster future investigations of the underlying mechanisms between network structures and data modalities and provide a new lens to disease pathology.
Sex, racial/ethnic, and APOE‐ε4 allele differences in longitudinal white matter microstructure in multiple cohorts of aging
Authors: Peterson Amalia Jo , Sathe Aditi , Yang Yisu , Durant Alaina , Shashikumar Niranjana , Pechman Kimberly R. , Dumitrescu Logan C. , Gifford Katherine A. , Risacher Shannon L. , Beason‐Held Lori L , An Yang , Schilling Kurt , Landman Bennett A. , Schneider Julie A. , Barnes Lisa L. , Bennett David A. , Jefferson Angela L. , Resnick Susan M , Saykin Andrew J. , Hohman Timothy J. , Archer Derek B. ,   the Alzheimer's Disease Neuroimaging Initiative (ADNI)
Published: January 2025

Background

There is growing recognition that white matter microstructural integrity is affected in Alzheimer’s disease. The goal of this study was to characterize sex, racial/ethnic, and apolipoprotein (APOE)‐ε4 allele differences in white matter integrity.

Methods

This study included participants from ADNI, BLSA, ROS/MAP/MARS, and VMAP, all longitudinal cohorts of aging. This combined dataset included 6,837 imaging sessions from 2,619 participants age 50+ with diffusion MRI (dMRI) and demographic and clinical data (60% female, 31.4% APOE‐ε4 carriers, 78.9% White). dMRI was preprocessed using the PreQual pipeline. Free‐water (FW) correction was used to generate FW and FW‐corrected intracellular metrics including fractional anisotropy (FAFWcorr), mean diffusivity (MDFWcorr), axial diffusivity (AxDFWcorr), and radial diffusivity (RDFWcorr). Conventional and FW‐corrected metrics were harmonized using the Longitudinal ComBat package. Linear mixed‐effects models related sex, race/ethnicity, and APOE‐ε4 allele status to longitudinal diffusion metrics in 48 white matter tracts, adjusting for age at baseline, sex, education, race/ethnicity, APOE‐ε4 carrier status, cognitive status at baseline, and converter status. All models were corrected for multiple comparisons using the FDR approach.

Result

Sex differences in white matter were most notable in projection tracts (Figure 1A) and were primarily in FW‐corrected metrics. Females had lower FAFWcorr and higher RDFWcorr, indicative of worse microstructure, but lower AxDFWcorr. This sex difference was most pronounced for FAFWcorr in the ventral premotor projection tract (p=1.53x10‐62). There were global differences in white matter integrity by race/ethnicity (Figure 1B). Non‐Hispanic White participants tended to have higher conventional FA, FAFWcorr and AxDFWcorr and lower RDFWcorr. There was no association between APOE‐ε4 status and white matter integrity and no significant sex x race/ethnicity, sex x APOE‐ε4, or race/ethnicity x APOE‐ε4 interactions for conventional or FW‐corrected metrics when corrected for multiple comparisons.

Conclusion

There were striking sex and racial/ethnic (but not APOE‐ε4) differences in white matter tract integrity in a large cohort of aging adults. Female participants tended to have measures reflective of worse white matter integrity, and non‐Hispanic White participants tended to have measures reflective of greater integrity. Additional research exploring the etiology of these differences will be important to better understand disparities in Alzheimer’s disease.
Modulating γ‐secretase activity to make precision medicine for AD
Authors: Chávez‐Gutiérrez Lucia
Published: January 2025

Gamma‐secretases play a pivotal role in the generation of Aβ peptides. Mutations in these enzymes that cause early‐onset, autosomal dominant AD shift Aβ production towards generation of longer peptides. We have recently shown that the mutation‐induced shifts in the ratio of short‐to‐long Aβ peptides not only inform about mutation pathogenicity but also allow experimental prediction of the age at dementia onset. This observation argues in favor of therapeutic strategies that shift Aβ production towards the generation of shorter and non‐toxic Aβ peptides.

By stabilizing GSEC‐APP interactions and activating the GSEC processive cleavage of APP, GSEC modulators (GSMs) have the potential to selectively reduce the levels of longer and toxic Aβ peptides, without hindering essential cellular processes that depend on the overall GSEC proteolytic activity. GSMs thus offer a nuanced approach to prevent, and potentially slow down, amyloid‐driven neurodegenerative cascades in AD therapy. However, thorough mechanistic investigation of the modulatory actions of GSMs on GSEC activities and biology is paramount to unlock the full therapeutic potential of GSMs in the clinic.

I will present and discuss our latest mechanistic studies of GSEC (dys)function and its modulation by GSMs acting as GSEC‐APP stabilizers.
targeting gamma‐secretase in the Dominantly Inherited AD patients
Authors: McDade Eric
Published: January 2025

Although amyloid b immunotherapies offer great potential for prevention or delay of symptoms in dominantly inherited AD (DIAD), the mechanism of action of this class of medications does not address the underlying mechanism of most DIAD mutations. Moreover, the need for repeated IV infusions or sub‐cutaneous injections with Ab immunotherapies may prove challenging for long‐term prevention approaches. The majority of DIAD mutations appear to affect the interaction of the gamma‐secretase enzyme with the Amyloid Precursor Protein (APP) making this enzyme an attractive target for disease modification. However, emerging evidence also suggests that different DIAD mutations can have significantly different effects on the processing of APP, which suggests that targeting this enzyme may have mutation dependent effects as well.

Developments in the understanding of the timing of amyloid b‐dependent changes in DIAD and the development of accurate measurements of Ab now enable precision‐based approaches necessary for targeting gamma‐secretase. Moreover, the presence of clinical trial platforms for DIAD facilitate the implementation of trials for targeting gamma‐secretase.

In this session, we will review approaches to testing next generation gamma‐secretase therapies in DIAD. Specifically, we will outline prevention approaches in DIAD that leverage fluid‐based biomarker measurements of Ab ‐peptides and sensitive, brief cognitive assessments to determine optimal mutation specific dosing approaches‐ i.e. precision medicine approach. Combining plasma, CSF and molecular PET imaging, we will outline how to assess gamma‐secretase targeting therapies for different mutations in DIAD along a timescale that utilizes early pharmacodynamic effects on Ab ‐peptides to predict long‐term effects on Ab ‐and downstream biomarkers of AD.
what would be needed to start a real primary prevention trial in Alzheimer’s Disease
Authors: Mummery Catherine J.
Published: January 2025

Anti‐amyloid therapies are ideal candidates for prevention trials. Secondary prevention in those at risk of ADAD (DIAN‐TU) has shown reduction of brain amyloid deposition leads to significant downstream biological change; early secondary prevention using a monoclonal antibody in sporadic AD (AHEAD 3‐45) is ongoing and will provide critical information on whether treating earlier leads to greater clinical benefit. However, this is not preventing disease but delaying onset in those with presymptomatic disease.

True primary prevention can be defined as treating before any evidence of disease, i.e. amyloid or tau pathology. So how do we identify that stage in sporadic AD? In addition, what is the best mechanism to target for primary prevention? Decreasing production of abeta is a prime candidate.

While there is sound logic in treating prior to disease onset to prevent the disease cascade commencing, there are significant ethical and practical challenges in optimising a prevention trial design. To design a true primary prevention trial in AD, one needs to identify reliably individuals at high risk of developing AD prior to pathology developing. A clear risk triage strategy would be required, alongside development of predictive biomarkers for disease. We need to understand early biological triggers/progression better to be able to define an at risk population and likely timescale to onset of disease. We will need to consider how long to treat for – if not a one‐off treatment, does this potentially commit someone to lifelong treatment? Outcome measures need to be designed to determine the success of a preventative rather than treatment strategy. There have been significant advances in blood biomarkers, but more sensitive clinical and biological markers of early disease onset are required. These trials will be long in duration and require large numbers of participants to commit years to show a treatment effect.

We are at the beginning of prevention trials in AD. In order to succeed, there must be close collaboration between discovery science, industry, the trials community and regulatory bodies to agree a framework that provides the best chance of optimising trial design and maximizing chances of success.
A Novel Blood Based Mitochondrial Biomarker for Alzheimer’s Disease
Authors: Hauger Brittany M , Smith Keith P , Strope Taylor A. , Oehmke Ellen , Kueck Paul J , Kemna Riley E , John Casey S. , Bantis Leonidas , Morris Jill K , Swerdlow Russell H , Wilkins Heather M
Published: January 2025

Background

Alzheimer’s disease (AD) pathology begins decades before clinical onset of dementia. Amyloid beta (Aβ) generally accumulates first in cognitively normal (ND) individuals, with tau and cognitive abnormalities following. AD pathologies have been found to correlate and interact with metabolic and mitochondrial outcomes in studies spanning numerous experimental paradigms. Targeting metabolic and mitochondrial function in clinical trials is an emerging theme for AD and highlights the importance and need for biomarkers which measure mitochondrial function.

Method

20 ND, 20 mild‐cognitive impairment, and 19 Alzheimer’s Disease (AD) subjects were recruited from the KU Alzheimer’s Disease Research Center Clinical Cohort. Blood was collected in ACD tubes. Lymphocytes were isolated using Accuspin tubes, histopaque 1077, and centrifugation. Lymphocytes were stained with MitoTracker/Annexin V, MitoSox/Hoechst, and TMRE/Hoechst. Fluorescent cells were quantified using flow cytometry and values normalized to Hoechst. Fluorescent measures were completed within 30 hours of blood draw. The mitochondrial health index (MHI) algorithm was calculated. Plasma NfL, pTau181, Aβ, and GFAP were determined using SIMOA. APOE genotypes were determined using a Taqman allelic discrimination assay.

Result

The MHI biomarker was significantly reduced in AD subjects and tracked with mini mental state exam (MMSE) scores. APOE ε4 carriers had reduced MHI regardless of diagnosis. Plasma GFAP, NfL, and pTau181 were increased in AD subjects. ROC analysis for individual biomarkers for ND/AD: Aβ 0.6658, GFAP 0.7194, NfL 0.7194, pTau181 0.7796, MHI 0.8028. ROC analysis for individual biomarkers for ND/MCI: Aβ 0.6700, GFAP 0.5737, NfL 0.5368, pTau181 0.7105, MHI 0.6025. ROC analysis for individual biomarkers for MCI/AD: Aβ 0.5632, GFAP 0.5965, NfL 0.6462, pTau181 0.5078, MHI 0.8139.

Conclusion

The MHI biomarker is a blood‐based biomarker with reasonable discrimination for AD diagnosis. Further studies are needed to fully understand how these potential biomarkers associate with disease progression and vary over time. However, mitochondrial biomarkers are urgently needed to assess therapeutic validity in upcoming clinical trials.
Large‐scale proteomics to enable precision medicine for Alzheimer’s disease
Authors: Smets Bart , Emon Asif , Greene Jon , García‐González Pablo , Puerta Raquel , Socorro Alfredo Cabrera , Timmers Maarten , Ruiz Agustin , Whelan Christopher D
Published: January 2025

Background

Precision neuroscience is emerging as a transformative approach that aims to identify the right treatment for the right patient at the right time. To enable this, it is important to move beyond the categorization of patients based on clinical symptoms towards a biological definition of disease. For Alzheimer’s disease, significant progress has been made in this direction, with the development of the “A/T/N” biomarker framework that classifies patients based on underlying pathophysiology.

Method

It is essential to further characterize the molecular processes that drive disease progression within individual patients and to correctly stage those processes along the disease trajectory. Therefore, we are bringing together large biofluids proteomics datasets from different neurodegenerative disease cohorts. Analyses leverage Cox proportional‐hazards regressions to identify predictors of disease progression and, hypothesis‐driven (GSVA) and hypothesis‐free approaches (WGCNA, consensus clustering) to characterize pathological processes and disease subtypes.

Result

Here, we present analyses of CSF proteomics data from the Spanish ACE Alzheimer’s disease cohort (n = 1321). MCI‐to‐dementia conversion analyses both replicate previous studies as well as identify novel biomarker candidates that might further augment the A/T/N framework (e.g. MMP10). We also provide an independent validation of work from Tijms et al. [1] that identified 3 different Alzheimer’s disease subtypes which are characterized by elevated levels of proteins associated with either (i) neuronal plasticity, (ii) innate immunity or (iii) blood‐brain barrier dysfunction. Extending upon these findings, we show that subtype 3 is characterized by an increase in CSF/plasma albumin ratio, further supporting the blood‐brain barrier dysfunction hypothesis. The subtypes stratify patients beyond the A/T/N categorization. The different subtypes might be valuable to increase precision.

Conclusion

Large‐scale proteomics is a crucial tool to accelerate the development of novel precision treatments for Alzheimer’s disease, enabling the identification of novel fluid biomarkers for patient identification, stratification and disease progression, the characterization of molecularly defined disease subtypes, and the discovery of novel drug targets that are linked to specific patient populations.

[1] Tijms et al. Pathophysiological subtypes of Alzheimer’s disease based on cerebrospinal fluid proteomics. Brain 143, 3776–3792 (2020).
Comparative EEG biosignatures in Alzheimer’s disease and frontotemporal dementia: A pilot study
Authors: Meghdadi Amir H. , Verma Ajay , Mendez Mario F. , Berka Chris
Published: January 2025

Background

Alzheimer's disease (AD) and frontotemporal dementia (FTD) are common causes of dementia, but differentiating between them can be challenging due to overlapping symptoms [1]. Quantitative electroencephalography (EEG) is emerging as a promising tool to identify potential biosignatures that can distinguish AD and FTD [2]–[5]. Prior EEG research has revealed slowing of the posterior dominant rhythm (PDR) in both AD and FTD patients compared to controls, reflecting underlying neurodegeneration. Our study aimed to compare quantitative EEG measures during resting‐state and attention tasks between bvFTD, PPAFTD, AD patients, and controls to determine if distinctive EEG/ERP profiles exist that can aid differential diagnosis.

Methods

Participants included individuals with behavioral‐variant Fronto‐temporal dementia (bvFTD, n=8, ages 42‐78), Primary Progressive Aphasia Frontotemporal dementia (PPAFTD, n=6, ages 53‐75), Alzheimer’s dementia (AD, n=20, ages 58‐79), and controls with normal cognition (HC, n=14, ages 47‐78). Twenty‐channel resting‐state EEG with eyes‐closed was collected during 5‐minutes of wakefulness (STAT X24). A subset of participants also completed a 3‐Choice‐vigilance‐task (3CVT) ERP attention task. Power spectral densities (PSD) during resting‐state and ERP waveforms elicited by the ERP task were computed and compared between groups.

Results

bvFTD on average exhibited a slowing of the posterior‐dominant rhythm (PDR) similar to the slowing observed in the AD group. However, unlike the AD group that showed a significant reduction in the power of the PDR (alpha power), both FTD groups had alpha power similar to HC. In the ERP attention task, FTD groups exhibited a delayed and reduced late positive potential (LPP) compared to controls.

Conclusions

We identified distinctive EEG biosignatures associated with Frontotemporal Dementia (FTD) and Alzheimer's Disease (AD). Quantitative analysis of the posterior dominant rhythm (PDR) revealed that both AD and FTD patients exhibited slowing of the PDR frequency. However, the power of PDR was significantly reduced in the AD while relatively preserved in FTD. FTD subtypes may also demonstrate distinct EEG abnormalities such as more pronounced PDR slowing in bvFTD/ more delayed event‐related potential (ERP) components in PPAFTD. Additional research is still needed to validate the reliability and specificity of these EEG biosignatures in differentiating FTD subtypes from each other and from AD.
Unraveling the Early Trajectory of Cortical Tau Accumulation Using 18F‐MK6240
Authors: Dore Vincent , Krishnadas Natasha , Bourgeat Pierrick , Leuzy Antoine , Feizpour Azadeh , Cox Timothy , Huang Kun , Haeberlein Samantha Budd , Fripp Jurgen , Villemagne Victor L , Rowe Christopher C.
Published: January 2025

Background

Tau PET is instrumental in tracking the longitudinal progression of Alzheimer's disease (AD). 18F‐MK6240 is a high affinity tracer targeting the 3R/4R paired helical filaments of tau in AD. We aimed to evaluate the early phase of the natural progression of tau accumulation using 18F‐MK6240.

Method

231 participants: 100 cognitively unimpaired (CU) Aβ− (Centiloid<25CL), 58 CU Aβ+, 73 cognitively impaired Aβ+ (41 with mild cognitive impairment (MCI) and 32 with dementia) from the AIBL cohort were followed‐up with 18F‐MK6240 PET over one to four years (median 2.2years). Meta‐Temporal CenTauR (CTR) were generated using CapAIBL and CU CL<15, N=120 and AD (typical AD tau pattern, MMSE>24, CL>50 & age<75, N=39) as 0 and 100CTR anchored points. Abnormal level of tau was defined at 2 standard deviations above the CU Aβ‐ (13CTR). Linear ordinary differential equations (ODE) were employed to model the mean natural history of CTR based on tau accumulators (CTR>13 or CTR rate>0) only. Given the limited numbers of individuals with CTR>100, our analysis concentrated on the early phase of tau accumulation (CTR<100, N=204).

Result

Figure 1A illustrates a linear relationship between the average and the rate of CTR, with a R of 0.72. Tau accumulation spanned from 0.5CTR/yr at 13CTR to 12.2CTR/yr at 100CTR, with a standard deviation of the residuals at 2.4CTR/yr. Figure 1B displays the individual’s trajectories projected on the ODE model. We estimated that, on average it takes 15.1 (CI:[12.6‐17.9]) years for an individual crossing 13CTR to reach 100CTR.

Conclusion

Longitudinal 18F‐MK6240 is a robust tool for estimating natural progression of tau accumulation. Our findings indicate that it typically takes around 15 years to reach the tau levels associated with mild AD once tau starts aggregating in the neocortex. These findings shed light into the initial stages of cortical tau accumulation, relevant for early diagnosis and therapeutic interventions in AD.
In vitro evaluation of neuroprotective effect of Anethum graveolens and its bioactives in H2O2‐induced oxidative stress model of SH‐SY5Y and biochemical studies
Authors: Sharma Himadri
Published: January 2025

Background

Anethum graveolans commonly known as Dill is an herb from celery family displaying anti‐oxidant benefits. The present study focused on the potential of Anethum graveolans as a multifunctional curative remedy for AD treatment.

Method

Hexane (H) and ethyl acetate (EA) extracts of Dill were prepared and subjected to GC‐MS for identification of important bioactive components. H2O2 was used to induce oxidative stress in SH‐SY5Y cells and evaluation was done based on neuroprotection, reduced reactive oxygen species, and restoration of mitochondrial membrane potential (MMP). Additionally, anti‐Aβ fibrilization/ oligomerization activities were also analyzed along with anti‐acetylcholinesterase activity.

Result

Based on GC‐MS results, 3 major components were identified apiole, carvone and dihydrocarvone (DHC). The extracts and pure compounds were assessed for their neuroprotective potential in which dose‐dependent increase in neuroprotection was observed in both extracts, apiole and carvone. Dill‐H displayed a dose‐dependent decrease in ROS levels which was more prominent than Dill‐EA extract. Pure compounds also exerted a decrease in ROS level with increasing concentration. Dill extracts (H/EA) exhibited dose‐dependent increase in mitochondrial membrane potential along with Carvone and DHC. Apiole showed less restoration of MMP compared to other pure compounds. For anti‐Aβ fibrilization activity, Dill‐EA, Carvone and Apiole show ≈40% inhibition followed by DHC (35%) and Dill‐H (30%). In MDS, maximum oligomerization inhibition was observed in DHC (26%) and apiole (14%). Dill extracts and compounds exhibit anti‐AChE activity and inhibited the enzyme through competitive inhibition except for DHC.

Conclusion

We focused our research on small molecules from food to prevent AD. There is a need for a drug that is easily accessible, cost‐effective and has no/fewer side effects. In our study, Dill extracts and its identified bioactive compounds exhibited a multitargeted neuroprotection in the SH‐SY5Y cells making it a promising candidate for AD drug development.