Markers Of Alzheimer's Disease Research Articles

Mapping amyloid beta predictors of entorhinal tau in preclinical Alzheimer's disease.

Amyloid beta (Aβ) plaques and hyperphosphorylated tau in the entorhinal regionsare key Alzheimer's disease (AD) markers, but the spatial Aβ pathways influencing tau pathology remain unclear. We applied predictive modeling to identify Aβ standardized uptake value ratio (SUVR) spatial patterns that predict entorhinal tau levels, future hippocampal volume, and Preclinical Alzheimer's Cognitive Composite (PACC) scores at 5-year follow-up. The model was trained on Alzheimer's Disease Neuroimaging Initiative (ADNI) (N=237), incorporating amyloid-PET (positron emission tomography), tau-PET, magnetic resonance imaging (MRI), and cognitive data, and validated on Harvard Aging Brain Study (HABS) (N=276). The model accurately predicted entorhinal tau levels (r=0.48, p<0.0001), future hippocampal volume (r=0.24, p=0.002), and PACC scores (r=0.35, p<0.0001) based on regional Aβ. Aβ in the rostral middle frontal, medial orbitofrontal, and striatal regions predict entorhinal tau levels, future hippocampal volume, and PACC scores, indicating their potential as early biomarkers in AD prediction models. Positron emission tomography (PET) imaging reveals amyloid beta (Aβ) patterns predicting entorhinal tau levels in preclinical Alzheimer's disease (AD). Aβ in medial orbitofrontal, rostral middle frontal, and nucleus accumbens best predicts tau. Aβ distribution in these regions predicts future hippocampal neurodegeneration and cognitive decline. Model validated with Alzheimer's Disease Neuroimaging Initiative (ADNI) and Harvard Aging Brain Study (HABS) data sets, showing robustness and reproducibility. Findings suggest early Aβ patterns can aid in diagnosing AD and guide anti-Aβ therapies.

Altered metabolic function induced by Aβ-oligomers and PSEN1 mutations in iPSC-derived astrocytes.

Altered energy metabolism in Alzheimer's disease (AD) is a major pathological hallmark implicated in the early stages of the disease process. Astrocytes play a central role in brain homeostasis and are implicated in multiple neurodegenerative diseases. Although numerous studies have investigated global changes in brain metabolism, redox status, gene expression and epigenetic markers in AD, the intricate interplay between different metabolic processes, particularly in astrocytes, remains poorly understood. Numerous studies have implicated amyloid-β and the amyloid-β precursor in the development and progression of AD. To determine the effects of amyloid-β peptides or the impact of amyloid-β precursor protein processing on astrocyte metabolism, we differentiated astrocytes from induced pluripotent stem cells derived from people with early onset familial AD and controls. This study demonstrates that familial AD-derived astrocytes exhibit significantly more changes in their metabolism including glucose uptake, glutamate uptake and lactate release, with increases in oxidative and glycolytic metabolism compared to acute amyloid-β exposure. In addition to changes in major metabolic pathways including glutamate, purine and arginine metabolism and the citric acid cycle, we demonstrate evidence of gliosis in familial AD astrocytes highlighting a potential pathological hallmark. This suggests that chronic alterations in metabolism may occur very early in the disease process and present significant risk factors for disease progression for patients with early onset AD. These findings may also reveal important drivers of disease in late onset dementia and highlights key targets for potential diagnostic features and therapeutic agents in the future.

Temporal modeling and AT profiles in the early phase of Alzheimer's disease

Background Identifying markers that have predictive value for disease progression and clinical manifestations, such as mild cognitive impairment (MCI), is important to detect Alzheimer's disease (AD) early. Objective In this study, we combined biomarkers from amyloid and tau pathologies (AT profiles) with the prediction of diagnosis and the temporal evolution of clinical symptoms. Methods Multiple disease progression models were developed through supervised and unsupervised techniques via a two-stage data-driven approach. Models whose natural histories most closely resembled the diagnostic predictions were selected. Finally, various hypotheses regarding the progression of cognitive decline were tested using longitudinal patient data and AT profiles. Results At baseline, 22.5% of the cognitively unimpaired (CU) individuals and 46.2% of the CU converters (who progressed to MCI during the first four years) in the studied population had amyloid pathology (A+). Only a small subset of neuropsychological measures was used to predict cognitive decline and its timeline. The study revealed that amyloid pathology occurred approximately 5 years after cognitive decline in the population under investigation. Additionally, patients who were A+ at baseline experienced a more accelerated progression toward cognitive decline than those who were not (A−). Conclusions Based on the proposed natural histories and cross-sectional and longitudinal analysis of AD markers, the results indicate that only a single cerebrospinal fluid sample is necessary during the early phase of AD. The progression from CU to MCI and its timeline can be predicted exclusively through neuropsychological measures.

Choroid plexus cysts on 7T MRI: Relationship to aging and neurodegenerative diseases.

The choroid plexus (CP) may play a crucial role in brain degeneration. We aim to assess whether CP cysts (CPCs), defined using ultra-high field magnetic resonance imaging (MRI), relate to aging and neurodegeneration. We used multi-sequence 7T MRI to observe CPCs, characterizing their presence and characteristics in healthy younger controls, healthy older controls (OCs), patients with Alzheimer's disease (AD), patients with Parkinson's disease (PD), and patients with uremic encephalopathy. CP volume (CPV) and CPC characteristics were compared across groups, and associations between CPV and CPC features were analyzed across all subjects. The AD group showed a significantly higher presence and number of CPCs compared to other groups and also had a significantly larger CPV than healthy OCs. The number and size of CPCs were associated with CPV. 7T MRI offers a distinct advantage in observing CPCs, and the high prevalence of CPCs in patients with AD warrants further investigation. 7T MRI enables visualization of the fine structures of the choroid plexus. Patients with Alzheimer's disease (AD) exhibit a higher number of choroid plexus cysts (CPCs) compared to healthy older adults and other patient groups. CPCs may serve as an auxiliary marker for AD.

Elevated cerebrospinal fluid biomarkers of neuroinflammation and neuronal damage in essential hypertension with secondary insomnia: Implications for Alzheimer's disease risk.

Essential hypertension (EH) with secondary insomnia is associated with increased risks of neuroinflammation, neuronal damage, and Alzheimer's disease (AD). However, its relationship with specific cerebrospinal fluid (CSF) biomarkers of neuronal damage and neuroinflammation remains unclear. This case-control study compared CSF biomarker levels across three groups: healthy controls (HC, n = 64), hypertension-controlled (HTN-C, n = 54), and hypertension-uncontrolled (HTN-U, n = 107) groups, all EH participants experiencing secondary insomnia. CSF samples from knee replacement patients were analyzed for key biomarkers, and sleep quality was assessed via the Pittsburgh Sleep Quality Index (PSQI). Our findings showed that the HTN-U group had significantly higher CSF levels of proinflammatory cytokines IL-6, TNF-α, and IL-17 than the HC and HTN-C groups (all p < 0.01). These cytokines correlated positively with secondary insomnia measures, with IL-6 (r = 0.285, p = 0.003), IL-17 (r = 0.324, p = 0.001), and TNF-α (r = 0.274, p = 0.005) linked to PSQI scores. In the HTN-U group, elevated IL-6, TNF-α, and IL-17 levels were also positively associated with neurofilament light (NF-L) and negatively with β-amyloid 42 (Aβ42), both key AD markers (all p < 0.05). Additionally, secondary insomnia was negatively correlated with Aβ42 (r = -0.225, p = 0.021) and positively with NF-L (r = 0.261, p = 0.007). Higher CSF palmitic acid (PA) levels observed in the HTN-U group were linked to poorer sleep quality (r = 0.208, p = 0.033). In conclusion, EH with secondary insomnia is associated with CSF biomarkers of neuronal damage, neuroinflammation, and neurodegeneration, suggesting a potential increase in AD risk among this population.

Excess Ub-K48 Induces Neuronal Apoptosis in Alzheimer's Disease.

K48-linked ubiquitin chain (Ub-K48) is a crucial ubiquitin chain implicated in protein degradation within the ubiquitin-proteasome system. However, the precise function and molecular mechanism underlying the role of Ub-K48 in the pathogenesis of Alzheimer's disease (AD) and neuronal cell abnormalities remain unclear. The objective of this study was to examine the function of K48 ubiquitination in the etiology of AD, and its associated mechanism of neuronal apoptosis. A mouse model of AD was constructed, and behavioral phenotypic changes were detected using an open field test (OFT). The expression of glial fibrillary acidic protein (GFAP), an early marker of AD, was detected by western blotting (WB). Neuronal apoptosis in the hippocampal region was assessed by hematoxylin and eosin (HE) and Nissl staining. Immunohistochemistry and immunofluorescence were performed to observe the changes in Phosphorylated tubulin associated unit (p-Tau) and Ub-K48 colocalization in neurons of the hippocampal region of AD mice. WB was further applied to detect the degree of ubiquitylation of K48 and the expression of Tau, p-Tau, B-cell lymphoma-2 (Bcl-2) and Bcl-2-associated X (Bax) proteins in neuronal cells of the hippocampus and cortical regions of mice. Mice with AD exhibited significantly longer resting times (p < 0.05) and shorter average speeds (p < 0.01), total distances travelled (p < 0.01), and distances travelled (p < 0.01) in the central region than those in the control group. This indicated cognitive impairment, which occurred concurrent with an increased expression of the AD marker GFAP protein (p < 0.001). The hippocampal region of AD mice showed abnormalities with sparsely and irregularly arranged cells, large gaps between cells, lighter staining, unclear boundaries of the cell membranes and nuclei, and agglutinated and condensed nuclei (p < 0.01). The neuronal cells of AD mice exhibited significantly elevated levels of p-Tau (p < 0.01) and Ub-K48 (p < 0.01), as well as a notable degree of co-localization within the cells. The intracellular pro-inflammatory protein Bax was significantly upregulated (p < 0.05), while the Bcl-2/Bax ratio was significantly lower than that in the control group (p < 0.05), thus inducing apoptosis in AD neuronal cells. Ub-K48 is strongly linked to the development of AD. p-Tau aggregate in neuronal cells in the hippocampal region of the AD brain and colocalize with Ub-K48, which in turn leads to cellular inflammation and the induction of apoptosis in neuronal cells.

Association of critically short telomeres with brain and blood markers of ageing and Alzheimer’s disease in older adults

BackgroundAccumulation of critically short telomeres (CST) is implicated in decreased tissular regenerative capacity and increased susceptibility to degenerative diseases such as Alzheimer’s disease (AD). Telomere shortening has also been associated with age-related brain changes. However, it remains unclear whether CST accumulation is directly associated with AD markers or instead amplifies age-related effects, potentially increasing susceptibility of developing AD in cognitively healthy older adults.MethodsThis cross-sectional study used baseline data of 129 community-dwelling cognitively healthy older adults from the Age-Well trial (NCT02977819), aged 65 years and older enrolled between 2016 and 2018, in France. Using linear regressions, we analyzed the relationship between an innovative marker of telomere shortening, the percentage of CST (%CST), structural, functional and molecular neuroimaging outcomes, and multiple blood-based biomarkers related to AD pathophysiology. The effect of apolipoprotein E ε4 genotype (APOE4) was assessed on these relationships using interaction analysis.ResultsA higher %CST was associated with lower global kurtosis fractional anisotropy (β = -.230; P = .010), particularly in frontal and temporal regions. A higher %CST was also related to higher plasma levels of Neurofilament light chain (β = .195; P = .020) and a lower subiculum volume (β = -.206; P = .020), although these associations did not meet the threshold for multiple comparisons. %CST was not associated with AD-related neuroimaging markers, including the AD-sensitive gray matter pattern (β = -.060; P = .441), glucose metabolism pattern (β = -.099; P = .372), brain perfusion pattern (β = -.106; P = .694) or hippocampus volume (β = -.106; P = .194). In APOE4 carriers, higher %CST was associated with lower subiculum (β = -.423; P = 0.003), DG (β = -.410; P = 0.018) and CA1 volumes (β = -.373; P = 0.024), even though associations with DG and CA1 volumes did not survive multiple comparison.ConclusionsAlthough an increase in %CST does not appear to be directly linked to the pathophysiology of AD in cognitively healthy older adults, it could heighten the susceptibility of APOE4 carriers to develop AD plausibly due to greater vulnerability to age-related effects. However, longitudinal studies would be necessary to determine whether %CST influences the development and progression of AD later in life.

Association between known Alzheimer’s disease risk genetic variants and hippocampal atrophy along the Alzheimer’s disease continuum in a Korean cohort

AbstractBackgroundLarge‐scale genome‐wide association studies (GWAS) of Alzheimer’s disease (AD) from European ancestry identified many genetic variants associated with clinical diagnosis of AD dementia. However, it remains unclear whether these AD‐related variants are associated with AD biomarkers, particularly hippocampal atrophy, a well‐known neurodegeneration biomarker of AD in a Korean population. In this study, we investigated the association between known AD risk single nucleotide polymorphisms (SNPs) and hippocampal atrophy along the AD continuum in older Korean adults.MethodA total of 487 participants (258 cognitively normal olde adults [CN], 144 mild cognitive impairment [MCI], 85 AD dementia) from the Korean Brain Aging Study for the Early Diagnosis and Prediction of Alzheimer’s disease (KBASE) were included for analysis. All participants underwent 11C‐PiB‐PET/MRI. Hippocampal volume adjusted for intracranial volume (HVa) was obtained from 3D T1‐weighted MRI scans using FreeSurfer and used as a neurodegeneration marker of AD. Global beta‐amyloid (Aβ) deposition was calculated from PiB uptake in the global cortical region‐of‐interest using SPM12. From the genetic evidence gathered by the AD Sequencing Project (ADSP), which consists of 76 SNPs associated with AD, we selected 38 SNPs with a minor allele frequency (MAF) greater than 1% from the genotyping data imputed using the TOPMed imputation server in the KBASE cohort.ResultAmong 38 known AD‐related SNPs, three SNPs (rs6966331 in EPDR1, rs2242595 in MYO15A, and rs17125924 in FERMT2) were associated with HVa in an initial exploratory analysis (p&lt;0.05). In a subsequent confirmatory analysis, the associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with HVa remained significant after controlling for age, sex, and APOE4 carrier status, as well as global Aβ deposition (p&lt;0.001 and p = 0.009 for rs6966331 and rs2242595, respectively) (Table 1).ConclusionOur study identified associations of rs6966331 in EPDR1 and rs2242595 in MYO15A with hippocampal volume in Korean older adults, and these associations were independent of cerebral Aβ deposition and APOE4 carrier status. These findings suggest that these AD‐related loci may contribute to the development of AD dementia via Aβ‐independent neurodegeneration.

Disentangling relationships between Alzheimer's disease plasma biomarkers and established biomarkers in patients of tertiary memory clinics.

Several plasma biomarkers for Alzheimer's disease (AD) have demonstrated diagnostic and analytical robustness. Yet, contradictory results have been obtained regarding their association with standard diagnostic markers of AD. This study aims to investigate the specific relationship between the AD biomarkers currently used in clinical practice and the plasma biomarkers. In a memory clinic cohort, we analysed plasma pTau181, pTau217, pTau231, respectively, GFAP, NfL, CSF pTau181, Aβ-PET scans, and MRI/CT visual read of atrophy. We utilized methods based on multiple linear regression to evaluate the specific associations between clinically used and recently developed plasma biomarkers, while also considering demographic variables such as age and sex. Although plasma pTau181, pTau217, pTau231, and GFAP were significantly associated with both Aβ-PET and CSF pTau181, Aβ-PET explained more variance in the levels of these biomarkers. The effect of CSF pTau181 on plasma GFAP and pTau181 was completely attenuated by Aβ-PET, whereas pTau231 and pTau217 were affected by both Aβ-PET and CSF pTau181 levels. Unlike these biomarkers, increased NfL was rather indicative of brain atrophy and older age. Based on the effect sizes, plasma pTau217 emerged as highly effective in distinguishing between A+ and A-, and T+ and T- individuals, with 60% of variance in plasma pTau217 explained by clinical AD biomarkers. Amyloid burden primarily drives the changes in plasma pTau181, pTau217, pTau231, and GFAP. In contrast to plasma pTau217, a significant portion of variance in plasma pTau181, pTau231, GFAP, NfL remains unexplained by clinical AD biomarkers. This research is supported by the Swedish Research CouncilVR: 2017-06086, 2020-4-3018, 2024-2027; Swedish Brain Foundation, Swedish Alzhzeimer Foundation, CIMED Region Stockholm/Karolinska Institutet;the Region Stockholm - Karolinska Institutet regional agreement on medical training and clinical research (ALF), Fondation Recherche sur Alzheimer (France).

In vivo 18F‐MK6240 tau PET imaging in relation to peripheral inflammation and episodic memory in late middle‐aged adults

AbstractBackgroundDetecting early stages of Alzheimer's disease (AD) remains a crucial yet complex challenge. While recent interest has surged in detecting biomarkers linked with the disease preclinical phase, a comprehensive understanding of the concomitant peripheral biological pathways before the potential disease onset is necessary. We aim to explore the associations between the 18F‐MK6240 tau PET tracer with plasma inflammatory markers, other AT(X)N biomarkers and episodic memory.MethodThe cross‐sectional sample consisted of n=132 cognitively unimpaired late middle‐aged Hispanic individuals (64.5 ± 3.4 years old, 34.1% APOE4 carriers, 69.7% female, 10.7 ± 4.0 years of education) from Northern Manhattan (AD Knowledge Center database). All individuals underwent multi‐modal imaging with T1‐weighted MRI, T2‐weighted FLAIR MRI, Aß PET (18F‐florbetaben), tau PET (18F‐MK6240), plasma measures of inflammation (OLINK panel of 92 markers), plasma neuronal injury (NfL), and neuropsychological assessments. Data on demographics: age, sex, education, APOE, body mass index (BMI), and diabetes mellitus, were also included. Using the median split to dichotomize global Aß and NfL measures, the study sample was stratified into four groups: “Aß‐low, NfL‐low” (Group 0); “Aß‐high, NfL‐low” (Group 1); “Aß‐high, NfL‐high” (Group 2); and “Aß‐low, NfL‐high” (Group 3).ResultOur results revealed that 18F‐MK6240 tau PET is sensitive in detecting early neocortical tau pathology, even without evident neuronal injury (Fig. 1). Plasma inflammation was not directly linked with Aß or tau pathologies but strongly associated with NfL (Fig. 2). Markers of neuronal injury (NfL), cerebrovascular injury (WMH) and specific inflammatory markers were associated with lower episodic memory (Fig. 1). High NfL correlated with factors such as high inflammation, BMI, diabetes and older age.ConclusionThe study emphasizes the complex nature of early AD markers suggesting that, aside from Aß and tau, peripheral markers of NfL and inflammation are also central. Our findings call for a broader perspective in identifying early AD markers, underscoring the interplay between neuronal damage, inflammation, comorbidities and early cognitive changes.

The relationship between postoperative cognitive dysfunction and cerebral small vessel disease: A comprehensive review.

Postoperative cognitive dysfunction (POCD) is a common complication in elderly patients, and cerebral small vessel disease (CSVD) has been suggested as a potential risk factor. This review examines the relationship between POCD and CSVD from epidemiological, pathophysiological, and clinical perspectives, while also considering the role of Alzheimer's disease (AD) pathology. We conducted a comprehensive literature search of major databases, supplemented by reference list checking, to ensure a thorough review of studies published between 2000 and 2023 on the relationship between POCD and CSVD. Epidemiological studies have shown that POCD and CSVD are associated in terms of common risk factors, including advanced age, vascular comorbidities, impaired baseline cognitive function, and certain population characteristics. Animal studies have revealed that CSVD and POCD share similar neuropathological changes, including abnormal cerebral hypoperfusion, inflammatory responses, and blood-brain barrier disruption. Furthermore, recent research suggests a complex interplay between CSVD, AD pathology, and POCD, with potential synergistic effects on cognitive decline. Neuroimaging studies have further demonstrated that preoperative CSVD burden and postoperative CSVD progression are associated with the development of POCD, and the presence of both CSVD and AD markers may increase the risk of cognitive decline. The association between CSVD and POCD has important implications for the perioperative management of elderly patients, including preoperative assessment, choice of anesthesia and surgical methods, intraoperative management, postoperative care, and long-term follow-up. A better understanding of the relationship between CSVD and POCD will guide evidence-based strategies to prevent and manage this debilitating complication in the aging population.

DNA Methylation Signature of a Lifestyle-based Resilience Index for Cognitive Health.

Cognitive resilience (CR) contributes to the variability in risk for developing and progressing in Alzheimer's disease (AD) among individuals. Beyond genetics, recent studies highlight the critical role of lifestyle factors in enhancing CR and delaying cognitive decline. DNA methylation (DNAm), an epigenetic mechanism influenced by both genetic and environmental factors, including CR-related lifestyle factors, offers a promising pathway for understanding the biology of CR. We studied DNAm changes associated with the Resilience Index (RI), a composite measure of lifestyle factors, using blood samples from the Healthy Brain Initiative (HBI) cohort. After corrections for multiple comparisons, our analysis identified 19 CpGs and 24 differentially methylated regions significantly associated with the RI, adjusting for covariates age, sex, APOE ε4, and immune cell composition. The RI-associated methylation changes are significantly enriched in pathways related to lipid metabolism, synaptic plasticity, and neuroinflammation, and highlight the connection between cardiovascular health and cognitive function. By identifying RI-associated DNAm, our study provided an alternative approach to discovering future targets and treatment strategies for AD, complementary to the traditional approach of identifying disease-associated variants directly. Furthermore, we developed a Methylation-based Resilience Score (MRS) that successfully predicted future cognitive decline in an external dataset from the Alzheimer's Disease Neuroimaging Initiative (ADNI), even after accounting for age, sex, APOE ε4, years of education, baseline diagnosis, and baseline MMSE score. Our findings are particularly relevant for a better understanding of epigenetic architecture underlying cognitive resilience. Importantly, the significant association between baseline MRS and future cognitive decline demonstrated that DNAm could be a predictive marker for AD, laying the foundation for future studies on personalized AD prevention.

Personality, Aging, and Alzheimer's Disease: Implications for Psychoneuroimmunology and Personalized Medicine.

Psychoneuroimmunology (PNI) advancements may revolutionize personalized medicine by identifying systemic biomarkers that enhance diagnosis and treatment. Inflammatory pathways connect personality traits with cognitive performance, aging-related disorders, and mortality risks. Studies have demonstrated the critical interactions between personality and various biological systems like the hypothalamic-pituitary-adrenal (HPA) axis. The gut-brain axis also affects behaviors and psychological states in older adults, with specific gut microbiota influencing cognition, mood, and personality. These findings underscore the practical implications of understanding personality-biology interactions. They can support preventive and personalized medicine for aging-associated disorders. Specifically, personality changes are prevalent in Alzheimer's disease (AD) patients, impacting clinical management and caregiver stress. Non-cognitive factors, such as personality traits and psychiatric symptoms, may serve as early markers of AD. Traits like high Neuroticism and low Openness can predict initial AD stages, often before a formal diagnosis. Personality alterations in AD are also linked to cerebrospinal fluid (CSF) and vascular imaging biomarkers, which can track AD pathology and serve as predictors. Dynamic personality assessment can aid in timely diagnosis, monitoring progression, and evaluating treatmentsof AD. Understanding personality traits is crucial for predicting burnout, lifespan, and intervention success. Integrating personality and PNI biomarkers into patient profiles will support the development of personalized and systems medicine.

Exploring the Therapeutic Potential of Noncoding RNAs in Alzheimer's Disease.

Despite significant research efforts, Alzheimer's disease (AD), the primary cause of dementia in older adults worldwide, remains a neurological challenge for which there are currently no effective therapies. There are substantial financial, medical, and personal costs associated with this condition.Important pathological features of AD include hyperphosphorylated microtubule-associated protein Tau, the formation of amyloid β (Aβ) peptides from amyloid precursor protein (APP), and continuous inflammation that ultimately results in neuronal death. Important histological markers of AD, amyloid plaques, and neurofibrillary tangles are created when Aβ and hyperphosphorylated Tau build-up. Nevertheless, a thorough knowledge of the molecular players in AD pathophysiology is still elusive. Recent studies have shown how noncoding RNAs (ncRNAs), including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), regulate gene expression at the transcriptional and posttranscriptional levels in a variety of diseases, including AD. There is increasing evidence to support the involvement of these ncRNAs in the genesis and progression of AD, making them promising as biomarkers and therapeutic targets. As a result, therapeutic approaches that target regulatory ncRNAs are becoming more popular as potential means of preventing the progression of AD. This review explores the posttranscriptional relationships between ncRNAs and the main AD pathways, highlighting the potential of ncRNAs to advance AD treatment. In AD, ncRNAs, especially miRNAs, change expression and present potential targets for therapy. MiR-346 raises Aβ through APP messenger Ribonucleic Acid (mRNA), whereas miR-107 may decrease Aβ by targeting beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). They are promising early AD biomarkers due to their stability in cerebrospinal fluid (CSF) and blood. Furthermore, additional research is necessary to determine the role that RNA fragments present in AD-related protein deposits play in AD pathogenesis.

PET Imaging in Alzheimer Disease: Pathology and Research Insights for Technologists.

Alzheimer disease (AD) is the sixth leading cause of death in the United States and is projected to affect over 13 million people by the year 2060. Although there is currently no cure for AD, disease-modifying treatments that target amyloid plaques have recently been approved for use. The advent of PET tracers that can reliably detect the presence of cortical amyloid plaques and tau pathologies has allowed researchers and clinicians to identify individuals who have pathologic markers of AD before the onset of cognitive decline. Although these tracers have been widely used in research settings for some time, they are now on the verge of being used to aid clinicians in the differential diagnosis of AD. As the use of these tracers increases, technologists will need to be educated on the best practices and potential problems they may encounter in their clinical populations. This article will review the available tracers for amyloid and tau PET scans and educate technologists about the most important practices and procedures that can be implemented to ensure patient safety and the capture of high-quality scans.

Circulating medium- and long-chain acylcarnitines are associated with plasma P-tau181 in cognitively normal older adults.

Alzheimer's disease (AD) pathogenesis involves dysregulation in diverse biochemical processes. Nevertheless, plasma tau phosphorylated at threonine 181 (P-tau181), a recognised AD biomarker, has been described to reflect early-stage cortical amyloid-β (Aβ) deposition in cognitively normal (CN) adults. Therefore, identifying changes in plasma metabolites associated with plasma P-tau181 at the pre-clinical stage may provide insights into underlying biochemical mechanisms to better understand initial AD pathogenesis. In the current study, plasma P-tau181, quantified via single molecule array (Simoa) technology, and plasma metabolites, quantified via targeted-mass spectrometry, were investigated for associations in CN older adults and upon stratification by positron emission tomography (PET)-Aβ load. In addition, the P-tau181-linked metabolites were evaluated for cognitive performance and neuroimaging markers of AD and the potential to distinguish between CN Aβ- and CN Aβ+ individuals. Significant positive associations of medium- and long-chain acylcarnitines (ACs) were observed with P-tau181 in the entire cohort, CN Aβ- and CN Aβ+, suggesting a link between initial Aβ pathology and fatty acid oxidation-mediated energy metabolism pathways. However, in CN Aβ-, additional linear associations of P-tau181 were observed with muscle metabolism and nitric oxide homeostasis-associated metabolites. Upon investigating the P-tau181-linked metabolites for cognitive performance, significant inverse correlations of the verbal and visual episodic memory and the global composite score were noted in CN Aβ+ with medium- and long-chain ACs, suggesting prognostic value of ACs accompanying weaker cognitive performance. While investigating neuroimaging markers, ACs had positive associations with PET-Aβ load and inverse associations with hippocampal volume in CN Aβ+, indicating connections of ACs with initial AD pathogenesis. Furthermore, based on receiver operating characteristics analysis, the associated ACs potentially classified PET-Aβ status in older adults. Therefore, plasma P-tau181-linked circulating ACs may serve as potential prognostic markers for initial AD pathogenesis in CN older adults. However, further cross-sectional and longitudinal research in highly characterised AD cohorts is needed to validate current findings.

Alzheimer's Disease: Understanding Motor Impairments.

Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and the leading cause of dementia worldwide, profoundly impacts health and quality of life. While cognitive impairments-such as memory loss, attention deficits, and disorientation-predominate in AD, motor symptoms, though common, remain underexplored. These motor symptoms, including gait disturbances, reduced cardiorespiratory fitness, muscle weakness, sarcopenia, and impaired balance, are often associated with advanced stages of AD and contribute to increased mortality. Emerging evidence, however, suggests that motor symptoms may be present in earlier stages and can serve as predictive markers for AD in older adults. Despite a limited understanding of the underlying mechanisms driving these motor symptoms, several key pathways have been identified, offering avenues for further investigation. This review provides an in-depth analysis of motor symptoms in AD, discussing its progression, potential mechanisms, and therapeutic strategies. Addressing motor symptoms alongside cognitive decline may enhance patient functionality, improve quality of life, and support more comprehensive disease management strategies.

HSV-1 Infection Alters MAPT Splicing and Promotes Tau Pathology in Neural Models of Alzheimer's Disease.

Herpes simplex virus 1 (HSV-1) infection alters critical markers of Alzheimer's Disease (AD) in neurons. One key marker of AD is the hyperphosphorylation of Tau, accompanied by altered levels of Tau isoforms. However, an imbalance in these Tau splice variants, specifically resulting from altered 3R to 4R MAPT splicing of exon 10, has yet to be directly associated with HSV-1 infection. To this end, we infected 2D and 3D human neural models with HSV-1 and monitored MAPT splicing and Tau phosphorylation. Further, we transduced SH-SY5Y-neurons with HSV-1 ICP27 which alters RNA splicing to analyze if ICP27 alone is sufficient to induce altered MAPT exon 10 splicing. We show that HSV-1 infection induces altered splicing of MAPT exon 10, increasing 4R-Tau protein levels, Tau hyperphosphorylation, and Tau oligomerization. Our experiments reveal a novel link between HSV-1 infection and the development of cytopathic phenotypes linked with AD progression. HSV-1 infection in forebrain organoids reduces the neurite length of MAP2-positive neurons.HSV-1 infection increases Tau hyperphosphorylation in both two-month-old and four-month-old forebrain organoids. HSV-1 infection increases Exon 10 containing (4R) MAPT mRNA and 4R-Tau protein expression in both forebrain organoids and human SH-SY5Y-neurons. HSV-1 ICP27 is both necessary and sufficient to induce increased 4R MAPT mRNA and 4R-Tau protein expression in SH-SY5Y-neurons. HSV-1 infection increases Tau oligomerization in both forebrain organoids and SH-SY5Y-neurons.

Comprehensive Analysis of the 5xFAD Mouse Model of Alzheimer’s Disease Using dMRI, Immunohistochemistry, and Neuronal and Glial Functional Metabolic Mapping

Alzheimer’s disease (AD) is characterized by complex interactions between neuropathological markers, metabolic dysregulation, and structural brain changes. In this study, we utilized a multimodal approach, combining immunohistochemistry, functional metabolic mapping, and microstructure sensitive diffusion MRI (dMRI) to progressively investigate these interactions in the 5xFAD mouse model of AD. Our analysis revealed age-dependent and region-specific accumulation of key AD markers, including amyloid-beta (Aβ), GFAP, and IBA1, with significant differences observed between the hippocampal formation and upper and lower regions of the cortex by 6 months of age. Functional metabolic mapping validated localized disruptions in energy metabolism, with glucose hypometabolism in the hippocampus and impaired astrocytic metabolism in the cortex. Notably, increased cortical glutaminolysis suggested a shift in microglial metabolism, reflecting an adaptive response to neuroinflammatory processes. While dMRI showed no significant microstructural differences between 5xFAD and wild-type controls, the study highlights the importance of metabolic alterations as critical events in AD pathology. These findings emphasize the need for targeted therapeutic strategies addressing specific metabolic disturbances and underscore the potential of integrating advanced imaging with metabolic and molecular analyses to advance our understanding of AD progression.

The Relationship Between Physical Activity and Non-Modifiable Risk Factors on Alzheimer's Disease and Brain Health Markers: A UK Biobank Study.

Modifiable (physical activity) and non-modifiable (sex and genotype) risk factors interact to affect Alzheimer's disease (AD) risk. Further investigation is necessary to understand if these factors influence brain volume and cognition. The study aimed to assess the effect of physical activity, APOE genotype, and sex on AD risk, brain volume, and cognition. UK Biobank data from 2006 to 2023 was accessed. Physical activity was measured by accelerometers, and International Physical Activity Questionnaire. Outcomes were AD incidence; brain volume (ventricular cerebrospinal fluid and total brain); and cognition (executive function, memory, visuospatial ability, processing speed, and reaction time). Logistic and linear regression models were conducted. 69,060 participants met inclusion criteria (mean age: 62.28 years, SD: 7.84; 54.64% female). Higher self-reported (OR = 0.63, 95% CI [0.40, 1.00], p = 0.047) and accelerometer-assessed (OR = 0.96 [0.93, 0.98], p = 0.002) physical activity was associated with lower disease incidence. Smaller ventricular cerebrospinal fluid volume (β= - 65.43 [- 109.68, - 17.40], p = 0.007), and larger total brain volume (β= 4398.46 [165.11, 8631.82], p < 0.001) was associated with increased accelerometer-assessed and self-reported physical activity respectively. Both brain volume analyses were moderated by sex. Increased accelerometer-assessed physical activity levels were associated with faster reaction time (β= - 0.43 [- 0.68, - 0.18], p = 0.001); though poorer visuospatial ability (β= - 0.06 [- 0.09, - 0.03], p < 0.001), and executive function (β= 0.49 [0.31, 0.66], p < 0.001; β= 0.27 [0.10, 0.45], p = 0.002) was related to self-reported physical activity levels. Higher levels of physical activity reduce AD risk independently of non-modifiable risk factors. Moderation of sex on brain volume highlighted the importance of incorporating non-modifiable risk factors in analysis.