Dementia with Lewy bodies (DLB) has a prolonged prodromal stage marked by heterogeneous onset presentations (OPs). However, the distribution, co-occurrence, and prognostic implications of core and supportive clinical features at onset remain underexplored. We aimed to characterize prodromal OPs and associated clinical features in a longitudinally confirmed DLB cohort and to examine their relationship with cognitive decline. Patients were enrolled from the CLIMB-DLB observational cohort at the Memory Clinic of Policlinico Tor Vergata (Rome), upon fulfilling consensus criteria for probable DLB. Patients were stratified by main OP (MCI-LB, psychiatric-onset, delirium-onset). Core (cognitive fluctuations [CF], visual hallucinations [VH], REM sleep behavior disorder [RBD], parkinsonism) and supportive (hyposmia, dysautonomia) features were coded at the prodromal stage. Pairwise associations were assessed using φ coefficients and odds ratios (ORs). Longitudinal cognitive trajectories were examined using linear mixed-effects models with random intercepts and slopes, adjusted for age and sex. Among 75 patients (mean age 73.2 ± 6.4 years; 26.7
Survivors of myocardial infarction (MI) face elevated risk of subsequent cognitive decline, yet the relative contributions of neurodegenerative susceptibility (APOE4) and lipid-mediated vascular burden (LPA risk variants) to post-MI dementia remain unclear, particularly in Asian populations historically underrepresented in dementia genetics research. We conducted a retrospective cohort study of 4,788 patients with confirmed MI enrolled in the China Medical University Hospital precision medicine program (January 1, 2004–December 31, 2021), with directly genotyped APOE (rs429358, rs7412) and LPA (rs10455872, rs3798220) variants linked to longitudinal electronic health records and the Taiwan National Death Registry. Patients were classified into four genetic risk groups: low-risk, LPA-only, APOE4-only, and dual-risk. The primary outcome was incident all-cause dementia within a fixed 5-year follow-up and was analyzed using Cox proportional hazards regression. Sensitivity analyses included a Fine–Gray subdistribution hazards model to describe the cumulative incidence of dementia in the presence of death as a competing event, along with subgroup analyses by age, sex, and cardiovascular comorbidity. The median age was 61.2 years (IQR 51.9–70.3). Compared with the low-risk reference, APOE4 carriers had substantially elevated dementia risk (APOE4-only: HR 2.49, 95
Amygdala shows early vulnerability in Alzheimer’s disease (AD), although its substructures have been less studied than hippocampal subfields. Neuropathological evidence suggests that tau pathology affects amygdala subnuclei differentially, yet in vivo characterization of subregional amygdala atrophy, its relationship with tau burden, blood-based biomarkers, and cognitive outcomes across the AD continuum remains limited. Clarifying whether amygdala degeneration follows a homogeneous or regionally selective pattern, how it relates to plasma tau biomarkers, and whether it has functional consequences is essential for improving early detection and disease modeling. The study analyzed data from 197 participants, including 71 Aβ-negative cognitively normal individuals (Aβ− CN), 31 Aβ-positive cognitively normal individuals (Aβ+ CN), and 95 Aβ-positive cognitively impaired individuals (Aβ+ CI). All participants underwent T1-weighted MRI, [18F]-MK-6240 tau PET imaging, comprehensive neuropsychological assessment, and plasma pTau181 and pTau217 and Aβ42/40 analyses. Amygdala subregion volumes and tau standardized uptake value ratios (SUVr) were extracted using FreeSurfer-based segmentation and classified into basal, centro-medial, and lateral amygdala subregions. Regional amygdala volumes and SUVr were compared across groups and examined for associations with plasma tau biomarkers and cognitive performance. Mediation analyses assessed whether subregional amygdala atrophy mediated the relationship between tau pathology and cognition. Pronounced regional heterogeneity was observed within the amygdala. Atrophy of the centro-medial subregion was detectable at the preclinical stage of AD, preceding cognitive impairment. Lower centro-medial amygdala volume was significantly associated with higher plasma pTau181 and pTau217 levels, as well as with lower memory and executive scores. Mediation analyses demonstrated that amygdala tau-PET burden fully mediated the relationship between plasma pTau biomarkers and centro-medial amygdala volume, while centro-medial amygdala volume mediated the effect of tau pathology on memory performance. Although the centro-medial subregion showed the earliest and most pronounced atrophy, it did not exhibit a correspondingly higher local tau-PET burden than other amygdala subregions. These findings suggest that amygdala involvement in AD is regionally heterogeneous, appears early in the AD continuum, and has clinically significant cognitive consequences. Subregional quantification of the amygdala, particularly when combined with plasma pTau biomarkers, may provide sensitive early indicators of disease-related neurodegeneration, reflect network-level vulnerability, and improve understanding of cognitive decline, confirming its potential utility as a biomarker in AD research and clinical practice.
To evaluate the efficacy of repetitive transcranial magnetic stimulation (rTMS) on global cognitive function in patients with mild-to-moderate Alzheimer’s disease (AD), explore the moderating effects of different treatment parameters, and provide evidence-based guidance for clinical parameter optimization. We systematically searched PubMed, Web of Science, the Cochrane Library, and Embase from inception to July 8, 2025. Randomized controlled trials (RCTs) comparing rTMS with sham rTMS in patients with mild-to-moderate AD were included. Cognitive function was assessed using the Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-cog) or the Mini-Mental State Examination (MMSE). The systematic review protocol was registered with PROSPERO (CRD420261388581). Twenty RCTs involving 776 eligible patients were included. For studies reporting mean ± standard deviation, rTMS significantly improved ADAS-cog scores (SMD = − 0.51; 95
Repetitive transcranial magnetic stimulation (rTMS) has emerged as a research focus in the treatment of Alzheimer’s disease (AD). However, the optimal stimulation target remains controversial and requires urgent resolution. To evaluate the cognitive effects of 5 Hz rTMS targeting the cerebellar Crus II region in patients with AD and to explore the underlying neural mechanisms using functional near-infrared spectroscopy (fNIRS). A total of 35 patients with AD diagnosed at the mild cognitive impairment or mild dementia stage based on cerebrospinal fluid biomarkers were initially enrolled and randomly assigned to a real rTMS group (n = 18) or a sham stimulation group (n = 17), with 33 patients (17 and 16, respectively) completing the full intervention and being included in the final analysis. All patients received two weeks of bilateral 5 Hz rTMS or sham stimulation over the cerebellar Crus II region. Neuropsychological assessments were performed at baseline, immediately post-treatment, and at week 12. Resting-state fNIRS data were collected at baseline and post-treatment. Between-group differences in cognitive scores, cerebral functional activity, and brain network topology after intervention were analyzed. Compared with the sham group, the real rTMS group showed significant improvement in global cognition post-treatment, and this effect persisted until week 12. fNIRS analysis revealed that after treatment, the real rTMS group exhibited significantly increased fractional amplitude of low-frequency fluctuations (fALFF) in the left frontal pole and left dorsolateral prefrontal cortex (DLPFC), along with enhanced functional connectivity across the cerebral cortex. Graph theory analysis showed significant increases in global efficiency, local efficiency, and clustering coefficient, and significant decreases in characteristic path length and normalized characteristic path length in the real rTMS group post-treatment. Correlation analysis indicated that the increase in fALFF in the DLPFC was positively correlated with improvements in MMSE and Digit Span Test scores, while improvement in delayed recall score of the Auditory Verbal Learning Test was correlated with decreased normalized characteristic path length. Five Hz rTMS applied to the cerebellar Crus II region effectively improves cognitive function in patients with mild AD, with benefits persisting for at least three months. fNIRS-based mechanistic analyses suggest that the therapeutic effects may involve cerebellar-cortical loop modulation of hemodynamic activity in key frontal regions, accompanied by enhanced whole-brain functional connectivity and optimized network topology. However, given that fNIRS measures hemodynamic responses rather than direct neuronal activity, these findings should be interpreted as network-level hemodynamic changes rather than as direct evidence of neuronal reorganization. The study was registered at chictr.org.cn website (ID: ChiCTR2200061754) on 02–07-2022.
Mitochondrial DNA (mtDNA) has emerged as a promising biomarker for Alzheimer’s disease (AD), but the role of plasma-derived extracellular vesicle (EV) mtDNA in aiding differential diagnosis remains to be further elucidated. In this study, we evaluated mtDNA from plasma-derived EVs as potential biomarkers to distinguish AD from other non-AD dementias, including vascular dementia (VaD), dementia with Lewy bodies (DLB), Parkinson’s disease dementia (PDD), and chronic traumatic encephalopathy (CTE). Across two independent cohorts comprising 168 healthy controls, 262 AD patients, and 312 non-AD dementia patients, we quantified the EV-associated mtDNA regions ND1, COX3, and DLOOP. Copy numbers of all three markers were significantly elevated in AD patients relative to both control and non-AD groups. Although their standalone diagnostic performance for AD was modest, mtDNA markers demonstrated strong discriminatory power in differentiating AD from other dementia subtypes, with composite area under the curves reaching 0.92 and 0.97 in training and validation sets, respectively. Correlation analyses further revealed strong associations between mtDNA levels and established AD-related biomarkers such as phosphorylated Tau217, GFAP, and the Aβ42/40 ratio. These findings suggest that EV mtDNA signatures—particularly ND1, COX3, and DLOOP—hold significant promise as differential diagnostic biomarkers, offering added value in distinguishing AD from other forms of dementia rather than serving as standalone diagnostic tools.
Ethno-racial disparities in Alzheimer's disease (AD) risk are well-documented, yet mechanisms underlying these differences remain poorly understood. This study investigates plasma AD biomarkers reflective of amyloid, tau, neurodegeneration, and inflammation across Hispanic, non-Hispanic Black/ African American, and non-Hispanic White adults, and examines whether social determinants of health (SDOH) and comorbidities mediate observed disparities. Data from the community-based Health and Aging Brain Study – Health Disparities (HABS-HD) included 1,256 Hispanic, 723 Black, and 1,243 non-Hispanic White participants. Group differences in plasma biomarkers (phosphorylated tau-217 [p-tau217], amyloid-β 42/40 ratio [Aβ42/40], phosphorylated tau-181 [p-tau181], total tau, neurofilament light chain [NfL], and glial fibrillary acidic protein [GFAP]) were assessed using ANCOVA adjusted for age, sex, APOE-ε4 status, and cognitive status. Multiple mediation models tested whether social determinants of health (income, education, area deprivation, chronic stress, social support) and comorbidity factors (BMI, creatinine, total cholesterol, HbA1c, systolic blood pressure) mediate group differences, with covariates and mediators considered simultaneously, resulting in 22 mediation models. Significant differences were observed across all plasma biomarkers. Both Black and Hispanic adults showed lower p-tau217 and p-tau181 compared to non-Hispanic White adults (p's < 0.001). Hispanic adults exhibited lower Aβ42/40 compared to both groups (p's < 0.05) and lower GFAP compared to non-Hispanic White adults (p = 0.002), but higher total tau (p's < 0.01) compared to both groups. Hispanics had higher NfL than Black adults (p < 0.001) but did not differ from non-Hispanic Whites, while Black adults had lower NfL than non-Hispanic White adults (p < 0.001). Comorbidity factors, particularly creatinine (10 of 22 models), BMI (8 models), and HbA1c (7 models), consistently mediated biomarker differences. SDOH factors demonstrated mediation for Aβ42/40, p-tau181, and NfL, with area deprivation and education as key mediators. SDOH and comorbidities were associated with plasma AD biomarker differences observed across ethno-racial groups, though their influence varies by biomarker type and comparison group. Renal function (creatinine), metabolic factors (BMI, HbA1c), and structural disadvantages (area deprivation, education) emerged as critical factors. However, many effects remain unexplained, suggesting additional biological, environmental, or unmeasured social factors contribute to disparities. These findings highlight the need for precision medicine approaches that integrate biological, systemic health, and social contexts when interpreting biomarkers and guiding dementia prevention.
Abnormal activation of a developmental process driven by a bioactive peptide T14, is posited as a key mechanism in the degeneration of the primarily vulnerable nuclei during the prodromal phase of Alzheimer’s Disease (AD). We use a range of anatomical, biochemical and genetic approaches to explore changes in T14 and its target, α7nAChR, in AD and in individuals with mood disorders, a frequent prelude to the disease. Using paired samples from the same patients, levels of T14 and α7nAChR increased in the hippocampus across the AD continuum. In contrast, in early Braak stages, T14 levels in the midbrain reach a plateau and are primarily localised to glia. Moreover, in a cognitively healthy cohort, CSF derived ex vivo revealed a differential profile between T14 and tau levels in individuals with mood disorders, a well-known precursor to AD. These observations confirm a key role of T14 in the neuropathology of AD. Finally, we show a Braak-stage dependant and selective increase in an acetylcholinesterase isoform (AChE-R) already associated with AD pathology, where the profile corresponds closely to that of T14, thereby providing further clues regarding its provenance. By highlighting region and cell-specific changes in the T14 profile as AD progresses, this study further validates a key role for T14 in the progression of neurodegeneration. Finally, the mood disorder-dependent changes based on T14 in CSF might reflect dysfunction in the primarily vulnerable isodendritic core and as such be viewed as a possible, albeit non-exclusive, prelude to AD. Collectively, these results underscore the importance of T14 in AD aetiology and could aid the development of precise and effective therapeutics to target its progression.
TAR DNA-binding protein of 43 kDa (TDP-43) is often found in the brains of patients with Alzheimer’s disease (AD), where it co-occurs with amyloid β plaques and tau neurofibrillary tangles, and associates with accelerated cognitive decline and brain atrophy. TDP-43’s function of repressing the inclusion of cryptic exons (CEs) during RNA splicing is compromised in AD. A single-nucleotide polymorphism (SNP) located within the CE in the UNC13A gene [rs12973192 (C > G)] is associated with higher disease risk and reduced survival in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) by weakening TDP-43 binding promoting CE inclusion. To investigate the influence of the rs12973192 UNC13A CE SNP and UNC13A cryptic splicing on TDP-43 pathology, survival and cognitive impairment in AD. We evaluated the UNC13A CE SNP in a cohort of 1,672 AD, including 643 AD brains with available cognitive measurements and 73 AD cases for which we measured cryptic RNA levels in the amygdala. We also evaluated a cohort of 466,517 from the UK Biobank to determine associations between the UNC13A CE SNP and dementia diagnosis. In AD, the UNC13A CE SNP associated significantly with cognitive decline, but not with TDP-43 pathology or with survival. UNC13A cryptic RNA levels in the amygdala were a better predictor of cognitive decline than the UNC13A CE SNP itself, while STMN2–another well-known CE target–exhibited no such association. These findings point to UNC13A cryptic splicing as a specific driver of cognitive decline in AD, outperforming both genetic risk and other cryptic targets.
Diagnostic testing and neurosurgical management involving CSF shunting in patients with idiopathic normal pressure hydrocephalus (iNPH) offers a unique, ethically sustainable opportunity to study the aging human brain. The common co-occurrence of neurodegenerative pathologies such as amyloid-β plaques and neurofibrillary tau tangles (NFT) provides a valuable window for research into the Alzheimer’s disease-related mechanisms. Interindividual variability among iNPH patients enables investigation and validation of biomarkers and molecular mechanisms, opening possibilities for new treatments. In vitro techniques and culturing methods for living brain tissue expand the utility of samples for electrophysiological studies, drug testing, and examining genetic risk variants. Careful sectioning and processing are essential for high-quality samples with intact cells for functional analysis. A rigorous pipeline is also needed for preserving samples for transcriptomic, proteomic, and structural analyses, with emphasis on RNA integrity and tissue architecture for single-cell sequencing and spatial analysis. Here, we review the use of small cortical brain biopsies in neurodegenerative diseases research and diagnostics. Furthermore, we share our team’s experience in acquiring and preserving living brain samples during iNPH CSF shunt surgeries, along with our protocols for resection, use, and preservation of biopsies for preclinical research. We highlight the potential of living human tissue for neuroscience, early neurodegenerative disease diagnosis, and targeted therapies.
Spatiotemporal patterns of tau accumulation differ between Alzheimer disease (AD) subtypes in brain networks related to clinical manifestations. Converging evidence suggests that accumulation may be driven by spreading through network connections and/or interactions with amyloid-β (Aβ). Persons with atypical AD presentations might carry pre-existing network-specific vulnerabilities, which might predispose these areas to tau pathology. However, it is unknown if regional patterns of Aβ and network connectivity differ between tau-defined subtypes and whether these patterns precede tau accumulation. We used Subtype-and-Stage-Inference (SuStaIn) to identify subtypes in 919 tau-PET scans from 709 participants in the Knight ADRC. We tested group differences between tau-defined subtypes in regional Aβ-PET and resting-state-functional-connectivity (RSFC) seed maps to early-stage tau epicenter regions using retrospective imaging data preceding the tau-PET scans by up to 14 years, including across stages of AD progression. Most participants were tau-negative (N = 522). Among tau-positive participants, we identified three tau-PET subtypes. Limbic tau was the most common subtype (N = 136, 73.9
Accurate detection of Alzheimer’s disease (AD) pathophysiological changes is crucial for research and clinical practice. While positron emission tomography (PET) imaging is an established reference standard for detecting brain amyloid and tau deposition, cerebrospinal fluid (CSF) biomarkers offer a more accessible alternative. This study aimed to identify optimal CSF biomarkers and thresholds for predicting tau and amyloid PET positivity in a memory clinic population. This cross-sectional, observational study included 220 participants from a memory clinic who underwent amyloid or tau PET scans and CSF biomarker analysis using either Fujirebio INNOTEST or LUMIPULSE assays. CSF biomarker performance was assessed via receiver operating characteristic (ROC) analysis. Double-threshold approaches were implemented to address classification uncertainty. Ratios combining biomarkers of both amyloid and tau, such as Aβ42/pTau, consistently outperformed individual biomarkers in detecting amyloid and tau PET positivity. For amyloid PET, the Aβ42/pTau ratio achieved an AUC of 0.93 (95
In Alzheimer’s disease(AD), core CSF biomarkers incompletely predict clinical progression. Synaptic biomarkers may add prognostic information by capturing distinct biological dimensions, from synaptic injury to adaptive network function. Although correlated, neurogranin (Ng) is interpreted as a marker of post-synaptic injury, whereas neuronal pentraxin-2(NPTX2) is more closely related to circuit homeostasis. We tested whether CSF NPTX2 contains a specific component statistically associated with a putative adaptive network signal, interpreted within a hypothesized compensatory framework, using clinical progression and brain metabolism as convergent readouts. We retrospectively studied 104 patients with typical MCI-AD. CSF core AD biomarkers, NPTX2 and Ng were measured with commercial immunoassays. Early and late MCI stages were defined by proximity to dementia conversion (LMCI ≤ 2 years; EMCI > 2 years or stable). A residual NPTX2 measure(Res_NPTX2) was derived by regressing z-transformed NPTX2 on Ng, an index of AD burden based on tau/amyloid ratio, and age. Associations with MMSE and time-to-conversion were tested using linear and survival models. In all patients, brain [18F]FDG PET was analyzed with voxel-based methods to identify metabolic correlates of NPTX2 and Res_NPTX2 relative to AD-related hypometabolic regions. Ng correlated strongly with NPTX2 (ρ = 0.67,p < 0.001). Res_NPTX2 was higher in EMCI than LMCI (p = 0.0006), associated with better baseline MMSE (p = 0.008), and predicted less MMSE decline over time (p = 0.002). During follow-up, 55/104 patients(52.9
Recent proteomic studies have identified both established and novel proteins in genetic frontotemporal lobar degeneration (FTLD). However, it remains unclear at what point in the disease these proteins deviate from normal levels and how their trajectories relate to one another. Defining the temporal sequence of protein abnormalities could not only improve disease staging but also help identify biomarkers most sensitive to early disease activity in pathogenic variant carriers. We aimed to apply discriminative event-based modelling (DEBM) to characterize the progression profiles of proteins identified in a previous cross-sectional proteomic analysis. Building on our prior cross-sectional CSF proteomic analysis of genetic FTLD using a proximity extension assay, we selected the top ten significant proteins for each genetic group (C9orf72, GRN, MAPT). We then applied DEBM to characterize temporal dynamics of these proteins separately in each genetic group and evaluated their potential as early disease markers. To validate model performance, each individual was assigned a disease stage according to their position along the estimated disease timeline, based on protein levels and independent of clinical labels. Next, we assessed how well these stages discriminated symptomatic from presymptomatic carriers and non-carriers. Across all genetic groups, NfL consistently became abnormal before TPM3, although the earliest abnormal proteins differed between groups. In C9orf72, ELAVL4 is the first protein to become abnormal; in GRN SEMA3G and GRN, and in MAPT MMP-10. Estimated individual-level disease stage effectively distinguished symptomatic carriers from presymptomatic carriers and non-carriers, demonstrating high diagnostic accuracy (range AUC 0.74–0.98). Our data-driven findings provide a temporal ordering of multiple CSF proteins, highlighting potential early biomarkers and disease dynamics in different forms of genetic FTLD. In addition, the model’s accurate estimation of disease stages underscores the value of DEBM for patient stratification, offering a promising tool to support clinical trial design.
Alzheimer’s disease (AD) and Parkinson’s disease (PD) pose escalating global health challenges, with early detection of mild cognitive impairment (MCI) being critical for timely intervention. The 2023 Delphi consensus highlights the need for scalable tools suitable for primary care. This study aimed to validate the MemTrax as a rapid memory-focused triage tool against consensus-recommended cognitive assessments, including the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA), for detecting MCI due to Alzheimer’s disease (AD-MCI) as the primary objective, and to explore its performance in MCI due to Parkinson’s disease (PD-MCI) as an exploratory aim, evaluating its utility as a rapid, accessible digital tool. We conducted a cross-sectional study enrolling 222 participants: 74 with AD-MCI, 73 healthy controls (HCs; primary cohort); 42 PD patients with normal cognition (PD-NC), 33 with PD-MCI (exploratory cohort). All participants underwent MMSE, MoCA and MemTrax testing. Diagnostic accuracy, optimal cut‑offs, and correlations between MemTrax parameters (percent correct [MTx‑
Abstract Background Semantic fluency is commonly assessed in the diagnostic work-up of individuals with suspected cognitive impairment due to neurodegenerative disease. Semantic fluency has a predictive value for survival in clinical AD and in healthy elderly individuals, but it is unknown if this also applies to biomarker-confirmed AD and non-AD memory clinic patients. Potential associations with and added value of imaging biomarkers of amyloid pathology and neurodegeneration have yet to be explored. Methods From our clinical registry, we included patients who were assessed at a memory clinic with the neuropsychological assessment battery of the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD-NAB) and whose vital status could be retrieved in 07/2024. We tested the association of semantic fluency performance at first assessment and over time (and, for comparison, further CERAD-NAB subtest scores) with mortality risk using age-adjusted single-predictor Cox proportional hazard models. Amyloid status (positive vs negative on clinical PET reads) and global cognitive impairment (MMSE) were included as covariates. In addition, we explored associations between semantic fluency performance and both regional cortical glucose metabolism (FDG PET) and global amyloid load (centiloids; PiB PET). Finally, the predictive value of global amyloid load and glucose metabolism in comparison to and in combination with semantic fluency performance was assessed. Results 583 patients were included (age 68.9 ± 8.7, 45% female). 280 patients (48%) had died and 303 (52%) were alive after a median of 8.0 years [95% C.I. 7.7—8.4]. Better semantic fluency (age-, sex- and education adjusted Z score, based on normative data) was significantly associated with lower mortality risk (HR = 0.71 [0.63 – 0.80], Bonferroni-corrected p < 0.001). Its predictive value was higher than that of all other CERAD-NAB subscores (e.g., memory, visuospatial abilities). Semantic fluency remained a significant predictor when amyloid status and global cognitive impairment were accounted for (HR = 0.75 [0.61 – 0.91], p = 0.0035). In patients with more than one assessment ( N = 163), longitudinal change of semantic fluency (derived from a linear mixed effects model) was also a significant predictor (HR = 0.66 [0.53—0.83], p < 0.001). In 218/583 patients who had received amyloid and FDG PET, worse semantic fluency was associated with decreased FDG uptake of left inferior and middle temporal, dorsolateral frontal, and posterior parietal cortical regions (Bonferroni-corrected p < 0.05), but not with amyloid load. FDG uptake of the left IFG (pars opercularis) was itself a predictor of survival (HR = 0.68 [0.55 – 0.84], Bonferroni-corrected p < 0.05), but to a lesser degree than semantic fluency (and MMSE, naming and figure drawing). Predictive accuracy of semantic fluency was further improved by including FDG uptake of the right anterior cingulate (Bonferroni-corrected p = 0.078). Global amyloid load was not associated with survival. Conclusions Survival of memory clinic patients can be predicted by semantic fluency, independently from amyloid status and global cognitive impairment. Anterior cortical glucose metabolism is itself a significant predictor of survival and slightly improves prediction by semantic fluency.
Cerebral amyloid angiopathy (CAA) is strongly associated with Alzheimer’s disease neuropathologic changes (ADNC), but its links with other brain pathologies remain unclear. We conducted a clinicopathological study of 3,267 participants from the National Alzheimer’s Coordinating Center (NACC) cohort. Neuropathological evaluations included potential risk factors for CAA, such as ADNC, Lewy body pathology (LBP), frontotemporal lobar degeneration (FTLD), and other neuropathologies. We found that ADNC and LBP were associated with increased odds of CAA, with the risk increasing according to ADNC severity and in cases of limbic/amygdala-predominant LBP. In contrast, FTLD, particularly the FTLD-TDP subtype, was inversely associated with CAA. Among other neuropathologies, CAA was positively associated with microinfarcts, arteriolosclerosis, white matter rarefaction, and hippocampus/cortical atrophy, but inversely associated with lobar atrophy and higher brain weight. In addition, APOE ε4 carriers with mixed ADNC, LBP, and FTLD exhibited the highest risk. Stronger associations between ADNC and CAA were observed in participants aged < 80 years and in males, whereas females demonstrated greater vulnerability to vascular- and atrophy-related correlates. Several neuropathology–CAA associations were also more pronounced among APOE ε4 carriers. These findings highlight the interplay of neurodegenerative, vascular, sex, and APOE ε4 in CAA susceptibility, with implications for risk stratification.
Higher cognitive ability in late adolescence and young adulthood associate with reduced risk of dementia, but such assessments are influenced by educational selection. Whether specific cognitive abilities earlier in childhood associate with later dementia risk, independent of known associations with cardiovascular disease (CVD) and diabetes, remains unclear. We studied a Swedish population-representative birth cohort with cognitive testing at age 13 (n = 10,539 born in 1948). Dementia and somatic morbidity were ascertained from nationwide inpatient and cause-of-death registers through November 2025 (> 6 decades). Cox models estimated associations between childhood inductive reasoning, verbal and spatial ability scores and dementia, somatic morbidity, CVD and diabetes, each modelled as outcomes and as time-varying covariates in dementia models. During follow-up, 287 individuals (2.7
As longevity increases and the population over age 65 expands, advancing age remains the most reliable predictor of cognitive decline, highlighting the need to identify biological mechanisms that support exceptional cognitive aging. We tested whether lower inherited risk of Alzheimer’s disease (AD) dementia predicts SuperAger status (adults ≥ 80 years with episodic memory at least as good as middle-age adults) using prospectively enrolled SuperAgers and Cognitively Average Controls (Controls) from the multisite SuperAging Research Initiative. We studied 231 participants (SuperAgers n = 142; Controls n = 89). We confirmed that the genetic ancestry structure across groups was comparable. We evaluated whether APOE status (ε2, ε3, ε4) and three AD polygenic risk scores (PRS) derived from large contemporary Genome-Wide Association Studies (GWAS) (PRSLambert, PRSWightman, PRSBellenguez) predicted SuperAging status using logistic regression models adjusted for age, sex, and education, considering ancestry interactions. APOE allele and genotype distributions did not differ between groups, and neither APOE nor any of the three PRS predicted SuperAger status. Results were unchanged when accounting for global non-European or African ancestry or principal components. In this well-characterized cohort, neither APOE nor contemporary PRS explained SuperAger status. These findings suggest that the exceptional late-life memory phenotype that is characteristic of SuperAging is not explained by common-variant AD genetic risk captured by APOE or contemporary AD PRS, motivating a deeper investigation of potential rare genetic variations and experiential factors contributing to exceptional cognitive aging.
Patients with Alzheimer’s disease (AD) exhibit early alterations in the Default Mode Network (DMN), a key brain network involved in episodic memory where the precuneus plays a central role. Precision-targeted, non-invasive brain stimulation represents a promising strategy to improve cognitive function in individuals with dementia. The DMN can be modulated through personalized non-invasive electromagnetic stimulation, a therapeutic approach that enhances neural plasticity and stabilizes network connectivity. This trial implements an innovative therapeutic protocol based on precision delivery of personalized electromagnetic stimulation targeting the precuneus, the main hub of the DMN. This phase 2 multicenter, randomized, double-blind, sham-controlled, three-arm trial evaluates the safety and efficacy of combined repetitive transcranial magnetic stimulation (rTMS) and transcranial alternating current stimulation (tACS) targeting the precuneus in AD patients. rTMS will be applied using the intermittent theta burst stimulation (iTBS) protocol, while tACS will be delivered at gamma frequency (70 Hz). Personalization of iTBS-tACS treatment is established using neuronavigated TMS with electroencephalography (TMS-EEG). The 24-week intervention starts with a 2-week intensive course of daily combined treatment over the precuneus (5 sessions per week), followed by a 22-week maintenance phase with weekly stimulation. The primary outcome measure is the change in the integrated Alzheimer Disease Rating Scale (iADRS) between baseline and week 24. Secondary outcomes include score changes in the Alzheimer’s Disease Cooperative Study – Activities of Daily Living (ADCS-ADL) scale, Clinical Dementia Rating Scale–Sum of Boxes (CDR-SoB), the Alzheimer’s Disease Assessment Scale–Cognitive Subscale (ADAS-Cog13), the Mini-Mental State Examination (MMSE), the Montreal Cognitive Assessment (MoCA), the Frontal Assessment Battery (FAB), the Face-Name Association Task (FNAT), the Neuropsychiatric Inventory (NPI), and the Apathy Motivation Index (AMI). Exploratory outcomes will include changes in cortical activity and connectivity (assessed through TMS-EEG, MRI), in blood based biomarkers of neurodegeneration, synaptic activity and neural inflammation, and sensorimotor functions in virtual environments. Evaluation at week 12 and a follow-up assessment at week 32 will be conducted to assess short-term and follow-up treatment effects, respectively. This trial aims to provide evidence that personalized combined electrical and magnetic stimulation of the DMN may slow functional and cognitive decline in AD patients, contributing to the development of personalized interventions for AD treatment. ClinicalTrials.gov, NCT07075770, registered 10 July 2025.
