A 2-min digital clock-drawing test (DCTclock) captures more granular features of the clock-drawing process than the pencil-and-paper clock-drawing test, revealing more subtle deficits at the preclinical stage of Alzheimer's disease (AD). A previous cross-sectional study demonstrated that worse DCTclock performance was associated with higher Aβ and tau burden in older cognitively normal (CN) participants. This study investigates whether longitudinal changes in DCTclock performance are associated with amyloid-β (Aβ) and tau burden in preclinical AD. A total of 219 CN participants completed baseline and follow-up DCTclock assessments, baseline Aβ ([11C]PiB) and tau ([18F]Flortaucipir) PET imaging. Global Aβ and regional tau burden were estimated. Linear mixed models examined associations between longitudinal DCTclock and (1) Aβ, (2) tau, and (3) Aβ and tau burden, adjusted for age, sex, and education. Cognitive domain-specific performance and fine-grained features of DCTclock were analyzed. Elevated baseline Aβ or tau was most strongly associated with accelerated decline in DCTclock performance, particularly in the Information Processing cognitive domain, with stronger associations noted for tau burden. The associations were driven by pen-stroke latency-related features. Participants without elevated Aβ or tau burden demonstrated improved performance in these latency features, suggesting practice effects. Longitudinal declines in DCTclock performance, especially in Information Processing involving speed and executive function, were linked to early Aβ and tau burden in preclinical AD. These findings highlight the potential of digital cognitive assessment tools for tracking disease progression and assessing therapeutic efficacy in clinical trials.

Background: Aβ1-42 and APOE concentrations, as well as Aβ42/40 ratio, may be considered as a link between hypertension (HTN) or diabetes mellitus (DM), brain amyloidosis, and dementia. HTN and DM are associated with cognitive impairment and may contribute to the development of Alzheimer’s disease (AD). This preliminary study aimed to evaluate the impact of vascular risk factors on the concentration of biochemical AD markers and cognitive state. As it is a cross-sectional study in nature, causal relationships cannot be established. Methods: The study was conducted in the south of Poland among a rural population over 65 years of age. A total of 58 patients qualified into the study were divided into groups according to the presence of HTN (n = 18) or HTN coexisting with DM (n = 40). A healthy control group was also formed (n = 20), resulting in 78 study participants. The study population was also divided based on M-ACE results, forming a normal cognition group (NC) and a deteriorated cognition group (DC). Biochemical tests, neurological scales assessments, and ultrasound examinations were conducted. Results: Patients who scored in the normal range on the M-ACE had higher Aβ1-42 (median 38.52 vs. 27.35 pg/mL, p = 0.02) and apoE concentrations (median 125.0 vs. 65.73 μg/mL, p = 0.002), and a higher Aβ42/40 ratio (median 0.39 vs. 0.29 p < 0.000) compared to the DC group. Considering the study groups, the highest Aβ42/40 ratio was found among the HC group (median 0.47). The median score for the M-ACE scale was 3 points lower when HTN and DM coexisted, compared to the sole diagnosis of HTN (25 points and 28 points, respectively). A higher number of years of education correlated with better M-ACE results. Lipid and uric acid concentrations were not related to M-ACE or MMSE scores. An inverse relationship connected Aβ1-40 and Aβ1-42 to BMI, the duration of HTN treatment, and glycated hemoglobin. Conclusions: Aβ1-42, APOE, and Aβ42/40 are not only correlated with cognition but also related to patient’s disease profile. The coexistence of DM and HTN was associated with the most significant decline in cognitive functioning. However, a higher number of years of education may protect against the development of dementia in old age. The roles of cholesterol and uric acid in cognitive decline are still inconclusive.

INTRODUCTIONDiffusion‐tensor imaging (DTI) analysis along the perivascular space (ALPS) has emerged as a non‐invasive marker of glymphatic function. Preclinical studies suggest that apolipoprotein E4 (APOE4), a major genetic risk factor for Alzheimer's disease, may exacerbate glymphatic dysfunction‐related accumulation of beta‐amyloid (Aβ) and tau, but human evidence is lacking. This study examined whether APOE4 moderates the relationship between glymphatic dysfunction, estimated by the ALPS index, and Aβ or tau deposition.METHODSWe analyzed 423 older adults (mean age 70.5 ± 8.1 years) with varying cognitive profiles who underwent DTI to calculate the ALPS index and [11C] Pittsburgh Compound B (PiB) positron emission tomography (PET) for Aβ deposition. Additionally, 132 underwent [1⁸F] AV‐1451 PET for tau imaging.RESULTSA significant interaction between APOE4 status and ALPS index was observed for Aβ deposition, but not for tau. A lower ALPS index was associated with higher Aβ only in APOE4‐positive individuals.DISCUSSIONAPOE4 enhances the association between glymphatic dysfunction and Aβ burden.HighlightsApolipoprotein E4 (APOE4) status moderates the link between analysis along the perivascular space (ALPS) index and cerebral beta‐amyloid.Lower ALPS index is associated with higher beta‐amyloid (Aβ) only in APOE4 carriers.No significant moderation by APOE4 on ALPS–tau association was found.ALPS index may offer non‐invasive glymphatic marker for beta‐amyloid burden.

Alzheimer’s disease (AD) pathology is typically associated with reduced brain volume and cortical thickness, interpreted as neurodegeneration. However, several cross-sectional studies in cognitively unimpaired individuals have paradoxically reported larger brain volume and thicker cortex in the presence of amyloid-β (Aβ), suggesting that Aβ–brain structure associations may not follow a simple linear pattern early in the disease. We leveraged over a decade of longitudinal data from the PREVENT-AD cohort (N=367, mean follow-up 7.17 years, range 0–11.27 years) to investigate how Aβ burden related to both cross-sectional levels and longitudinal changes in brain volume, cortical thickness, and cortical tissue mean diffusivity (MDT) derived from free-water corrected diffusion tensor imaging. We examined associations separately in individuals below (Aβ−) and above (Aβ+) the Aβ-positivity threshold, tested for nonlinearity across all participants, and aligned structural trajectories to the estimated years from Aβ-positivity onset. We found that higher Aβ was associated with larger brain volume, higher cortical thickness and lower MDT in regions such as the fusiform gyrus, supramarginal gyrus, hippocampal volume, inferior parietal and middle temporal cortex in the Aβ− group. The opposite associations were found in the Aβ+ group. Across all participants, volume and thickness showed an inverse U-shaped relationship with Aβ, while MDT followed a U-shaped pattern. Longitudinally, the rate of cortical thickness change showed an inverse U-shaped association with Aβ, whereas Aβ burden was associated with faster volume loss and greater MDT increase. When structural measures were aligned to the estimated time of Aβ positivity onset, volume and thickness increased years before the expected Aβ positivity onset and declined thereafter, while MDT showed no association with time relative to Aβ positivity onset. Our results help reconcile inconsistencies across prior studies and suggest that brain structural changes related to Aβ pathology start years before Aβ positivity onset and follow nonlinear trajectories. These early structural changes might be due to pathological processes such as neuroinflammatory swelling early in the course of the disease.

Alzheimer’s disease (AD) develops over a prolonged asymptomatic phase marked by silent pathology. Identifying cognitively unimpaired individuals likely to progress to mild cognitive impairment (MCI) is essential for early intervention. We investigated whether multimodal combinations of biomarkers, including frequency-specific neurophysiological activity, enhance prediction beyond demographic and genetic factors in older adults (n = 102; 31 progressors; mean follow-up = 5.9 years). Biomarkers included MEG-derived alpha power, MRI-derived hippocampal volume, plasma Aβ42/40 ratio and p-tau217, and neocortical Aβ and entorhinal tau PET. Cox regression models estimated progression risk and tested time-varying prognostic effects. Neurophysiological and proteinopathy biomarkers improved prediction beyond clinical and genetic factors. Elevated alpha power predicted short-term risk, but its predictive value weakened over time, whereas high neocortical Aβ became increasingly predictive with longer follow-up. Plasma Aβ42/40, p-tau217, and tau PET each conferred higher risk, while hippocampal volume did not. Findings support a multimodal, time-sensitive framework for individualized risk prediction in preclinical AD.

Several studies implicate circadian rhythm disturbances in Alzheimer’s disease. However, very little is known about how circadian rhythms are associated with Alzheimer’s pathological biomarkers in older adults at early stages of the disease, and how these relationships map onto cognition. This cross-sectional study used 24-h accelerometry data to investigate the relationships between circadian rhythms, amyloid-β (Aβ), tau, and cognition in 68 older adults with objective early cognitive impairment. Participants wore GENEActiv accelerometers for ∼1 month (mean = 31.8 days). Circadian rhythms measures were quantified from accelerometer data and included acrotime (average time of day of peak activity) and intradaily variability (IV) (average circadian rhythm fragmentation within a day). Aβ was measured as a composite, and tau (n = 67) was measured in Braak staging regions of interest I/II and III/IV using positron emission tomography. The cognitive domains used were verbal memory (California Verbal Learning Test short delay free recall) and attention/processing speed (Digit Symbol Substitution Test). Multivariable linear regression models were conducted to test for associations between circadian rhythms and the outcome variables of Aβ, tau, and cognition. The moderating effects of age, sex, and apolipoprotein E4 (APOE4) carrier status were assessed in these associations. To investigate mechanistic pathways through which circadian rhythms may impact cognition, exploratory mediation analyses were conducted post hoc. Models were adjusted for age, sex, APOE4 carrier status, and years of education. The study included 68 older adults (mean age = 66.8 years, age range = 55–80 years, 63.2% female, 26.5% APOE4 carriers). Earlier acrotime was associated with higher Aβ and tau, the former of which was stronger in APOE4 carriers relative to non-carriers. Higher IV was related to higher tau in Braak regions III/IV. Age and sex modified the association between IV and tau, in which the relationships strengthened with increasing age and disproportionately affected men. Earlier acrotime was associated with worse verbal memory, but later acrotime was associated with worse attention/processing speed. Tau in Braak regions I–IV mediated the relationship between acrotime and verbal memory. The insights from this study revealed that circadian rhythms were associated with Aβ, tau, and cognition in older adults with objective early cognitive impairment. We provide novel evidence for tau as a biological mediator in the relationship between circadian timing and cognition. This work identified circadian rhythms as a promising point of intervention to reduce Alzheimer’s disease risk and potentially mitigate pathological progression and cognitive decline.

INTRODUCTIONPolygenic risk score (PRS) identifies individuals at high genetic risk for Alzheimer's disease (AD), but its utility in predicting cognitive trajectories and AD pathologies remains unclear. We optimized PRS (optPRS) for AD, investigated its association with cognitive trajectories and AD phenotypes of cerebral organoids.METHODSUsing genome‐wide association study (GWAS) summary statistics from a European population, we developed optPRS to predict AD in Korean individuals (n = 1634). We analyzed the association between optPRS and cognitive trajectories (n = 771). We generated induced pluripotent stem cell–derived cerebral organoids from patients with high (n = 3) and low (n = 4) optPRS to evaluate amyloid beta (Aβ) and phosphorylated tau (p‐tau) levels.RESULTSOptPRS predicted AD dementia and Aβ positivity, independent of apolipoprotein E (APOE). Higher optPRSs correlated with rapid cognitive decline. Cerebral organoids from the high optPRS group exhibited increased Aβ insolubility and p‐tau levels.CONCLUSIONOptPRS predicted cognitive decline and AD phenotypes of cerebral organoids, supporting its use in risk assessments and drug‐screening platform.HighlightsOptimized polygenic risk scores (optPRSs) improve the prediction of Alzheimer's disease (AD) dementia and amyloid beta positivity (Aβ+).High optPRS is associated with faster cognitive decline, particularly in Aβ+.Induced pluripotent stem cell (iPSC)–derived cerebral organoids from high optPRSs show high Aβ insolubility and phosphorylated tau (p‐tau).PRS genetic risk stratification provides insight into AD progression and pathology.

With the recent approval of anti-amyloid beta (Aβ) monoclonal antibody infusion therapies for Alzheimer’s disease (AD), more feasible and safter Aβ-reducing approaches are anticipated. Previous studies showed that 750-mg/day or 1000-mg/day (but not 500-mg/day) sodium benzoate treatment improved cognitive function in AD patients with excellent safety and that benzoate decreased Aβ burden in an animal AD model. The current study aimed to explore whether oral sodium benzoate was able to reduce Aβ peptides in AD patients and whether Aβ before treatment was correlated with cognitive improvement after treatment. This secondary analysis used data from a double-blind trial, in which 149 patients with mild AD were randomized to receive oral placebo or one of three benzoate doses (500, 750, or 1000 mg/day). Cognitive function and plasma Aβ 1–40 and Aβ 1–42 levels were measured before and after treatment. When compared to placebo, benzoate therapy at effective doses (750 and 1000 mg/day) reduced Aβ 1–40 and the sum of both Aβ peptides (Aβ 1–40 plus Aβ 1–42) in AD patients. Moreover, higher Aβ 1–42 levels at baseline were associated with better cognitive improvements after benzoate treatment at effective doses in the patients. The findings suggest that sodium benzoate therapy can reduce Aβ 1–40 and the total Aβ in AD patients and higher Aβ 1–42 levels before treatment predict better cognitive improvements. Due to its superior safety and convenient administration, sodium benzoate has the potential to be a novel Aβ-reducing therapy for AD treatment.Trial registrationName of trial registry: NMDA Enhancer for the Treatment of Mild Alzheimer’s Disease. Identifying number: ClinicalTrials.gov Identifier: NCT03752463 (https://clinicaltrials.gov/ct2/show/NCT03752463). Registration date: 2018-11-21.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) accumulation, leading to the formation of neurotoxic soluble oligomers (AβOs) that impair calcium homeostasis in neurons and astrocytes. Aducanumab, a fully human monoclonal antibody targeting aggregated Aβ, has been approved for AD treatment due to its ability to reduce amyloid plaque burden. However, its specificity toward different AβO species and its functional impact on calcium homeostasis remain unclear. We investigated aducanumab's ability to recognize and immunodeplete low-molecular-weight (LMW) and high-molecular-weight (HMW) AβOs using three Aβ preparations: (1) transgenic conditioned media (TgCM) from cultured Tg2576 neurons, (2) synthetic Aβ42-derived diffusible ligands (ADDLs), and (3) TBS-soluble fractions from aged Tg2576 mouse brain. Size exclusion chromatography and ELISA were used to characterize AβO species. Multiphoton calcium imaging of neuron-astrocyte co-cultures was performed to assess the impact of aducanumab on AβO-induced calcium overload. Aducanumab preferentially bound and immunodepleted HMW AβOs in ADDLs and the TBS-soluble fraction of Tg2576 mouse brain extracts but did not recognize LMW AβOs in TgCM. In calcium imaging experiments, all three AβO preparations induced calcium overload in neuron-astrocyte co-cultures. Immunodepletion with aducanumab prevented calcium overload in cultures exposed to ADDLs and Tg2576 brain extracts but not in those treated with immunodepleted TgCM, indicating that aducanumab selectively neutralizes HMW AβOs. Our findings demonstrate that aducanumab specifically targets HMW AβOs, mitigating their neurotoxic effects by restoring intracellular calcium homeostasis. These results provide mechanistic insight into aducanumab's therapeutic action and support its potential role in modifying AD pathology by selectively neutralizing Aβ species.

Oligodendrocyte dysfunction, myelin degeneration, and white matter changes are critical events in the cognitive decline of Alzheimer’s disease (AD). Amyloid-β peptide (Aβ), a hallmark of AD, disrupts oligodendrocyte and myelin homeostasis, through mechanisms that remain poorly understood. Here, transcriptomic profiling of Aβ-exposed oligodendrocytes revealed widespread gene expression changes, particularly in RNA-related processes. Among these, hnRNP A2, a key regulator of RNA transport and myelin protein regulation, was aberrantly upregulated in hippocampal oligodendrocytess from AD patients with high Aβ levels, from AD mouse models, and in Aβ-treated oligodendrocytes. RNA-immunoprecipitation sequencing of the hnRNP A2 interactome revealed Aβ-induced changes in mRNA interactions, particularly enriched binding to Mbp and Mobp, indicating impaired RNA metabolism of myelin components. Furthermore, Aβ, through hnRNP A2 disruption, increased the number, cargo and dynamics of Mbp- and Mobp-containing granules, enhanced MBP and MOBP synthesis, and decreased oligodendroglial voltage-gated Ca2+ influx in an MBP-dependent manner. These findings suggest that Aβ-induced dysregulation of hnRNP A2 impairs RNA metabolism and myelin protein synthesis, altering the intracellular Ca2+ homeostasis critical for oligodendrocyte function. Graphical abstractSupplementary InformationThe online version contains supplementary material available at 10.1007/s00018-025-05823-5.

BackgroundBlood-based biomarkers hold significant promise for the early detection and diagnosis of Alzheimer’s disease (AD) and other dementias. Age-related changes in blood levels of AD biomarkers are well-documented but poorly understood. Epigenetic clocks are mathematical models based on DNA methylation patterns that reflect various aspects of the multidimensional aging process. We investigated the associations of epigenetic aging with five blood-based AD biomarkers in 2656 Hispanic/Latino adults (mean age 62.5 years; 65% females) from the Hispanic Community Health Study/Study of Latinos. We used multivariable linear regression models to estimate the associations of acceleration in each of five epigenetic clocks with each biomarker in the total sample and in sex-specific strata, controlling for chronological age, sex (except in sex-stratified analyses), Hispanic/Latino background, recruitment site, risk factors, and comorbid medical conditions.ResultsThere were varying strengths of association between acceleration of the clocks and the plasma biomarkers. There were significant associations of acceleration in all epigenetic clocks with higher plasma levels of neurofilament light chain (NfL) (Beta = 0.0045 to 0.0193; P = 0.022 to 4.9 × 10–15). There were significant associations of acceleration in all epigenetic clocks except DunedinPACE with higher plasma levels of amyloid beta (Aβ)40 (Beta = 0.0033 to 0.0049; P = 0.024 to 1.7 × 10–5). PC-PhenoAge acceleration was associated with all circulating biomarkers but its associations with Aβ42, Aβ42/40 ratio, and phosphorylated Tau 181 (p-Tau181) showed heterogeneity by sex. Specifically, PC-PhenoAge acceleration was associated with higher Aβ42 and p-Tau181 levels in males (Beta = 0.0066, P = 0.002 and Beta = 0.0158, P = 2 × 10–4, respectively) but not females, while it was associated with lower Aβ42/40 ratio in females (Beta = − 0.0032, P = 0.012) but not males.ConclusionsEpigenetic age acceleration is associated with circulating biomarkers of AD in Hispanic/Latino adults. The second‐generation clock PC-PhenoAge showed strong and consistent associations across all biomarkers, and thus may reflect biological processes most relevant to age-related changes in AD biomarkers. Considering sex differences in the relationship between biological aging and circulating AD biomarkers is paramount.Supplementary InformationThe online version contains supplementary material available at 10.1186/s13148-025-01941-w.

Proteome Profiling of Cerebrospinal Fluid and Machine Learning Reveal Protein Classifiers of Two Forms of Alzheimer's Disease Characterized by Increased or Not Altered Levels of Tau.

ALI increase raises MCI to AD conversion odds by 15%.ALI increases in those progressing to AD and decreases in stable participants.Higher ALI was linked to high CSF tau, plasma Aβ42, and low CSF Aβ1-42These associations were moderated by age, APOE ε4 status, and baseline CSF tau.

BackgroundEvidence suggests that plant-based diets (PBDs) may be protective against neurodegenerative diseases such as Alzheimer's disease (AD).ObjectiveThis study examined associations between blood-based AD biomarkers in individuals 30-75 years without current or diagnosed cardiovascular disease following different PBDs versus regular meat-eating diets (RMEs).MethodsThis secondary analysis of the Plant-based Diets study measured Aβ1-42/Aβ1-40, p-tau181, NFL, and GFAP in 237 plasma samples using SIMOA from individuals following vegan, pesco-vegetarian (PVs), lacto-ovo vegetarian (LOVs), semi-vegetarian (SVs), or RME diets. Multivariable regression adjusted for age and sex.ResultsFollowing adjustments for age and sex, plasma Aβ1-42/Aβ1-40 ratio was significantly higher in PVs 0.011 (CI: 0.006, 0.016, p < 0.01), LOVs 0.011 (CI: 0.007, 0.016, p < 0.01) and SVs 0.015 (0.009-0.020, p < 0.01) groups compared to RMEs. Plasma p-tau181 was significantly higher in PVs 3.4 (CI: 0.4-6.4, p < 0.05) and LOVs 7.1 (CI: 2.5, 11.8, p < 0.01), NFL higher in PVs 5.2 (CI: 1.6, 8.7, p < 0.01) and LOVs 4.0 (CI: 1.6, 6.5, p = 0.01), and GFAP higher in PVs 26 (CI: 6, 47, p < 0.05) and LOVs 21 (5, 367, p = 0.01), all compared to RMEs.ConclusionsThis analysis suggests that PBDs may be associated with blood-based AD biomarkers. Higher Aβ1-42/Aβ1-40 levels in PV, LOV and SV dietary patterns compared to RMEs could indicate lesser amyloid burden, but elevated levels of other AD biomarkers in some PBDs warrant further investigation into nutrient-specific roles in AD pathology.

Older individuals without dementia often have amyloid-beta (Aβ) Thal phases similar to patients with Alzheimer disease (AD), suggesting that Aβ pathology may be a benign consequence of aging. To explore whether Aβ pathology in centenarians is associated with cognitive performance. This longitudinal cohort study used cross-sectional data on antemortem cognitive performance and postmortem neuropathology of participants in the Dutch 100-plus Study. Cognitive performance was measured a median of 10 (IQR, 3-13) months before postmortem brain donation. From January 2013 to July 2022, 1187 centenarians who self-reported being cognitively healthy, confirmed by proxy, were approached: 406 were included and 95 donated their brain. Centenarians were compared with patients with clinicopathologically confirmed AD from the Netherlands Brain Bank. Data were analyzed from June 2022 to October 2024. Aβ pathology was assessed with the Thal phase for Aβ progression and by determining quantitative Aβ loads (percentage positive area) in the frontal, parietal, temporal, and occipital neocortices, 3 parahippocampal, and 5 hippocampal subregions. Aβ pathology was associated with performance on 13 neuropsychological tests assessing memory, fluency, attention/processing speed, and executive functioning, as well as 4 measures of global cognition. This study evaluated Aβ pathology in 95 centenarians (median age at brain donation, 103.5 [IQR, 102.3-104.7] years; 71 female [75%] and 24 male [25%]) and 38 patients with AD (median age, 84 [IQR, 78-90] years; 18 female [47%] and 20 male [53%]). Global cognition parameters were available for all 95 centenarians and complete cognitive assessment for 72 centenarians (76%). A fraction of the centenarians had no Aβ load (9 of 95 [9%]), most had low Aβ load (53 of 95 [56%]) and, despite high Thal phases, about one-third (33 of 95 [35%]) had high Aβ load comparable with patients with AD. Centenarians with no or low Aβ load had significantly higher cognitive performance than centenarians with high Aβ loads. Higher Aβ loads across all 4 neocortical regions, cornu ammonis 3, cornu ammonis 1/subiculum, and the entorhinal cortex specifically affected executive functioning. Interestingly, 5 resilient centenarians maintained high cognitive performance despite having high Aβ loads; they had significantly less tau pathology compared with centenarians with high Aβ loads and low cognitive performance. These results indicate that Aβ pathology is not a benign consequence of aging. Even in the oldest individuals, Aβ and tau pathology interaction was consistent with the amyloid cascade hypothesis.

To investigate whether cerebrospinal fluid (CSF) circulation markers alter in patients with probable cerebral amyloid angiopathy (pCAA) and whether they are associated with brain degeneration and cognitive impairment. We screened pCAA patients from the ADNI3 database according to the Boston 2.0 Criteria. Fifty-two patients with cognitive impairment (26 pCAA; 26 age-sex-matched non-pCAA) and 26 age-sex-matched cognitively normal control (NC) were included in this study. All participants underwent neurological MRI and cognitive assessments. Choroid plexus (ChP) was segmented using a deep learning-based method and its volume was extracted. Diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) was used to assess perivenous fluid mobility. AD pathological markers (Aβ and tau) were assessed using positron emission tomography. Brain parenchymal damage markers included white matter hyperintensities (WMH) volume and brain atrophy ratio. All markers were compared among the three groups. Correlations among the ChP volume, DTI-ALPS index, parenchymal damage markers, and cognitive scales were analyzed in the pCAA group. The three groups exhibited significant differences in cognitive scores, AD biomarkers, and imaging markers. Post hoc analyses showed that patients with pCAA had significantly higher WMH volume, higher Aβ and tau deposition, and lower DTI-ALPS compared to NC. However, no difference in ChPs volume was found among the groups. Controlling for age, sex, and vascular risk factors, partial correlation analyses showed a significant negative correlation between the DTI-ALPS and WMH volume fraction (r = -0.606, p = 0.002). ChP volume was significantly associated with the Montreal cognitive assessment score (r = -0.492, p = 0.028). CSF circulation markers were associated with elevated WMH burden and cognitive impairments in probable CAA.

In Alzheimer's disease (AD), the amyloid β (Aβ) protein self-assembles, whereby Aβ40 and Aβ42 peptides interact, forming a mixed fibrillar assembly. Evaluating local Aβ40:Aβ42 mixed fibril conformations remains challenging, requiring a simple method to compare microscopic (molecular-scale) and macroscopic (plaque-scale) findings. The aim of the current study was to design a method to analyze Aβ fibril formation in a single sample without drying via fluorescent thioflavin T (ThT) labeling. The analysis revealed spectral heterogeneity associated with the ThT-binding mixed fibrils. Although the fluorescence wavelength associated with higher Aβ42:Aβ40 fibril ratios remained relatively unchanged, those associated with lower Aβ42:Aβ40 fibril ratios exhibited significant heterogeneity. This suggests that the local β-sheet structure exhibits significant variability at lower Aβ42:Aβ40 ratios. This specific feature can be attributed to differences in the shape of the "funnel" in the energy landscape during Aβ assembly. Thus, our protocol facilitates rapid and efficient screening of fibril conformational alterations compared to conventional techniques. Cumulatively, our results demonstrate that comparing the spectral features of ThT with the kinetic and morphological characteristics of a single sample provides specific molecular insights related to the origin of Aβ42:Aβ40 ratio-dependent molecular mechanism-insights that cannot be detected through conventional kinetic and morphological analyses alone.

The cerebrospinal fluid (CSF) Aβ42/40 ratio has proven to be a more reliable biomarker for amyloid pathology than CSF Aβ42 in Alzheimer's disease (AD), helping to correctly classify patients with positive tau biomarkers (T+) that would otherwise have remained outside of the AD continuum. It was shown that the Aβ42/40 ratio better captures a relative decrease of Aβ42 in patients with high CSF Aβ. However, whether patients with high-amyloid (HiA) AD, in whom A+ is defined by the Aβ42/40 ratio, exactly compare with their low-amyloid (LoA) counterparts, in whom A+ is defined by Aβ42 solely, deserves further analysis. We retrospectively included patients with A+T+ AD and evidence of cognitive and neurodegenerative changes (N+). LoA patients were operationally defined as patients with T+N+ and low CSF Aβ42, while HiA patients were defined as patients with T+N+ and normal CSF Aβ42 but abnormal Aβ42/40 ratio. Tau CSF biomarkers, neuropsychological profile, rates of cognitive decline, structural and metabolic imaging, ApoE genotype and brain neuropathology were compared between the HiA and LoA groups. At the time of the lumbar puncture, LoA patients were significantly younger than the HiA patients (68.9±8.7years vs. 71.8±9.4; P=0.0015) and had a lower Mini-Mental Status Examination (MMSE) (18.7±6.4 vs. 20.7±6.2; P=0.0005). There was no difference in the neuropsychological profile nor in the annual rates of cognitive decline between the two groups with early AD. No differences were retrieved between groups on CSF Tau and P-Tau biomarkers, atrophy and brain metabolism, distribution of the APOE4 allele and APOE4/E4 genotype, and neuropathology. Overall, our study supports the surrogate use of the Aβ42/40 ratio as an equivalent to Aβ42 to define AD. We showed that HiA CSF profiles were not associated with differences in cognition, brain structures and metabolism, APOE genotype tau CSF biomarkers or the rates of cognitive decline, but may be the associated with later-onset and early-stage AD.

Longitudinal investigation of the Apolipoprotein E (APOE) genotype's impact on Alzheimer's disease (AD) biomarker progression, focusing on amyloid beta (Aβ) accumulation and gray matter (GM) atrophy, integrating cognitive decline and baseline levels. Longitudinal florbetapir-PET and T1-weighted MRI data from 100 cognitively normal (CN) and mild cognitive impaired (MCI) participants both with considerable global Aβ accumulation ("high Aβ accumulators") were analyzed using a voxel-wise approach. Associations of APOE genotype and memory decline with Aβ accumulation and GM atrophy were examined separately for each neuroimaging modality, controlling for baseline Aβ levels and diagnosis. Alternatively, the effect of baseline diagnosis, while controlling for memory decline, was investigated. A multimodal analysis evaluated interactions between genotype, memory decline, and GM atrophy on Aβ accumulation. High Aβ accumulators displayed extensive Aβ pathology predominantly in the medial orbito-frontal cortex, cingulate cortex, and precuneus, along with GM atrophy in temporal, occipital, orbito-frontal, and parietal areas. ɛ4 carriers with memory decline exhibited greater Aβ accumulation and GM atrophy in selective regions compared to non-carriers with memory decline, while no genotype difference was observed in individuals without decline. No interaction effect was observed for MCI diagnosis. Regional associations between the two biomarkers were similarly dependent on genotype and memory decline. ɛ4 carriers exhibiting memory decline present an accelerated neurobiological pattern at predementia stages, supporting early ɛ4 carrier monitoring and interventions in this at-risk group. Importantly, memory decline might be more informative than MCI regarding AD pathology progression emphasizing the importance of repeated cognitive assessments.

Relationships between core Alzheimer's disease (AD) biomarker accumulation and cognitive decline are well-established and the literature generally suggests a favorable relationship of cardiorespiratory fitness (CRF) on AD biomarker accumulation and cognition. Differences in risk of biomarker status conversion or accumulation rates by CRF, or their potential interactive relationships with cognitive decline remain largely unknown. Participants (N=533; MeanAGE=65, 70% female) from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Prevention underwent serial blood draws, and cognitive and imaging assessments (MeanFollow-up=6.0 years). PET imaging of amyloid-β (Aβ) and tau (T) and plasma phosphorylated tau-217 (pTau-217) were used to determine biomarker status (+/-). Sex-specific estimated CRF (eCRF) tertiles were created using a validated equation. Kaplan-Meier survival curves and Cox-proportional hazards models characterized the risk of becoming biomarker-positive. Linear mixed effects models estimated associations between baseline eCRF and core AD biomarker accumulation and whether eCRF modified relationships between biomarker accumulation and cognitive decline. Analyses were stratified by biomarker +/- status. No significant relationships were observed between eCRF and biomarker trajectories. However, those in the high eCRF group who were also Aβ- (HR[95%CI]=0.42[0.20, 0.88]) and pTau-217-(HR[95%CI]=0.45[0.21, 0.97]) at baseline had a significantly lower risk of becoming biomarker-positive. There was a significant attenuation of the detrimental relationship between Aβ accumulation and cognitive decline for those with high eCRF and Aβ+/T+. While CRF did not influence core AD biomarker accumulation trajectories, high CRF did seem to protect against becoming biomarker-positive and attenuate the known deleterious relationship between biomarker accumulation and cognitive decline in Aβ+/T+.