• Publikační typ
• časopisecké články MeSH

The ABCB1 gene, encoding the ATP-dependent translocase ABCB1, plays a crucial role in the clearance of amyloid-beta (Aβ) peptides and the transport of cholesterol, implicating it in the pathogenesis of Alzheimer's disease. The study aims to investigate the association between polymorphisms in the ABCB1 gene and cognitive decline in individuals with MCI, particularly focusing on language function. A longitudinal cohort study involving 1005 participants from the Czech Brain Aging Study was conducted. Participants included individuals with Alzheimer's disease, amnestic mild cognitive impairment (MCI), non-amnestic MCI, subjective cognitive decline, and healthy controls. Next-generation sequencing was utilized to analyze the entire ABCB1 gene. Cognitive performance was assessed using a comprehensive battery of neuropsychological tests, including the Boston Naming Test and the semantic verbal fluency test. Ten ABCB1 polymorphisms (rs55912869, rs56243536, rs10225473, rs10274587, rs2235040, rs12720067, rs12334183, rs10260862, rs201620488, rs28718458) were significantly associated with cognitive performance, particularly in language decline among amnestic MCI patients. In silico analyses revealed that some of these polymorphisms may affect the binding sites for transcription factors (HNF-3alpha, C/EBPβ, GR-alpha) and the generation of novel exonic splicing enhancers. Additionally, polymorphism rs55912869 was identified as a potential binding site for the microRNA hsa-mir-3163. Our findings highlight the significant role of ABCB1 polymorphisms in cognitive decline, particularly in language function, among individuals with amnestic MCI. These polymorphisms may influence gene expression and function through interactions with miRNAs, transcription factors, and alternative splicing mechanisms.

• Klíčová slova
• ATP-binding cassette transporters, ATP-dependent translocase, Alzheimer's disease, DNA polymorphisms, Language decline,
• Publikační typ
• časopisecké články MeSH

BackgroundKLOTHO-VS heterozygosity (KL-VSHET) and soluble α-Klotho (sαKl) protein interfere with Alzheimer's disease (AD) pathophysiology, but the specific relationships remain unclear. This study explored these associations across the AD continuum, focusing on core AD biomarkers and markers of neurodegeneration, neuroinflammation, and synaptic dysfunction.ObjectiveWe investigated whether 1) KL-VSHET is associated with lower AD biomarker burden (Aβ42, Aβ42/40 ratio, P-tau181, T-tau) and neurodegeneration (NfL); 2) sαKl relates to AD biomarkers, neurodegeneration (NfL), neuroinflammation (GFAP), and synaptic dysfunction (Ng); 3) associations vary by APOE ε4 status and clinical subgroup.MethodsParticipants (n = 223) were categorized as cognitively healthy (n = 38), aMCI-AD (n = 94), and AD dementia (n = 91). KLOTHO genotyping was available for 128 participants; 138 had cerebrospinal fluid (CSF) and serum sαKl measurements; and 42 had both. Multiple linear regression evaluated associations between KL-VSHET, sαKl levels, and biomarkers, stratified by APOE ε4 status and clinical subgroup.ResultsOverall, the associations between KL-VSHET and higher CSF Aβ42 and Aβ42/40 ratio were non-significant (ps ≥ 0.059) except when restricted to APOE ε4 carriers only (β = 0.11, p = 0.008 and β = 0.16, p = 0.033, respectively). Within clinical subgroups, KL-VSHET was positively associated with Aβ42/40 ratio only in aMCI-AD (β = 0.23, p = 0.034). No significant associations were observed between KL-VSHET and tau biomarkers or NfL. For sαKl, associations with biomarkers were non-significant except for a negative association of serum sαKl with P-tau181 in aMCI-AD (β = -0.25, p = 0.036) and a positive association with Aβ42/40 ratio in APOE ε4 non-carriers (β = 0.24 p = 0.047).ConclusionsKL-VSHET may help protect against amyloid pathology, particularly in the presence of APOE ε4, and regardless of APOE status in aMCI-AD.

• Klíčová slova
• APOE, Alzheimer's disease, KLOTHO-VS heterozygosity, biomarkers, α-Klotho,
• Publikační typ
• časopisecké články MeSH

OBJECTIVE: Dementia with Lewy bodies (DLB) and Parkinson's disease (PD) share clinical, pathological, and genetic risk factors, including GBA1 and APOEε4 mutations. Biomarkers associated with the pathways of these mutations, such as glucocerebrosidase enzyme (GCase) activity and amyloid-beta 42 (Aβ42) levels, may hold potential as predictive indicators, providing valuable insights into the likelihood of cognitive decline within these diagnoses. Our objective was to determine their association with cognitive decline in DLB and PD. METHODS: A total of 121 DLB patients from the European-DLB Consortium and 117 PD patients from the Norwegian ParkWest Study were included in this study. The four most commonly associated variants of GBA1 mutations (E326K, T369M, N370S, L444P), APOEε4 status, and cerebrospinal fluid (CSF) Aβ42 levels and GCase activity were assessed, as well as global cognition using the Mini-Mental State Examination. Linear mixed-effects regression models were used to evaluate the association of CSF biomarkers with cognitive decline in each diagnostic group, adjusted for age, sex, education, and genetic mutation profile. RESULTS: Low CSF Aβ42 levels were associated with accelerated cognitive decline in DLB, whereas reduced CSF GCase activity predicted faster cognitive decline in PD. These associations were independent of GBA1 gene mutations or APOEε4 status. INTERPRETATION: Our study provides important evidence on the relationship between brain Aβ deposition and GCase activity in the Lewy body disease spectrum independent of their genetic mutation profile. This information could be relevant for designing future clinical trials targeting these pathways.

• Publikační typ
• časopisecké články MeSH

IMPORTANCE: Depressive symptoms are associated with cognitive decline in older individuals. Uncertainty about underlying mechanisms hampers diagnostic and therapeutic efforts. This large-scale study aimed to elucidate the association between depressive symptoms and amyloid pathology. OBJECTIVE: To examine the association between depressive symptoms and amyloid pathology and its dependency on age, sex, education, and APOE genotype in older individuals without dementia. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analyses were performed using data from the Amyloid Biomarker Study data pooling initiative. Data from 49 research, population-based, and memory clinic studies were pooled and harmonized. The Amyloid Biomarker Study has been collecting data since 2012 and data collection is ongoing. At the time of analysis, 95 centers were included in the Amyloid Biomarker Study. The study included 9746 individuals with normal cognition (NC) and 3023 participants with mild cognitive impairment (MCI) aged between 34 and 100 years for whom data on amyloid biomarkers, presence of depressive symptoms, and age were available. Data were analyzed from December 2022 to February 2024. MAIN OUTCOMES AND MEASURES: Amyloid-β1-42 levels in cerebrospinal fluid or amyloid positron emission tomography scans were used to determine presence or absence of amyloid pathology. Presence of depressive symptoms was determined on the basis of validated depression rating scale scores, evidence of a current clinical diagnosis of depression, or self-reported depressive symptoms. RESULTS: In individuals with NC (mean [SD] age, 68.6 [8.9] years; 5664 [58.2%] female; 3002 [34.0%] APOE ε4 carriers; 937 [9.6%] had depressive symptoms; 2648 [27.2%] had amyloid pathology), the presence of depressive symptoms was not associated with amyloid pathology (odds ratio [OR], 1.13; 95% CI, 0.90-1.40; P = .29). In individuals with MCI (mean [SD] age, 70.2 [8.7] years; 1481 [49.0%] female; 1046 [44.8%] APOE ε4 carriers; 824 [27.3%] had depressive symptoms; 1668 [55.8%] had amyloid pathology), the presence of depressive symptoms was associated with a lower likelihood of amyloid pathology (OR, 0.73; 95% CI 0.61-0.89; P = .001). When considering subgroup effects, in individuals with NC, the presence of depressive symptoms was associated with a higher frequency of amyloid pathology in APOE ε4 noncarriers (mean difference, 5.0%; 95% CI 1.0-9.0; P = .02) but not in APOE ε4 carriers. This was not the case in individuals with MCI. CONCLUSIONS AND RELEVANCE: Depressive symptoms were not consistently associated with a higher frequency of amyloid pathology in participants with NC and were associated with a lower likelihood of amyloid pathology in participants with MCI. These findings were not influenced by age, sex, or education level. Mechanisms other than amyloid accumulation may commonly underlie depressive symptoms in late life.

• MeSH
• amyloidní beta-protein * mozkomíšní mok   metabolismus   MeSH
• apolipoprotein E4 genetika   MeSH
• biologické markery mozkomíšní mok   MeSH
• deprese * MeSH
• dospělí MeSH
• kognitivní dysfunkce * MeSH
• lidé středního věku MeSH
• lidé MeSH
• peptidové fragmenty mozkomíšní mok   MeSH
• pozitronová emisní tomografie * MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• věkové faktory MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloid beta-protein (1-42) MeSH Prohlížeč
• amyloidní beta-protein * MeSH
• apolipoprotein E4 MeSH
• biologické markery MeSH
• peptidové fragmenty MeSH

Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer's disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile).Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.

• Klíčová slova
• Autophagy, Frontotemporal lobar degeneration, MAPT, Neurocognitive impairment, PINK1, TDP-43, TFEB,
• MeSH
• Alzheimerova nemoc * krev   patologie   mozkomíšní mok   MeSH
• autofagie * fyziologie   MeSH
• biologické markery * mozkomíšní mok   krev   MeSH
• frontotemporální lobární degenerace * patologie   mozkomíšní mok   krev   MeSH
• homolog Atg1 metabolismus   MeSH
• intracelulární signální peptidy a proteiny MeSH
• lidé středního věku MeSH
• lidé MeSH
• mitofagie * MeSH
• proteinkinasy metabolismus   krev   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• biologické markery * MeSH
• homolog Atg1 MeSH
• intracelulární signální peptidy a proteiny MeSH
• proteinkinasy MeSH
• PTEN-induced putative kinase MeSH Prohlížeč
• ULK1 protein, human MeSH Prohlížeč

DOPA Decarboxylase (DDC) has been proposed as a cerebrospinal fluid (CSF) biomarker with increased concentrations in Lewy body disorders (LBDs) and highest levels in patients receiving dopaminergic treatment. Here we evaluate plasma DDC, measured by proximity extension assay, and the effect of dopaminergic treatment in three independent LBD (with a focus on dementia with Lewy bodies (DLB) and Parkinson's disease (PD)) cohorts: an autopsy-confirmed cohort (n = 71), a large multicenter, cross-dementia cohort (n = 1498) and a longitudinal cohort with detailed treatment information (n = 66, median follow-up time[IQR] = 4[4, 4] years). Plasma DDC was not altered between different LBDs and other disease groups or controls in absence of treatment. DDC levels increased over time in PD, being significantly associated to higher dosages of dopaminergic treatment. This emphasizes the need to consider treatment effect when analyzing plasma DDC, and suggests that plasma DDC, in contrast to CSF DDC, is of limited use as a diagnostic biomarker for LBD, but could be valuable for treatment monitoring.

• MeSH
• biologické markery * krev   mozkomíšní mok   MeSH
• demence s Lewyho tělísky * farmakoterapie   krev   mozkomíšní mok   MeSH
• DOPA-dekarboxylasa * metabolismus   MeSH
• dopaminové látky terapeutické užití   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• longitudinální studie MeSH
• Parkinsonova nemoc * farmakoterapie   krev   mozkomíšní mok   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• biologické markery * MeSH
• DOPA-dekarboxylasa * MeSH
• dopaminové látky MeSH

IMPORTANCE: Baseline cerebral microbleeds (CMBs) and APOE ε4 allele copy number are important risk factors for amyloid-related imaging abnormalities in patients with Alzheimer disease (AD) receiving therapies to lower amyloid-β plaque levels. OBJECTIVE: To provide prevalence estimates of any, no more than 4, or fewer than 2 CMBs in association with amyloid status, APOE ε4 copy number, and age. DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used data included in the Amyloid Biomarker Study data pooling initiative (January 1, 2012, to the present [data collection is ongoing]). Data from 15 research and memory clinic studies were pooled and harmonized. Participants included individuals for whom data on age, cognitive status, amyloid status, and presence of CMBs were available. Data were analyzed from October 22, 2023, to April 26, 2024. MAIN OUTCOMES AND MEASURES: The main outcomes were age, cognitive status, amyloid status and presence, location, and number of CMBs. Presence of amyloid pathology was determined based on 42 amino acid-long form of amyloid-β peptide (Aβ42) levels in cerebrospinal fluid or on amyloid-positron emission tomography. Presence and, in a subset, location (lobar vs deep) and number of CMBs were determined on magnetic resonance imaging (locally with visual rating). RESULTS: Among 4080 participants included in the analysis, the mean (SD) age was 66.5 (8.9) years, and 2241 (54.9%) were female. A total of 2973 participants had no cognitive impairment (cognitive unimpairment [CU]), and 1107 had mild cognitive impairment (MCI) or AD dementia (ADD). One thousand five hundred and thirteen participants (37.1%) had amyloid pathology, 1368 of 3599 (38.0%) with data available were APOE ε4 carriers, and 648 (15.9%) had CMBs. In the CU group, amyloid pathology and APOE ε4 copy number were not associated with presence of any, no more than 4, or fewer than 2 CMBs but were associated with increased odds of lobar CMBs (odds ratio [OR] for amyloid, 1.42 [95% CI, 1.20-1.69], P < .001; OR for 2 vs 0 alleles, 1.81 [95% CI, 1.19-2.74], P = .006; OR for 1 vs 0 alleles, 1.10 [95% CI, 0.83-1.46], P = .49; and OR for 2 vs 1 allele, 1.64 [95% CI, 0.90-2.97], P = .11; overall P = .02). In the MCI-ADD group, amyloid pathology was associated with presence of any CMBs (OR, 1.51 [95% CI, 1.17-1.96], P = .002), no more than 4 CMBs (OR, 1.44 [95% CI, 1.18-1.82], P = .002), and fewer than 2 CMBs (OR 1.34 [95% CI, 1.03-1.74], P = .03) but not lobar CMBs. APOE ε4 copy number was associated with presence of any (OR for 2 vs 0 alleles, 1.72 [95% CI, 0.88-3.35], P = .11; OR for 1 vs 0 alleles, 0.78 [95% CI, 0.59-1.04], P = .09; and OR for 2 vs 1 allele, 2.20 [95% CI, 1.32-3.67], P = .002; overall P < .001) and no more than 4 CMBs (OR for 2 vs 0 alleles, 1.31 [95% CI, 0.64-2.68], P = .45; OR for 1 vs 0 alleles, 0.75 [95% CI, 0.54-1.04], P = .08; and OR for 2 vs 1 allele, 1.76 [95% CI, 0.97-3.19], P = .06; overall P = .03) but not with fewer than 2 or lobar CMBs. Prevalence estimates of CMBs ranged from 6% at 50 years of age in a non-APOE ε4 allele carrier with no amyloid pathology and no cognitive impairment to 52% at 90 years of age in an APOE ε4 homozygote carrier with amyloid pathology and cognitive impairment. CONCLUSIONS AND RELEVANCE: In this cross-sectional study of 4080 participants, prevalence estimates of CMBs were associated with amyloid status, APOE ε4 copy number, and age. CMB prevalence estimates may help inform safety evaluations for antiamyloid clinical trials.

• MeSH
• Alzheimerova nemoc * epidemiologie   genetika   MeSH
• amyloidní beta-protein * metabolismus   mozkomíšní mok   MeSH
• amyloidní plaky patologie   MeSH
• apolipoprotein E4 genetika   MeSH
• biologické markery * mozkomíšní mok   MeSH
• cerebrální krvácení * epidemiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• magnetická rezonanční tomografie metody   MeSH
• pozitronová emisní tomografie MeSH
• průřezové studie MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• apolipoprotein E4 MeSH
• biologické markery * MeSH

Due to methodological reasons, the X-chromosome has not been featured in the major genome-wide association studies on Alzheimer's Disease (AD). To address this and better characterize the genetic landscape of AD, we performed an in-depth X-Chromosome-Wide Association Study (XWAS) in 115,841 AD cases or AD proxy cases, including 52,214 clinically-diagnosed AD cases, and 613,671 controls. We considered three approaches to account for the different X-chromosome inactivation (XCI) states in females, i.e. random XCI, skewed XCI, and escape XCI. We did not detect any genome-wide significant signals (P ≤ 5 × 10-8) but identified seven X-chromosome-wide significant loci (P ≤ 1.6 × 10-6). The index variants were common for the Xp22.32, FRMPD4, DMD and Xq25 loci, and rare for the WNK3, PJA1, and DACH2 loci. Overall, this well-powered XWAS found no genetic risk factors for AD on the non-pseudoautosomal region of the X-chromosome, but it identified suggestive signals warranting further investigations.

• Publikační typ
• časopisecké články MeSH

• Publikační typ
• dopisy MeSH