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Abstract: Cognitive impairment is a common non-motor symptom of Parkinson’s disease (PD), which often progresses to PD dementia. PD patients with and without dementia may differ in certain biochemical parameters, which could thus be used as biomarkers for PD dementia. The enzyme paraoxonase 1 (PON1) has previously been investigated as a potential biomarker in the context of other types of dementia. In a cohort of PD patients, we compared a group of 89 patients with cognitive impairment with a group of 118 patients with normal cognition. We determined the kinetic parameters Km and Vmax for PON1 for the reaction with dihydrocoumarin and the genotype of four single nucleotide polymorphisms in PON1. We found that no genotype or kinetic parameter correlated significantly with cognitive impairment in PD patients. However, we observed associations between PON1 rs662 and PON1 Km (p < 10−10), between PON1 rs662 and PON1 Vmax (p = 9.33 × 10−7), and between PON1 rs705379 and PON1 Vmax (p = 2.21 × 10−10). The present study is novel in three main aspects. (1) It is the first study to investigate associations between the PON1 genotype and enzyme kinetics in a large number of subjects. (2) It is the first study to report kinetic parameters of PON1 in a large number of subjects and to use time-concentration progress curves instead of initial velocities to determine Km and Vmax in a clinical context. (3) It is also the first study to calculate enzyme-kinetic parameters in a clinical context with a new algorithm for data point removal from progress curves, dubbed iFIT. Although our results suggest that in the context of PD, there is no clinically useful correlation between cognitive status on the one hand and PON1 genetic and enzyme-kinetic parameters on the other hand, this should not discourage future investigation into PON1’s potential associations with other types of dementia.
Keywords: Parkinson disease, cognitive impairment, paraoxonase 1
Published in DiRROS: 03.08.2026; Views: 73; Downloads: 50
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Abstract: Anti-amyloid therapy (AAT) with monoclonal antibodies (mAbs) modestly slow cognitive and functional decline in early Alzheimer’s disease (AD). However, both the magnitude of clinical benefit and the risk of treatment-related complications vary substantially even among patients with similar biomarker profiles. Frailty, both brain and systemic, is highly prevalent in older adults with AD and affects a large proportion of those considered for AAT. Despite this, it has been largely absent from current decision frameworks. Brain frailty, defined by structural and microvascular damage (e.g., small-vessel disease, microbleeds, and atrophy), limits the clinical benefit of amyloid clearance and increases susceptibility to amyloid-related imaging abnormalities. In contrast, systemic frailty, reflecting reduced physiological reserve, mainly affects treatment tolerance and recovery from adverse events. In this narrative, conceptual review, we synthesize evidence that both forms of frailty act as biologically grounded modifiers of AAT efficacy and safety and may limit the clinical benefit while increasing susceptibility to complications and decompensation. Importantly, the precise empirical thresholds at which frailty begins to exert harmful effects remain unknown. We further outline how MRI-based markers of brain frailty, combined with brief systemic frailty measures, could support risk stratification, patient selection, monitoring intensity, and shared decision-making, including deferring treatment when the benefit–risk balance is unfavorable, while avoiding exclusion of patients who may still benefit. Taken together, we propose that future studies should incorporate frailty measures and perform precise assessments of both brain and systemic frailty, as this may improve patient stratification and better characterize the effects of AAT.
Keywords: Alzheimer’s disease, frailty, brain frailty, systemic frailty, monoclonal antibodies, amyloid-related imaging abnormalities (ARIA), precision medicine, cerebral small vessel disease, risk-benefit stratification
Published in DiRROS: 03.08.2026; Views: 110; Downloads: 64
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Abstract: IMPORTANCE: Higher diet quality has been linked to reduced dementia incidence, but whether it buffers dementia onset in individuals with Alzheimer disease (AD) pathology or broader neurobiological risk is unclear. OBJECTIVE: To explore the association of diet quality with dementia risk across biomarker levels of AD pathology (phosphorylated tau at threonine 217 [p-tau217]) and broader neurodegenerative and glial processes (neurofilament light chain [NFL], glial fibrillary acidic protein [GFAP]). DESIGN, SETTING, AND PARTICIPANTS: This cohort study analyzed data from adults without dementia aged 60 years or older from the population-based Swedish National Study on Aging and Care in Kungsholmen, which enrolled participants between March 2001 and August 2004 and examined them up to 6 times until February 2016 to November 2019. Adherence to 3 dietary patterns was examined: the Alternate Mediterranean Diet (AMED), Alternative Healthy Eating Index (AHEI), and reversed Empirical Dietary Inflammatory Index (rEDII). Data were analyzed between September 2024 and August 2025 and reanalyzed in March and April 2026. EXPOSURES Baseline serum p-tau217, NFL, and GFAP concentrations and repeated adherence over 6 years to the AMED, AHEI, and rEDII dietary patterns. MAIN OUTCOMES AND MEASURES: The primary outcome was all-cause dementia identified by clinical diagnosis, medical records, and death certificates. The secondary outcome was AD-related dementia. Dementia risk was analyzed using adjusted Cox regression models. Ten-year dementia probabilities and restricted mean time lost due to dementia were also estimated. RESULTS: A total of 1865 participants were included (mean [SD] age at baseline, 70.5 [9.3] years; 1125 female [60.3%]). Over a mean follow-up of 8.4 years (range, <0.1 to 15.9 years), 240 participants developed dementia. Higher adherence to healthier dietary patterns was associated with lower dementia risk in participants with elevated AD and neurobiological risk biomarkers. For rEDII, each 1–z-score increase in adherence was associated with lower dementia risk among those with elevated p-tau217, NFL, and GFAP levels, with hazard ratios of 0.71 (95% CI, 0.58-0.88), 0.79 (95% CI, 0.66-0.95), and 0.73 (95% CI, 0.60-0.89), respectively. Associations of AMED and AHEI with lower dementia risk were generally found only among participants with lower biomarker levels. Similar findings were observed for AD-related dementia. CONCLUSIONS AND RELEVANCE: This cohort study of older adults found that adherence to a dietary pattern with lower inflammatory potential was associated with lower dementia risk among individuals with AD pathology and broader neurobiological risk. These findings reinforce the importance of targeted dietary dementia prevention strategies not only for the general population but also for individuals already at elevated risk.
Published in DiRROS: 22.07.2026; Views: 134; Downloads: 102
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Abstract: Blood phosphorylated tau (p-tau) biomarkers, including p-tau217, show high associations with Alzheimer’s disease (AD) neuropathologic change and clinical stage. Certain plasma p-tau217 assays recognize tau forms phosphorylated additionally at threonine-212, but the contribution of p-tau212 alone to AD is unknown. We developed a blood-based immunoassay that is specific to p-tau212 without cross-reactivity to p-tau217. Here, we examined the diagnostic utility of plasma p-tau212. In five cohorts (n = 388 participants), plasma p-tau212 showed high performances for AD diagnosis and for the detection of both amyloid and tau pathology, including at autopsy as well as in memory clinic populations. The diagnostic accuracy and fold changes of plasma p-tau212 were similar to those for p-tau217 but higher than p-tau181 and p-tau231. Immunofluorescent staining of brain tissue slices showed prominent p-tau212 reactivity in neurofibrillary tangles that co-localized with p-tau217 and p-tau202/205. These findings support plasma p-tau212 as a peripherally accessible biomarker of AD pathophysiology.
Keywords: plasma p-tau212, diagnostics, Alzheimer disease, neuropathology
Published in DiRROS: 15.06.2026; Views: 214; Downloads: 147
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Abstract: Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases. Their treatment options are rather limited, and no neuroprotective or disease-modifying treatments are available. Anti-diabetic drugs, such as glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) agonists, have been suggested as a potential therapeutic option. Aims: Assess GLP1R and GIPR genetic variability in relation to AD- and PD-related phenotypes. Methods: AD, PD patients and healthy control subjects were included in the study. Cerebrospinal fluid (CSF) biomarkers of Alzheimer's disease were measured in AD patients, while cognitive impairment was evaluated in PD. All participants were genotyped for three SNPs: GLP1R rs10305420, GLP1R rs6923761 and GIPR rs1800437. Results: GLP1R rs10305420 genotypes were associated with increased odds for AD and PD development. GLP1R rs10305420 and GLP1R rs6923761 genotypes were significantly associated with Aβ42/40 ratio (p = 0.041 and p = 0.050), while GLP1R rs6923761 was also associated with p-tau levels (p = 0.022). Finally, GIPR rs1800437 heterozygotes as well as carriers of at least one GIPR rs1800437 C allele presented with increased odds for the development of dementia in PD (OR = 1.92; 95 % CI = 1.05-3.51; p = 0.034 and OR = 1.95; 95 % CI = 1.08-3.52; p = 0.027, respectively). Conclusion: GLP1R and GIPR genetic variability may affect the occurrence of AD and PD and is also associated with AD CSF biomarkers for Alzheimer's disease and dementia in PD. The data on GLP1R and GIPR genetic variability may support the function of incretin receptors in neurodegeneration.
Keywords: Alzheimer's disease, biomarker, glucagon-like peptide 1 receptor, glucose-dependent insulinotropic polypeptide, Parkinson's disease, polymorphism
Published in DiRROS: 09.06.2026; Views: 213; Downloads: 190
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