👤 Maria Schindler

Cerebrospinal fluid amyloid beta 42, total tau, and phosphorylated tau 181 are well accepted markers of Alzheimer's disease. These biomarkers better reflect disease pathogenesis compared to clinical diagnosis. Here, we perform a genome wide association study meta-analysis including 18,948 individuals of European ancestry and identify 12 genome-wide significant loci across all three biomarkers, eight of them novel. We replicate the association of biomarkers with APOE, CR1, GMNC/CCDC50 and C16orf95/MAP1LC3B. Novel loci include BIN1 for amyloid beta and GNA12, MS4A6A, SLCO1A2 with both total tau and phosphorylated tau 181, as well as additional loci on chr. 8, near ANGPT1 and chr. 9 near SMARCA2. We also demonstrate that these variants have significant association with Alzheimer's disease risk, disease progression and/or brain amyloidosis. The associated genes are implicated in lipid metabolism independent of APOE, coupled with autophagy and brain volume regulation driven by total tau and phosphorylated tau 181 dysregulation. Show less

Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease associated with exposure to repetitive head impacts (RHIs), characterized by tau tangles around small blood vessels at the depths of the sulci. Currently, CTE can be diagnosed only Show less

Sporadic late-onset Alzheimer's disease (AD) is characterized by a long pre-clinical phase where amyloid-beta (Aβ) and tau begin to accumulate in the brain. The primary objective was to determine the age at which AD starts by finding the average population age when both positron emission tomography (PET) Aβ (Aβ-PET) and plasma Aβ42/40 become abnormal. Two high performance immunoprecipitation-mass spectrometry (IP-MS) assays (WashU/C2N and Shimadzu) were tested on samples from 1,450 participants who were diagnosed as cognitively unimpaired (CU), mild cognitive impairment (MCI), or AD-dementia across 4 international cohorts. Natural history modeling and trajectory analyses of the combined Aβ-PET and plasma Aβ42/40 data were analyzed. Data from both assays demonstrated Aβ42/40 undergoes a rapid change at approximately 15 Centiloid (CL), at an average population disease age at 66 years. On average, plasma Aβ42/40 becomes abnormal approximately 2 years before Aβ-PET, whereby it falls sharply to a stable level at the onset of preclinical AD. Average disease age where Aβ42/40 becomes abnormal, and the corresponding Centiloid level are lower for APOE allele carriers compared with non-carriers. Plasma Aβ42/40 ratio presents a step-like function of peripheral change shortly before the detection of plaques by Aβ-PET. Results are consistent with plasma Aβ42/40 falling to a steady-state level in participants with Aβ-PET levels greater than approximately 14CL for both assays. The age at which this occurs is dependent on APOE ε4 carriership, consistent with the approximate 7-year age difference in Centiloid abnormality between carriers and non-carriers. ANN NEUROL 2026;99:1327-1342. Show less

The agreement between plasma Aβ42/40 and Aβ positron emission tomography (PET) is approximately 75 %, with ∼85 % of discrepancies due to positive plasma but negative PET results. It is unclear whether this reflects Aβ changes in plasma before PET-detectable. To assess the influence of Aβ42/40 positivity on risk of progression to Aβ PET positivity, and feasibility of using plasma Aβ42/40 tests to enrich a primary prevention trial. A prospective longitudinal cohort study. Participants of Australian Imaging, Biomarkers and Lifestyle study (AIBL), Alzheimer's Disease Neuroimaging Initiative (ADNI), and Open Access Series of Imaging Studies 3 (OASIS3). 507 cognitively unimpaired adults at baseline, with a baseline Aβ PET < 20 Centiloid (CL) and available longitudinal Aβ PET data. Baseline Aβ PET and plasma Aβ42/40 measurement by mass-spectrometry, followed by 1-6 additional Aβ PET scans every 1.5-3 years. Those < 5 CL were classified as PET- and 5-20 CL as PET At baseline, 283 were Plasma-/PET-, 97 Plasma+/PET-, 76 Plasma-/PET Cognitively unimpaired individuals with abnormal Aβ42/40 are at increased risk for future Aβ PET positivity. In the 5-20 CL subgroup, baseline CL is the main driver of this risk. Combining blood-based pre-screening with PET imaging may help efficiently enrich primary prevention trials. Show less

Sleep is a marker of brain function that could potentially identify patients for early intervention by detecting cognitive change during the early asymptomatic stages of Alzheimer disease (AD). We examined the relationship between sleep and cognition in cognitively unimpaired older adults and evaluated whether the relationship was altered by AD risk factors. Cognitively unimpaired older adults (N = 319, age 54-97 years) were administered a sleep diary (1x/day) and brief cognitive assessments (4x/day) for seven consecutive days via a smartphone application. We evaluated if a previous night's sleep predicts next-day cognition and if sleep averaged over a week predicts cognitive performance averaged over a week. Additional analyses included the effects of carrying an apolipoprotein (APOE) ε4 allele and cerebrospinal fluid biomarkers of AD pathology. At the between-person level, no associations were observed between sleep and cognition. Within-person analyses revealed that deviations (both higher and lower scores) from an individual's usual sleep pattern were associated poorer next day cognitive performance. Carriage of the APOE ε4 allele and AD biomarkers did not interact with sleep-cognition relationships. Remote, multi-day assessments of cognition and sleep revealed subtle non-linear associations between nightly sleep and next-day cognition in cognitively unimpaired older adults. Furthermore, the individualized nature of sleep-cognition relationships underscores the importance of maintaining consistent person-centered sleep health metrics to support cognitive function. Capturing latent AD-related changes in sleep and cognition among asymptomatic older adults may require repeated assessments across extended timeframes. Show less

During the first days of development the preimplantation embryo is supplied with nutrients from the surrounding milieu. Maternal diabetes mellitus affects the uterine microenvironment, leading to a metabolic adaptation processes in the embryo. We analysed embryonic fatty acid (FA) profiles and expression of processing genes in rabbit blastocysts, separately in embryoblasts (EBs) and trophoblasts (TBs), to determine the potential consequences of maternal diabetes mellitus on intracellular FA metabolism. Insulin-dependent diabetes was induced by alloxan in female rabbits. On Day 6 post coitum, FA profiles in blastocysts (EB, TB and blastocoel fluid) and maternal blood were analysed by gas chromatography. The expression levels of molecules involved in FA elongation (fatty acid elongases, ELOVLs) and desaturation (fatty acid desaturases, FADSs) were measured in EB and TB. Maternal diabetes mellitus influenced the FA profile in maternal plasma and blastocysts. Independent from metabolic changes, rabbit blastocysts contained a higher level of saturated fatty acids (SFAs) and a lower level of polyunsaturated fatty acids (PUFAs) compared to the FA profile of the maternal plasma. Furthermore, the FA profile was altered in the EB and TB, differently. While SFAs (palmitic and stearic acid) were elevated in EB of diabetic rabbits, PUFAs, such as docosahexaenoic acid, were decreased. In contrast, in the TB, lower levels of SFAs and higher levels of oleic acid were observed. EB and TB specific alterations in gene expression were found for ELOVLs and FADSs, key enzymes for FA elongation and desaturation. In conclusion, maternal diabetes mellitus alters embryonic FA metabolism differently in EB and TB, indicating a lineage-specific metabolic adaptive response. Show less