Henrik Zetterberg’s research while affiliated with University of Wisconsin–Madison and other places

Importance While clinical disease stages remained largely unchanged in the 2024 update of the Alzheimer disease (AD) criteria, tau–positron emission tomography (PET) was introduced as a core biomarker and its spatial extent was incorporated into the revised biological stages of the disease. It is important to consider both the clinical and the biological stages and understand their discrepancies. Objective To compare individuals who have discrepant biological and clinical stages with those who have congruent stages in terms of copathologies, comorbidities, and demographics. Design, Setting, and Participants Participants were from the Swedish BioFINDER-2 (inclusion from 2017 through 2023) and the Alzheimer’s Disease Neuroimaging Initiative (ADNI) (inclusion from 2015 through 2024). BioFINDER-2 included a prospective population-based (cognitively normal [CN] older adults) and memory clinic–based cohort (participants with subjective cognitive impairment [SCD], mild cognitive impairment [MCI], and dementia). ADNI included a volunteer-based sample. All participants who were amyloid-β positive and had undergone tau-PET were included. In BioFINDER-2, 838 participants of a total of 1979 were included, and of 927 with tau-PET in ADNI, 380 were included. Exposures The clinical (CN to dementia) and biological (based on PET; initial [amyloid-β-positive only] to advanced [amyloid-β-positive, elevated, and widespread tau]) stages from the revised AD criteria. Main Outcomes and Measures Cross-sectional measures of neurodegeneration (cortical thickness, TAR DNA-binding protein 43 [TDP-43] imaging signature, neurofilament light [NfL]), α-synuclein cerebrospinal fluid status, plasma glial fibrillary acidic protein, white matter lesions, infarcts, microbleeds, comorbidities, and demographics. Results There were 838 BioFINDER-2 participants (mean age, 73.9 [SD, 7.3] years; 431 women [51%]; 407 men [49%]) and 380 ADNI participants (average age, 72.9 [SD, 7.0] years; 194 women [51%]; 186 mean [49%]) included. In BioFINDER-2, 37.7% of the sample had congruent biological and clinical stages (reference group), 51.3% had more advanced clinical impairment compared with their clinical stage (clinical > biological) and 11.0% had the opposite (biological > clinical). The main differences were between the reference group and the clinical > biological group: the latter participants were more often positive for α-synuclein pathology, had higher NfL levels, greater TDP-43–like atrophy, and higher burden of cerebral small vessel disease lesions (all false discovery rate P < .05). The only difference between the biological > clinical and the reference group was that the former had less neurodegeneration (thicker cortex; all false discovery rate P < .001). The main results were replicated in the independent ADNI cohort, where congruent 56.1% of participants had biological and clinical stages; 36.1% were in the category clinical > biological, and 7.9% in biological > clinical. Conclusions and Relevance Copathologies play an important role in symptom severity in individuals who harbor less tau-tangle pathology than expected for their clinical impairment. These results highlight the importance of measuring non–AD biomarkers in patients with AD with worse cognitive impairment than expected based on their biological stage, which could impact the clinical diagnosis and prognosis.

INTRODUCTION The α‐synuclein (αSyn) seed amplification assay (αSyn‐SAA) is an accurate tool to detect αSyn seeds in patients with Parkinson's disease (PD). However, a minority of clinically diagnosed PD patients are negative for αSyn. METHODS The αSyn‐SAA was performed in cerebrospinal fluid (CSF) of individuals with PD (n = 93), multiple system atrophy (MSA, n = 26), progressive supranuclear palsy (PSP, n = 18), corticobasal syndrome (n = 3), and healthy controls (n = 29). RESULTS The αSyn‐SAA detected αSyn in 90% of PD and 81% of MSA patients, while exhibiting high specificity (97%). SAA– PD patients had a distinct phenotype compared to SAA+ PD, including a marked postural instability/gait disorder (P = 0.002), impaired episodic memory, and lower CSF amyloid beta42 (P = 0.03). SAA+ PSP also displayed distinctive traits. DISCUSSION A negative αSyn‐SAA in PD is associated with a distinct phenotype and pathological findings suggesting that these patients may have a motor subtype of Alzheimer's disease. This could influence future clinical trials. Highlights The α‐synuclein seed amplification assay (αSyn‐SAA) is a robust assay. αSyn‐SAA–negative Parkinson's disease shows a distinct motor–cognitive phenotype. Autopsy showed Alzheimer's disease (AD) pathology in parkinsonian diseases. AD stands as a major clinical confounder for the diagnosis of movement disorders.

Background The neurochemical alterations in cerebrospinal fluid (CSF) associated with the typical symptomatology in idiopathic normal pressure hydrocephalus (iNPH) and their association with outcome after shunt surgery are unsettled. Aim To explore associations between concentrations of CSF biomarkers reflecting amyloid- and tau pathology, neuronal degeneration as well as astrocytic activation and the characteristic symptomatology in iNPH and to examine whether these biomarkers can predict the postoperative outcome in all patients and in patients without evidence of Alzheimer’s disease (AD) pathology. Methods This explorative study included 81 patients diagnosed with iNPH at the Hydrocephalus research unit, Sahlgrenska. Symptoms were assessed using the iNPH-scale and standardized clinical tests measuring gait, balance, cognition and urinary incontinence before and median 8 months after shunt surgery. Pre-operative lumbar CSF concentrations of Aβ38, Aβ40, Aβ42, ratio Aβ42/Aβ40, sAPPα, sAPPβ, T-tau, P-tau, MCP-1, and NFL were analyzed. A low Aβ42/Aβ40 ratio defined patients with AD pathology. Correlation and regression analyses between biomarker concentrations and clinical symptoms at baseline as well as postoperative change in symptoms after surgery, were performed. Results Higher NFL correlated with more pronounced impairment in all clinical tests, i.e. included measures of gait, balance, cognition and urinary incontinence (rp=0.25–0.46, p < 0.05). Higher T-tau and P-tau correlated with poorer performance in cognitive tests (rp=0.26–0.39, p < 0.05). No biomarker could differentiate between improved and unimproved patients in the whole sample or in AD-pathology negative patients. Low ratio Aβ42/Aβ40 lacked predictive value. A higher preoperative P-tau was weakly correlated with less pronounced overall clinical improvement (rp = -0.238, p = 0.036). Conclusions Axonal degeneration, as indicated by elevated NFL, is probably involved in the generation of the full iNPH tetrade of symptoms and tau pathology more specifically with iNPH cognitive impairment. No CSF biomarker could identify shunt responders. CSF evidence of Alzheimer pathology should not be used to exclude patients from shunt surgery.

INTRODUCTION Further research is needed to understand the performance of plasma phosphorylated tau (p‐tau)217 in the diagnostic thinking at the individual patient level. We evaluated the incremental diagnostic value of plasma p‐tau217, expressed in terms of diagnostic confidence of Alzheimer's disease (DCAD; range 0—100). METHODS Two hundred thirty‐two patients with dementia were included and scored in terms of DCAD in a three‐step consecutive assessment: (1) clinical work‐up, (2) clinical work‐up plus plasma p‐tau217, and (3) clinical work‐up, plasma p‐tau217, plus conventional amyloid markers. Two blinded neurologists were asked to review DCAD at each step. RESULTS DCAD accuracy, expressed as area under the curve, significantly increased from 0.93 with clinical work‐up alone, to 0.97 with clinical work‐up plus plasma p‐tau217 (P = 0.01), with no further increase with the addition of conventional amyloid markers (0.99, P = 0.13). DISCUSSION Plasma p‐tau217 in addition to routine assessment significantly enhances diagnostic confidence that is comparable to well‐established amyloidosis biomarkers. Highlights Plasma phosphorylated tau (p‐tau)217 measurements increase diagnostic confidence of Alzheimer's disease. Plasma p‐tau217 increases diagnostic confidence comparable to traditional markers. Plasma p‐tau217 dosage may be helpful in addition to routine assessment.

The amyloid precursor protein (APP) is processed by multiple enzymes to generate biologically active peptides, including amyloid-β (Aβ), which aggregates to form the hallmark pathology of Alzheimers disease (AD). Aβ is produced through an initial β-secretase cleavage of APP, generating a 99-amino acid C-terminal fragment (APP-C99). Subsequent cleavage of APP-C99 by γ-secretase produces Aβ peptides of varying lengths. To better understand the transcriptional regulation of Aβ production, we employed long-read RNA sequencing and identified previously unannotated transcripts encoding APP-C99 with an additional methionine residue (APP-C100), generated independently of β-secretase cleavage. These transcripts are expressed separately from full-length APP , and we observed that cells lacking full-length APP can still produce Aβ through these shorter isoforms. Importantly, mass spectrometry analysis of cerebrospinal fluid (CSF) revealed peptides consistent with the methionine-extended Aβ species, supporting the in vivo translation of these transcripts. Our findings reveal an alternative pathway for Aβ generation and aggregation, highlighting a potential new target for modulating Aβ accumulation in AD.

INTRODUCTION Multi‐etiology dementia necessitates in vivo markers of copathologies including misfolded α${{\alpha}}$‐synuclein (syn). We measured misfolded syn aggregates (syn‐seeds) via qualitative seed amplification assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD). METHODS Cerebrospinal fluid (CSF) was obtained from 420 participants in two AD risk cohorts (35% male; 91% cognitively unimpaired; mean [standard deviation] age, 65.42 [7.78] years; education, 16.17 [2.23]) years). synSAA results were compared to phosphorylated tau (T), amyloid beta (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects. RESULTS Syn positivity (synSAA+) co‐occurred with T (in synSAA+ vs. synSAA−, 36% vs. 20% T+; Pp = 0.011) and with cognitive impairment (10% vs. 7% mild cognitive impairment; 10% vs. 0% dementia; p = 0.00050). synSAA+ participants’ cognitive performance declined ≈ 40% faster than synSAA– for Digit Symbol Substitution, but not other tests. DISCUSSION Findings support prevalent syn copathology in a mostly unimpaired AD risk cohort. Relationships with progression should be evaluated once more have declined. Highlights In a middle‐aged sample, misfolded α${{\alpha}}$‐synuclein (syn) co‐occurred with phosphorylated tau181 (T). syn+/T+ status was linked with higher levels of other cerebrospinal fluid biomarkers. syn+ individuals were more likely than syn– to be cognitively impaired. syn+ status was linked to faster decline on an executive function task.

Objectives Neurofilament light (NfL) is an established biofluid marker of neuroaxonal injury for neurological diseases. Several high-throughput and sensitive immunoassays have been developed to quantify NfL in blood and cerebrospinal fluid (CSF), facilitating the use of NfL as a biomarker in research and clinical practice. However, because of the lack of rigorous comparisons of assays, it has been difficult to determine whether data are comparable and whether assay performance differs. Here, we compared the performance of five NfL immunoassays. Methods To assess the five NfL immunoassays (Fujirebio, ProteinSimple, Quanterix, Roche and Siemens), we used pooled plasma or pooled CSF, as well as unique samples from 20 healthy controls and 20 individuals with El Escorial defined probable or definite amyotrophic lateral sclerosis (ALS), to evaluate precision, parallelism and/or bias. We also examined correlations between plasma and CSF NfL concentrations within and across assays and evaluated their ability to differentiate healthy controls from individuals with ALS. Results Four of the five assays demonstrated exemplary performance based on our analyses of precision and parallelism. Across the five assays, NfL concentrations were lower in plasma than in CSF, although they displayed a high degree of correlation. We noted bias across assays; plasma NfL concentrations were lowest for the Roche assay and highest for the ProteinSimple assay. In addition, all assays reliably distinguished healthy controls from individuals with ALS using plasma or CSF NfL. Conclusions Four NfL assays demonstrated similar analytic performance. Alongside performance, other factors such as costs, accessibility, useability, footprint, and intended use, should be considered.

INTRODUCTION: This study uses longitudinal amyloid biomarker and cognitive data to generate sample size estimates for two-armed, pre-clinical amyloid clearance clinical trials. METHODS: PET PiB DVR ranges defined three amyloid groups (positive, "A+"; sub threshold/low positive, "subA+"; and negative, "A-") in cognitively unimpaired Wisconsin Registry for Alzheimer's Prevention participants. Amyloid group trajectories estimated from mixed effects models informed per-treatment-arm sample size estimates to detect plausible treatment effects over 3-year (biomarker) or 6-year (cognition) study windows (80% power). RESULTS: To detect 60% slowing in PiB accumulation, 40 may be needed per arm for both SubA+ and A+; to detect the same effect sizes in plasma p-tau217 trajectories, ~50-1700 are needed, depending on assay and amyloid subgroup. Among cognitive outcomes, Digit Symbol Substitution and a 5-test Preclinical Alzheimer's Cognitive Composite consistently required fewest (<2000) per arm. DISCUSSION: Early intervention study planning will benefit from selection of outcomes that are most sensitive to AD biomarker-related preclinical change.