Targeted proteomics of postmortem human brain reveals neurobiologic heterogeneity in Alzheimer’s disease using NULISA technology

Association Between Postmortem Pathologic Burden and the Rate of Clinical Progression in Patients With Frontotemporal Lobar Degeneration.

BACKGROUND AND OBJECTIVES Histopathologic staging of Alzheimer disease has led to validation of imaging techniques that guide diagnosis and treatment. We previously constructed preliminary phases of the sequential progression of TDP-43 and tau to guide similar efforts in behavioral-variant frontotemporal dementia (bvFTD). In this article, we expand this work using digital pathology and longitudinal clinical data to more comprehensively model the relationship between clinical progression and the distribution and severity of postmortem frontotemporal lobar degeneration (FTLD) pathology. METHODS In this retrospective cohort study, 101 patients (42% female, median age at symptom onset = 63 years) were selected from the Penn Integrated Neurodegenerative Disease Database and had both longitudinal assessments and primary neuropathologic diagnosis of FTLD-Tau or FTLD-TDP. We used validated methods to quantify the burden of primary pathology from up to 6 cortical regions across hemispheres. FTLD-TDP pathologic phase was constructed from diagnostic pathology data based on published criteria. We tested the association between pathologic metrics and (1) disease duration or (2) the rate of clinic progression measured by 2 independent global measures (Clinical Dementia Rating Scale-Sum of Boxes [CDR-SB] and Mini-Mental State Examination [MMSE]). Linear regression and linear mixed-effects models were adjusted for hemisphere sampled, sex, age at onset, pathogenic variant status, and pathologic subtype. RESULTS Disease duration did not associate with pathologic burden in multiple regression (FTLD-TDP β = 0.01 [-0.06, 0.09]; p = 0.7; FTLD-Tau β = 0.1 [-0.4, 0.7]; p = 0.7). By contrast, mean TDP-43 burden, but not FTLD-Tau burden, was associated with both worse relative CDR-SB (β = 0.1 [0.06, 0.2]; p = 0.0001) and MMSE (β = -0.1 [-0.2, -0.03]; p = 0.009) among all FTLD-TDP patients. TDP-43 phase also associated with worse CDR-SB (β = 0.07 [0.02, 0.1]; p = 0.005) and MMSE (β = -0.2 [-0.3, -0.1]; p = 0.000005). TDP-43 burden (CDR-SB (β = 0.1 [0.03, 0.2]; p = 0.005 and MMSE (β = -0.2 [-0.4, -0.05]; p = 0.009)), but not phase (CDR-SB (β = 0.02 [-0.03, 0.08]; p = 0.4 and MMSE (β = -0.04 [-1, 0.07]; p = 0.5)), associated with relative decline in sensitivity analyses limited to bvFTD. DISCUSSION Greater TDP-43 burden was most closely associated with antemortem clinical decline rather than cumulative aggregation through the disease course. These human data suggest that the temporal dynamics of protein aggregation may differ among FTLD proteinopathies, with implications for the interpretation of FTLD-Tau and FTLD-TDP‑specific biomarkers as these are developed.

Refining the genetic landscape of Alzheimer's disease : insights from a novel neuropathological cohort

Alzheimer’s disease (AD) is the leading cause of dementia in aging populations, affecting approximately 10% of individuals over the age of 65 and accounting for roughly 70% of dementia cases. While AD is classically characterized by extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau, the neuropathological landscape is markedly heterogeneous. Most patients exhibit additional co-morbid lesions, including cerebral amyloid angiopathy (CAA), phosphorylated TDP-43 (TDP-43) inclusions, Lewy bodies, granulovacuolar degeneration (GVD), and Hirano bodies (HBs), which influence disease progression and complicate diagnosis. Although genome-wide association studies (GWAS) have identified numerous genetic risk loci for AD, these are typically derived from clinically defined cohorts, potentially introudcing phenotypic heterogeneity. This PhD project aimed to elucidate the genetic architecture of both hallmark and co-existing neuropathological features using a deeply phenotyped autopsy cohort of European ancestry. In the first phase, 85 known AD risk variants were evaluated for association with 12 neuropathological traits in 325 individuals. A significant association between a variant in APH1B and NFT pathology was identified and validated through meta-analysis in an independent cohort, with network modelling suggesting a direct link to tau pathology. Additional subthreshold and suggestive associations, including TPCN1 with TDP-43 and UMAD1 with Lewy bodies, were observed. In the second phase, novel GWAS was performed for a total cohort of 414 individuals to allow the discovery of novel risk genes. GWAS for major neuropathological features identified a robust association between KCNQ4 and NFTs. Largely understudied but frequently observed lesions were studied as well. GWAS of HB pathology revealed signals near NRF1 and within GDPD3, with replication in an independent cohort confirming the findings. GWAS of GVD stage identified six genome-wide significant loci (FANCD2OS, XAF1, HIPK1, SMIM21, SPDYE3, and PREX2), with implicated genes predominantly involved in apoptotic and inflammatory pathways. Collectively, this work expands current understanding of the genetic determinants underlying both hallmark and co-morbid AD neuropathologies. By leveraging a uniquely characterized autopsy cohort, it provides novel insights into disease mechanisms and identifies potential targets for therapeutic intervention.

An analysis of cerebral amyloid angiopathy based on samples from human brain bank

Background Cerebral amyloid angiopathy (CAA) is a common age-associated cerebrovascular disease marked by amyloid-β (Aβ) accumulation in cerebral vessel walls, and it is tightly linked to Alzheimer’s disease (AD) and cognitive impairment. However, the specific mechanism in CAA progression remains poorly elucidated. Methods We analyzed 49 autopsy samples obtained from the Human Brain Bank of Hebei Medical University, collected basic pathological data and explored the correlations between CAA and Alzheimer’s disease neuropathologic change (ADNC). Transcriptomic sequencing was performed on 21 occipital lobe specimens to screen differentially expressed genes underlying CAA and its pathological subtypes. Results Neuropathological examination identified CAA pathology in 29 of 49 community donors (59.18%). Both CAA type and stage were significantly correlated with ADNC. In particular, CAA type 1 was closely associated with AD pathology and cognitive decline. Transcriptome analysis revealed that the GO functional enrichment was mainly concentrated in immune response-activating and -regulating signaling pathways. Triggering receptor expressed on myeloid cells 1 (TREM1) gene was involved in the amplification of immune signals, and it was expressed more strongly in the CAA1 subtype. Conclusion CAA is not simply an independent cerebrovascular disorder but also serves as a critical synergistic risk factor for ADNC progression. TREM1 is a potential gene that could be associated with a more severe pathological progression of CAA1 type.

Clinicopathologic Evaluation of Amyloid Clearance in Alzheimer Disease

Importance: The long-term efficacy of amyloid targeting therapies hinge on their ability to slow downstream neuropathologic change, but little is known about the influence of amyloid clearance on tau pathology and neurodegeneration. Objective: To determine the post-mortem and in vivo association between post-treatment amyloid levels and downstream neuropathology in a patient with patchy areas showing minimal residual amyloid following aducanumab therapy. Design, Setting, and Participants: Clinicopathologic case report from a single academic memory center. A p.R47H TREM2 (a variant associated with higher Alzheimer disease risk) male carrier in his 50s with mild cognitive impairment who received aducanumab in the EMERGE/EMBARK trials and 14 age- or TREM2-matched untreated controls from the Penn Center for Neurodegenerative Disease Research. Exposures: 30 doses of aducanumab (cumulative dose 280mg/kg) over 4.5 years. Main Outcomes and Measures: Neuropathologic evaluation of amyloid, tau, and neuroinflammation; Amyloid PET and Tau PET standardized uptake value ratio, longitudinal change in cortical thickness. Results: Four years after receiving his final dose of aducanumab, the patient died and autopsy demonstrated variable levels of amyloid pathology, including regions with very low amyloid juxtaposed with regions showing typical high amyloid burden in deep cortical layers with only low amyloid burden in superficial layers. Regions showing low post-treatment amyloid were preferentially found in gyral crests and were associated with less tau pathology than untreated controls on autopsy and slower longitudinal atrophy on in vivo MRI (β = −0.50, [−0.62, −0.37], t = −7.96, p < .001). In contrast, regions with high amyloid burden were preferentially found in sulcal depths and had similar levels of tau pathology as seen in untreated controls on autopsy. Conclusion and Relevance: In this case report, areas of extensive amyloid clearance following amyloid targeting therapy were associated with less downstream neuropathological change and appear to preferentially occur in gyral crests. Future studies should evaluate the differential mechanisms involved in amyloid clearance from superficial and deep cortical layers and in gyri and sulci, as extensive amyloid clearance may be necessary to achieve downstream neuropathologic benefit following amyloid removal.

Neural substrates of cognitive decline and tremor in neuronal intranuclear inclusion disease: a morphometric MRI study

Advances in biomarker discovery for canine cognitive dysfunction: a comprehensive structured narrative review and future perspectives

Canine Cognitive Dysfunction (CCD) is a naturally occurring neurodegenerative syndrome in aging dogs that shares clinical and neuropathological parallels with Alzheimer’s disease (AD). As the demand for objective diagnostic tools grows, identifying reliable biofluid biomarkers is essential for clinical staging and therapeutic monitoring. This review synthesizes evidence on cerebrospinal fluid (CSF) and blood-based biomarkers (BBM) of CCD, focusing on amyloid-β (Aβ), neurofilament light chain (NfL), tau, and glial fibrillary acidic protein (GFAP). Evidence shows that Aβ42 and Aβ42/Aβ40 ratios exhibit stage-dependent, non-linear alterations resembling early compensatory phases in human AD. In contrast, tau pathology in CCD consists mainly of pre-tangle synaptic hyperphosphorylation rather than abundant neurofibrillary tangles, limiting its current diagnostic utility. GFAP, a marker of astroglial activation, shows inconsistent associations with cognitive decline and remains exploratory. Conversely, NfL has emerged as the most robust biomarker; CSF and plasma NfL levels consistently increase with age, correlate with cognitive impairment, and reflect central axonal pathology, making it the leading candidate for staging and monitoring disease progression. Overall, the CCD biomarker landscape supports a multimodal approach integrating Aβ dysregulation, axonal injury, and glial activation. Advancing this field requires harmonized diagnostic criteria, standardized sampling, and longitudinal studies. Such efforts will strengthen the translational value of CCD as a model for human dementia, accelerating discovery and therapeutic development across species.