Clinicopathologic Heterogeneity and Glial Activation Patterns in Alzheimer Disease.

Importance: Factors associated with clinical heterogeneity in Alzheimer disease (AD) lay along a continuum hypothesized to associate with tangle distribution and are relevant for understanding glial activation considerations in therapeutic advancement. Objectives: To examine clinicopathologic and neuroimaging characteristics of disease heterogeneity in AD along a quantitative continuum using the corticolimbic index (CLix) to account for individuality of spatially distributed tangles found at autopsy. Design, Setting, and Participants: This cross-sectional study was a retrospective medical record review performed on the Florida Autopsied Multiethnic (FLAME) cohort accessioned from 1991 to 2020. Data were analyzed from December 2022 to December 2023. Structural magnetic resonance imaging (MRI) and tau positron emission tomography (PET) were evaluated in an independent neuroimaging group. The FLAME cohort includes 2809 autopsied individuals; included in this study were neuropathologically diagnosed AD cases (FLAME-AD). A digital pathology subgroup of FLAME-AD cases was derived for glial activation analyses. Main Outcomes and Measures: Clinicopathologic factors of heterogeneity that inform patient history and neuropathologic evaluation of AD; CLix score (lower, relative cortical predominance/hippocampal sparing vs higher, relative cortical sparing/limbic predominant cases); neuroimaging measures (ie, structural MRI and tau-PET). Results: Of the 2809 autopsied individuals in the FLAME cohort, 1361 neuropathologically diagnosed AD cases were evaluated. A digital pathology subgroup included 60 FLAME-AD cases. The independent neuroimaging group included 93 cases. Among the 1361 FLAME-AD cases, 633 were male (47%; median [range] age at death, 81 [54-96] years) and 728 were female (53%; median [range] age at death, 81 [53-102] years). A younger symptomatic onset (Spearman ρ = 0.39, P < .001) and faster decline on the Mini-Mental State Examination (Spearman ρ = 0.27; P < .001) correlated with a lower CLix score in FLAME-AD series. Cases with a nonamnestic syndrome had lower CLix scores (median [IQR], 13 [9-18]) vs not (median [IQR], 21 [15-27]; P < .001). Hippocampal MRI volume (Spearman ρ = -0.45; P < .001) and flortaucipir tau-PET uptake in posterior cingulate and precuneus cortex (Spearman ρ = -0.74; P < .001) inversely correlated with CLix score. Although AD cases with a CLix score less than 10 had higher cortical tangle count, we found lower percentage of CD68-activated microglia/macrophage burden (median [IQR], 0.46% [0.32%-0.75%]) compared with cases with a CLix score of 10 to 30 (median [IQR], 0.75% [0.51%-0.98%]) and on par with a CLix score of 30 or greater (median [IQR], 0.40% [0.32%-0.57%]; P = .02). Conclusions and Relevance: Findings show that AD heterogeneity exists along a continuum of corticolimbic tangle distribution. Reduced CD68 burden may signify an underappreciated association between tau accumulation and microglia/macrophages activation that should be considered in personalized therapy for immune dysregulation.

The SERPINA5 coding variant E228Q does not contribute to clinicopathologic characteristics in Alzheimer's disease: A cross-sectional study.

We previously demonstrated that increased expression of the SERPINA5 gene is associated with hippocampal vulnerability in Alzheimer's disease (AD) brains. SERPINA5 was further demonstrated to be a novel tau-binding partner that colocalizes within neurofibrillary tangles. Our goal was to determine whether genetic variants in the SERPINA5 gene contributed to clinicopathologic phenotypes in AD. To screen for SERPINA5 variants, we sequenced 103 autopsy-confirmed young-onset AD cases with a positive family history of cognitive decline. To further assess the frequency of a rare missense variant, SERPINA5 p.E228Q, we screened an additional 1114 neuropathologically diagnosed AD cases. To provide neuropathologic context in AD, we immunohistochemically evaluated SERPINA5 and tau in a SERPINA5 p.E228Q variant carrier and a matched noncarrier. In the initial SERPINA5 screen, we observed 1 individual with a rare missense variant (rs140138746) that resulted in an amino acid change (p.E228Q). In our AD validation cohort, we identified an additional 5 carriers of this variant, resulting in an allelic frequency of 0.0021. There was no significant difference between SERPINA5 p.E228Q carriers and noncarriers in terms of demographic or clinicopathologic characteristics. Although not significant, on average SERPINA5 p.E228Q carriers were 5 years younger at age of disease onset than noncarriers (median: 66 [60-73] vs 71 [63-77] years, P = .351). In addition, SERPINA5 p.E228Q carriers exhibited a longer disease duration than noncarriers that approached significance (median: 12 [10-15]) vs 9 [6-12] years, P = .079). More severe neuronal loss was observed in the locus coeruleus, hippocampus, and amygdala of the SERPINA5 p.E228Q carrier compared to noncarrier, although no significant difference in SERPINA5-immunopositive lesions was observed. Throughout the AD brain in either carrier or noncarrier, areas with early pretangle pathology or burnt-out ghost tangle accumulation did not reveal SERPINA5-immunopositive neurons. Mature tangles and newly formed ghost tangles appeared to correspond well with SERPINA5-immunopositive tangle-bearing neurons. SERPINA5 gene expression was previously associated with disease phenotype; however, our findings suggest that SERPINA5 genetic variants may not be a contributing factor to clinicopathologic differences in AD. SERPINA5-immunopositive neurons appear to undergo a pathologic process that corresponded with specific levels of tangle maturity.

Global neuropathologic severity of Alzheimer's disease and locus coeruleus vulnerability influences plasma phosphorylated tau levels.

BACKGROUND: Advances in ultrasensitive detection of phosphorylated tau (p-tau) in plasma has enabled the use of blood tests to measure Alzheimer's disease (AD) biomarker changes. Examination of postmortem brains of participants with antemortem plasma p-tau levels remains critical to understanding comorbid and AD-specific contribution to these biomarker changes. METHODS: We analyzed 35 population-based Mayo Clinic Study of Aging participants with plasma p-tau at threonine 181 and threonine 217 (p-tau181, p-tau217) available within 3 years of death. Autopsied participants included cognitively unimpaired, mild cognitive impairment, AD dementia, and non-AD neurodegenerative disorders. Global neuropathologic scales of tau, amyloid-ß, TDP-43, and cerebrovascular disease were examined. Regional digital pathology measures of tau (phosphorylated threonine 181 and 217 [pT181, pT217]) and amyloid-ß (6F/3D) were quantified in hippocampus and parietal cortex. Neurotransmitter hubs reported to influence development of tangles (nucleus basalis of Meynert) and amyloid-ß plaques (locus coeruleus) were evaluated. RESULTS: The strongest regional associations were with parietal cortex for tau burden (p-tau181 R = 0.55, p = 0.003; p-tau217 R = 0.66, p < 0.001) and amyloid-ß burden (p-tau181 R = 0.59, p < 0.001; p-tau217 R = 0.71, p < 0.001). Linear regression analysis of global neuropathologic scales explained 31% of variability in plasma p-tau181 (Adj. R2 = 0.31) and 59% in plasma p-tau217 (Adj. R2 = 0.59). Neither TDP-43 nor cerebrovascular disease global scales independently contributed to variability. Global scales of tau pathology (ß-coefficient = 0.060, p = 0.016) and amyloid-ß pathology (ß-coefficient = 0.080, p < 0.001) independently predicted plasma p-tau217 when modeled together with co-pathologies, but only amyloid-ß (ß-coefficient = 0.33, p = 0.021) significantly predicted plasma p-tau181. While nucleus basalis of Meynert neuron count/mm2 was not associated with plasma p-tau levels, a lower locus coeruleus neuron count/mm2 was associated with higher plasma p-tau181 (R = -0.50, p = 0.007) and higher plasma p-tau217 (R = -0.55, p = 0.002). Cognitive scores (Adj. R2 = 0.25-0.32) were predicted by the global tau scale, but not by the global amyloid-ß scale or plasma p-tau when modeled simultaneously. CONCLUSIONS: Higher soluble plasma p-tau levels may be the result of an intersection between insoluble deposits of amyloid-ß and tau accumulation in brain, and may be associated with locus coeruleus degeneration.

Phosphorylated tau sites that are elevated in Alzheimer's disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the post mortem brain.

INTRODUCTION: Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. METHODS: We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non-AD neuropathologies and tauopathies. Thioflavin-S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. RESULTS: Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin-S. Hippocampal burden generally increased with each Braak stage. DISCUSSION: These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. HIGHLIGHTS: Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline-rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi-quantitative frequency to calculate tangle maturity frequency.

Association of plasma biomarkers of amyloid and neurodegeneration with cerebrovascular disease and Alzheimer's disease.

The objective of this study was to determine the differential mapping of plasma biomarkers to postmortem neuropathology measures. We identified 64 participants in a population-based study with antemortem plasma markers (amyloid-ß [Aß] x-42, Aßx-40, neurofilament light [NfL], and total tau [T-tau]) who also had neuropathologic assessments of Alzheimer's and cerebrovascular pathology. We conducted weighted linear-regression models to evaluate relationships between plasma measures and neuropathology. Higher plasma NfL and Aß42/40 ratio were associated with cerebrovascular neuropathologic scales (p < 0.05) but not with Braak stage, neuritic plaque score, or Thal phase. Plasma Aß42/40 and NfL explained up to 18% of the variability in cerebrovascular neuropathologic scales. In participants predominantly with modest levels of Alzheimer's pathologic change, biomarkers of amyloid and neurodegeneration were associated with cerebrovascular neuropathology. NfL is a non-specific marker of brain injury, therefore its association with cerebrovascular neuropathology was expected. The association between elevated Aß42/40 and cerebrovascular disease pathology needs further investigation but could be due to the use of less specific amyloid-ß assays (x-40, x-42).

Transcriptomic analysis to identify genes associated with selective hippocampal vulnerability in Alzheimer's disease.

Selective vulnerability of different brain regions is seen in many neurodegenerative disorders. The hippocampus and cortex are selectively vulnerable in Alzheimer's disease (AD), however the degree of involvement of the different brain regions differs among patients. We classified corticolimbic patterns of neurofibrillary tangles in postmortem tissue to capture extreme and representative phenotypes. We combined bulk RNA sequencing with digital pathology to examine hippocampal vulnerability in AD. We identified hippocampal gene expression changes associated with hippocampal vulnerability and used machine learning to identify genes that were associated with AD neuropathology, including SERPINA5, RYBP, SLC38A2, FEM1B, and PYDC1. Further histologic and biochemical analyses suggested SERPINA5 expression is associated with tau expression in the brain. Our study highlights the importance of embracing heterogeneity of the human brain in disease to identify disease-relevant gene expression.

Visualization of neurofibrillary tangle maturity in Alzheimer's disease: A clinicopathologic perspective for biomarker research.

Neurofibrillary tangles, one of the neuropathologic hallmarks of Alzheimer's disease, have a dynamic lifespan of maturity that associates with progressive neuronal dysfunction and cognitive deficits. As neurofibrillary tangles mature, the biology of the neuron undergoes extensive changes that may impact biomarker recognition and therapeutic targeting. Neurofibrillary tangle maturity encompasses three levels: pretangles, mature tangles, and ghost tangles. In this review, we detail distinct and overlapping characteristics observed in the human brain regarding morphologic changes the neuron undergoes, conversion from intracellular to extracellular space, tau immunostaining patterns, and tau isoform expression changes across the lifespan of the neurofibrillary tangle. Post-translational modifications of tau such as phosphorylation, ubiquitination, conformational events, and truncations are discussed to contextualize tau immunostaining patterns. We summarize accumulated and emerging knowledge of neurofibrillary tangle maturity, discuss the current tools used to interpret the dynamic nature in the postmortem brain, and consider implications for cognitive dysfunction and tau biomarkers.