Alzheimer's Disease Neuropathologic Change Research Articles

Clinical criteria for limbic-predominant age-related TDP-43 encephalopathy.

Limbic predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) is highly prevalent in late life and a common co-pathology with Alzheimer's disease neuropathologic change (ADNC). LATE-NC is a slowly progressive, amnestic clinical syndrome. Alternatively, when present with ADNC, LATE-NC is associated with a more rapid course. With the emergence of anti-amyloid therapeutics, discrimination of LATE-NC from ADNC is critical and will lead to greater clinical recognition of amnestic patients without ADNC. Furthermore, co-pathology with LATE-NC may influence outcomes of these therapeutics. Thus there is a need to identify patients during life with likely LATE-NC. We propose criteria for clinical diagnosis of LATE as an initial framework for further validation. In the context of progressive memory loss and substantial hippocampal atrophy, criteria are laid out for probable (amyloid negative) or possible LATE (amyloid biomarkers are unavailable or when amyloid is present, but hippocampal neurodegeneration is out of proportion to expected pure ADNC). HIGHLIGHTS: Limbic-predominant age-related TDP-43 encephalopathy (LATE) is a highly prevalent driver of memory loss in late life. LATE neuropathic change (LATE-NC) is a common co-pathology with Alzheimer's disease neuropathic change (ADNC) and may influence outcomes with emerging disease-modifying medicines. We provide initial clinical criteria for diagnosing LATE during life either when LATE-NC is the likely primary driver of symptoms or when observed in conjunction with AD. Definitions of possible and probable LATE are provided.

Medical Histories Associated With Absence of Alzheimer Disease Neuropathologic Changes in the Oldest-Old: The 90+ Study.

Exploration of medical histories and medications associated with Alzheimer disease neuropathologic change (ADNC) absence and potential resistance may identify protective factors against ADNC. This was a retrospective examination of data from participants age ≥90 years who enrolled in The 90+ Study, a longitudinal study based in California. Participants underwent neuropathologic analysis for the presence of neuritic amyloid plaques (NPs) (any), beta amyloid plaques (Thal phase > 0), and neurofibrillary tangles (>2). Odds ratios (ORs) for the presence of pathologic changes to APOE genotype, self-reported medical histories, and medication use were estimated by logistic regression and (a)djusted for sex, age at death (continuous), and education. We examined 267 participants; 75% were female, with a mean age at death of 98 (± 3.5) years. Variables associated with ADNC absence/presence were for NPs: heart disease (adjusted OR [aOR] = 0.46), APOE-ε4 (aOR = 3.48), angiotensin-converting enzyme (ACE) inhibitors (aOR = 0.46), cataracts (aOR = 0.26), and beta-blockers (aOR = 0.51); for Aβ: heart disease (aOR = 0.33) and APOE-ε4 (aOR = 8.10); and for neurofibrillary tangles: ACE inhibitors (aOR = 0.46), glaucoma (aOR = 0.29), HTN (aOR = 0.44), seizures (aOR = 0.16), APOE-ε2 presence (aOR = 0.39), and vasodilators (aOR = 0.36). These observations would not survive multiple comparison corrections. Cataract formation, APOE status, ACE inhibitors, and beta-blockers may be associated with ADNC absence because of differential lipid trafficking. Survival bias and type 1 errors warrant consideration.

Posterior hippocampal sparing in Lewy body disorders with Alzheimer's copathology: An in vivo MRI study.

Lewy body disorders (LBD), encompassing Parkinson disease (PD), PD dementia (PDD), and dementia with Lewy bodies (DLB), are characterized by alpha-synuclein pathology but often are accompanied by Alzheimer's disease (AD) neuropathological change (ADNC). The medial temporal lobe (MTL) is a primary locus of tau accumulation and associated neurodegeneration in AD. However, it is unclear the extent to which AD copathology in LBD (LBD/AD+) contributes to MTL-specific patterns of degeneration. We employ a MTL subregional segmentation strategy of T1-weighted (T1w) MRI in biomarker-supported or autopsy-confirmed LBD and LBD/AD+to investigate the anatomic consequences of co-occurring LBD/AD+pathology on neurodegeneration. We studied 167 individuals with clinical diagnoses of LBD (PD, n=124 (74.3%); PDD, n=11 (6.6%); DLB, n=32 (19.2%)) with available T1w MRI and AD biomarkers or autopsy evidence of ADNC. Individuals were further biologically classified as LBD/AD+based on hierarchical evidence of ADNC pathology: 1) AD "intermediate" or "high" by ABC neuropathologic criteria (n=39 (23.4%)); 2) positive amyloid PET (n=2 (1.2%)); or 3) CSF β-amyloid1-42<185.7pg/mL n=126 (75.4%)). The T1 Automated Segmentation of Hippocampal Subfields (ASHS) pipeline was used to compute volume and thickness measurements of MTL subregions in LBD/AD- and LBD/AD+. Linear regression tested the association of AD copathology and subregion volume/thickness, covarying for age and sex, and intracranial volume for volume measurements. Secondary analyses correlated MTL subregional volume/thickness with cognition and neuropathology. LBD/AD+had decreased volume/thickness compared to LBD/AD- in all MTL subregions except posterior hippocampus. The greatest effect sizes were seen in Brodmann Area 35 (BA35) (Cohen's d=0.62, p=0.002, β=0.107±0.034), and entorhinal cortex (ERC) (Cohen's d=0.56, p=0.006, β=0.088±0.031). Smaller differences were seen in the parahippocampal cortex (PHC) (Cohen's d=0.5, p=0.012, β=0.082±0.033), BA36 (Cohen's d=0.47, p=0.021, β=0.090±0.039) and anterior hippocampus (Cohen's d=0.45, p=0.029, β=111.790±50.595). Verbal memory scores positively correlated with volume/thickness in anterior and posterior hippocampus, BA35, ERC and PHC, while visuospatial memory positively correlated only in BA35. In the subset of participants with autopsy, lower ERC volume was associated with a higher tau load in ERC (adjusted odds ratio 0.013, 95% CI [0.0002, 0.841], uncorrected p=0.041). Relative to LBD/AD-, LBD/AD+has greater T1w MRI evidence of atrophy in multiple MTL subregions. Atrophy in MTL subregions associates with memory performance and tau pathological load. The observed pattern of atrophy largely follows expectation from AD Braak stages, except for posterior hippocampus. Longitudinal studies are needed to validate the hypothesized spread of neurodegeneration.

Current Status and Future Perspective of Seoul National University Hospital-Dementia Brain Bank with Concordance of Clinical and Neuropathological Diagnosis.

This paper introduces the current status of Seoul National University Hospital Dementia Brain Bank (SNUH-DBB), focusing on the concordance rate between clinical diagnoses and postmortem neuropathological diagnoses. We detail SNUH-DBB operations, including protocols for specimen handling, induced pluripotent stem cells (iPSC) and cerebral organoids establishment from postmortem dural fibroblasts, and adult neural progenitor cell cultures. We assessed clinical-neuropathological diagnostic concordance rate. Between 2015 and September 2024, 162 brain specimens were collected via brain donation and autopsy. The median donor age was 73 years (1-94) with a male-to -female ratio of 2:1. The median postmortem interval was 9.5 hours (range: 2.5-65). Common neuropathological diagnoses included pure Lewy body disease (10.6%), Lewy body disease (LBD) with other brain diseases (10.6%), pure Alzheimer's disease-neuropathological change (ADNC) (6.0%), ADNC with other brain diseases (10.7%), vascular brain injury (15.2%), and primary age-related tauopathy (7.3%). APOE genotype distribution was following: ε3/ε3: 62.3%, ε2/ε3: 9.6%, ε2/ε4: 3.4%, ε3/ε4: 24.0%, and ε4/ε4: 0.7%. Concordance rates between pathological and clinical diagnoses were: ADNC/AD at 42.4%; LBD at 59.0%; PSP at 100%; ALS at 85.7%; Huntington's disease 100%. The varying concordance rates across different diseases emphasize the need for improved diagnostic criteria and biomarkers, particularly for AD and LBD. Tissues have been distributed to over 40 national studies. SNUH-DBB provides high-quality brain tissues and cell models for neuroscience research, operating under standardized procedures and international guidelines. It supports translational research in dementia and neurodegenerative diseases, potentially advancing diagnostic and therapeutic strategies.

Unraveling the clinical-pathological correlations of subjects with isolated and mixed neurodegenerative processes in the National Alzheimer's Coordinating Center dataset.

Although Alzheimer disease neuropathologic change (ADNC) is the most common pathology underlying clinical dementia, the presence of multiple comorbid neuropathologies is increasingly being recognized as a major contributor to the worldwide dementia burden. We analyzed 1051 subjects with specific combinations of isolated and mixed pathologies and conducted multivariate logistic regression analysis on a cohort of 4624 cases with mixed pathologies to systematically explore the independent cognitive contributions of each pathology. Alzheimer disease neuropathologic change and limbic-predominant age-related TDP-43 encephalopathy neuropathologic change (LATE-NC) were both associated with a primary clinical diagnosis of Alzheimer disease (AD) and were characterized by an amnestic dementia phenotype, while only ADNC associated with logopenic variant primary progressive aphasia (PPA). In subjects with ADNC and comorbid LATE-NC, Lewy body disease, and/or cerebrovascular disease, the clinical phenotype was usually diagnosed during life as "Probable AD." Conversely, the combination of ADNC with frontotemporal lobar degeneration with TDP-43, progressive supranuclear palsy (PSP), or corticobasal degeneration (CBD) resulted in a mixed clinical picture, with variable features of amnestic dementia, PPA subtypes, behavioral variant FTD, PSP syndrome, and CBD syndrome. These findings elucidate the cumulative effects of mixed pathologies and provide insights into interactions between neurodegenerative pathologies contributing to a variety of clinical dementia presentations.

Lewy body co-pathology in Alzheimer's disease and primary age-related tauopathy contributes to differential neuropathological, cognitive, and brain atrophy patterns.

Alzheimer's disease (AD) co-pathology with Lewy bodies (LB) is frequent and influences clinical manifestations and outcomes. Its significance in primary age-related tauopathy (PART) is unknown. We investigated the influence of LB on cognition and brain atrophy in AD and PART. We performed a retrospective cohort study in a large sample of autopsied participants with AD neuropathological change (ADNC) with and without LB and PART with and without LB, with corresponding ante mortem magnetic resonance imaging (MRI) data from the National Alzheimer's Coordinating Center dataset. LB co-pathology worsened cognitive impairment in both PART and ADNC. On longitudinal follow-up, LB impacted cognitive decline in multiple domains. Additionally, LB influenced brain atrophy on MRI across groups and LB regional staging was different in PART and ADNC, accompanying tauopathy progression. These results suggest that LB co-pathology is associated with divergent patterns of cognitive impairment, brain atrophy, and regional pathological distribution in PART and AD. Lewy body (LB) co-pathology is frequent in Alzheimer's disease (AD) with important clinical implications. LB co-pathology is also present in primary age-related tauopathy (PART), but its significance is still understudied. In PART and AD, LB leads to higher cognitive impairment and brain regional atrophy. In PART and AD, LB tends to accompany neurofibrillary tangle progression, suggesting amyloid pathology might be a trigger for regional pathology progression.

Lumipulse-Measured Cerebrospinal Fluid Biomarkers for the Early Detection of Alzheimer Disease.

CSF biomarkers of Aβ42 and phosphorylated tau (p-tau181) are used clinically for the detection of Alzheimer disease (AD) pathology during life. CSF biomarker validation studies have largely used clinical diagnoses and/or amyloid PET imaging as the reference standard. The few existing CSF-to-autopsy studies have been restricted to late-stage AD. This CSF-to-autopsy study investigated associations between CSF biomarkers of AD and AD neuropathologic changes among brain donors who had normal cognition at the time of lumbar puncture (LP). This was a retrospective study of brain donors from the National Alzheimer's Coordinating Center who had normal cognition at the time of LP and who had measurements of CSF Aβ42 and p-tau181 performed with Lumipulse assays. All brain donors were from Washington University Knight ADRC. Staging of AD neuropathologic change (ADNC) was made based on National Institute on Aging-Alzheimer's Association criteria. For this study, participants were divided into 2 categories: "AD-" (no AD/low ADNC) and "AD+" (intermediate/high ADNC). Accuracy of each biomarker for discriminating AD status was evaluated using area under the curve (AUC) statistics generated using predicted probabilities from binary logistic regressions that controlled for age, sex, APOE ε4, and interval between LP and death. The average age at LP was 79.3 years (SD = 5.6), and the average age at death was 87.1 years (SD = 6.5). Of the 49 brain donors, 24 (49%) were male and 47 (95.9%) were White. 20 (40.8%) had autopsy-confirmed AD. The average interval from LP until death was 7.76 years (SD = 4.31). CSF p-tau181/Aβ42 was the optimal predictor of AD, having excellent discrimination accuracy (AUC = 0.97, 95% CI 0.94-1.00, p = 0.003). CSF p-tau181 alone had the second-best discrimination accuracy (AUC = 0.92, 95% CI 0.84-1.00, p = 0.001), followed by CSF Aβ42 alone (AUC = 0.92, 95% CI 0.85-1.00, p = 0.007), while CSF t-tau had the numerically lowest discrimination accuracy (AUC = 0.87, 95% CI 0.76-0.97, p = 0.005). Effects remained after controlling for prevalent comorbid neuropathologies. CSF p-tau181/Aβ42 was strongly associated with CERAD ratings of neuritic amyloid plaque scores and Braak staging of NFTs. This study supports Lumipulse-measured CSF Aβ42 and p-tau181 and, particularly, the ratio of p-tau181 to Aβ42, for the early detection of AD pathophysiologic processes. This study provides Class II evidence that Lumipulse measures of p-tau181/Aβ42 in the CSF accurately discriminated cognitively normal participants with and without Alzheimer disease neuropathologic change.

Preferential clustering of microglia and astrocytes around neuritic plaques during progression of Alzheimer's disease neuropathological changes.

Neuroinflammation plays an important role in the pathological cascade of Alzheimer's disease (AD) along with aggregation of extracellular amyloid-β (Aβ) plaques and intracellular aggregates of tau protein. In animal models of amyloidosis, local immune activation is centered around Aβ plaques, which are usually of uniform morphology, dependent on the transgenic model used. In postmortem human brains a diversity of Aβ plaque morphologies is seen including diffuse plaques (non-neuritic plaques, non-NP), dense-core plaques, cotton-wool plaques, and NP. In a recent study, we demonstrated that during the progression of Alzheimer's disease neuropathologic changes (ADNC), a transformation of non-NP into NP occurs which is tightly linked to the emergence of cortical, but not hippocampal neurofibrillary tangle (NFT) pathology. This highlights the central role of NP in AD pathogenesis as well as brain region-specific differences in NP formation. In order to correlate the transformation of plaque types with local immune activation, we quantified the clustering and phenotype of microglia and accumulation of astrocytes around non-NP and NP during the progression of ADNC. We hypothesize that glial clustering occurs in response to formation of neuritic dystrophy around NP. First, we show that Iba1-positive microglia preferentially cluster around NP. Utilizing microglia phenotypic markers, we furthermore demonstrate that CD68-positive phagocytic microglia show a strong preference to cluster around NP in both the hippocampus and frontal cortex. A similar preferential clustering is observed for CD11c and ferritin-positive microglia in the frontal cortex, while this preference is less pronounced in the hippocampus, highlighting differences between hippocampal and cortical Aβ plaques. Glial fibrillary acidic protein-positive astrocytes showed a clear preference for clustering around NP in both the frontal cortex and hippocampus. These data support the notion that NP are intimately associated with the neuroimmune response in AD and underscore the importance of the interplay of protein deposits and the immune system in the pathophysiology of AD.

Neuropathology of trisomy 21 mosaicism in a case with early-onset dementia.

This study investigated the impact of trisomy 21 mosaicism (mT21) on Alzheimer's disease (AD) neuropathology in a well-characterized clinical case described by Ringman etal. We describe AD neuropathology in mT21 including amyloid beta, phosphorylated tau, astrogliosis, microgliosis, α-synuclein, and TAR DNA-binding protein 43 (TDP-43) in cerebral cortex, hippocampal subregions, and amygdala using immunohistochemistry. We observed high AD neuropathologic change with a score of A3B3C3. In addition, there was widespread astrogliosis, cerebral amyloid angiopathy, and perivascular space widening throughout the brain. Lewy bodies and neurites were noted in the amygdala only and no TDP-43 was observed. The findings in this case report highlight that mT21 is sufficient to induce AD neuropathology and early-onset dementia. Trisomy 21 mosaicism (mT21) occurs when three copies of chromosome 21 are present in some but not all somatic cells in an individual. mT21 accounts for ≈ 2% of people diagnosed with Down syndrome (DS). Immunohistochemical identification of amyloid beta, tau, astrocytes, microglia, α-synuclein, and TAR DNA-binding protein 43 show that Alzheimer's disease (AD) pathology in mT21 is similar to full trisomy 21. The findings in this case report highlight that mT21 is sufficient to induce AD neuropathology and early-onset dementia.

Alzheimer's disease-like pathology induced by Porphyromonas gingivalis in middle-aged mice is mediated by NLRP3 inflammasome via the microbiota-gut-brain axis.

Porphyromonas gingivalis (P. gingivalis) has been found to enter the brain and induce inflammation, contributing to Alzheimer's disease (AD). P. gingivalis is also closely linked to gut dysbiosis. However, does P. gingivalis induce AD-like pathology through the microbiota-gut-brain axis? There is limited literature on this topic. To determine the precise causal link among P. gingivalis, intestinal inflammation, and AD-related pathology. 12- to 13-month-old female C57BL/6J mice were subjected to ligature placement and oral administration of P. gingivalis over a 24-week period. Then, cognitive performance was evaluated with behavioral tests, while AD neuropathological changes, neuroinflammation, and intestinal inflammation were assessed through qPCR, immunofluorescence, and western blot, and gut microbiota was analyzed by 16S rRNA. Mice exposed to P. gingivalis showed impaired behavior in open field test, novel object recognition, and Y-maze tests. The bacterium infiltrated their brains, increasing Aβ42, AβPP, and Aβ fragments, promoting tau phosphorylation and microglial activation, and reducing levels of ZO-1, PSD95, SYP, and NeuN proteins. Inflammatory factors like NLRP3, caspase-1, IL-1β, IL-6, and TNF-α were elevated in both brains and intestine, while ZO-1 and occludin levels decreased in intestine. P. gingivalis also altered gut microbial compositions. P. gingivalis induced gut dysbiosis and activated the NLRP3 inflammasome in the intestine and brains of mice. This led to impairment of both the intestinal and brain-blood barriers, triggering neuroinflammation and promoting the progression of AD. These findings highlight the critical role of NLRP3 inflammasome activation in the microbiota-gut-brain axis in the AD-like pathology induced by P. gingivalis.

Comorbidities in early-onset sporadic versus presenilin-1 mutation-associated Alzheimer disease dementia: Evidence for dependency on Alzheimer disease neuropathological changes.

Studying comorbidities in early onset Alzheimer disease (AD) may provide an advantageous perspective on their pathogenesis because aging factors may be largely inoperative for these subjects. We compared AD comorbidities between early-onset sporadic cases and American and Colombian cases with PSEN1 mutations. AD neuropathological changes (ADNC) were very severe in all groups but more severe in the PSEN1 groups. Lewy body disease and cerebral white matter rarefaction were the most common (up to 60%) of AD comorbidities, followed by arteriolosclerosis (up to 37%), and large-vessel atherosclerosis (up to 20%). Differences between the 3 groups included earlier age of onset in the American PSEN1 cases, shorter disease duration in sporadic cases, and more frequent large-vessel atherosclerosis and cerebral amyloid angiopathy in the Colombian PSEN1 cases. Logistic regression models adjusted for age and sex found the presence of a PSEN1 mutation, an apolipoprotein ε4 allele and TDP-43 pathology to predict an earlier age of onset; Hispanic ethnicity and multiracial subjects were predictive of severe CAA. Comorbidities are common in early onset AD and should be considered when planning clinical trials with such subjects. However, they may be at least partially dependent on ADNC and thus potentially addressable by anti-amyloid or and/anti-tau therapies.

Diagnosing Alzheimer Disease.

This article reviews the current understanding of Alzheimer disease (AD), including the natural history, common risk factors, and expected progression of AD neuropathologic change so that neurologists can apply this knowledge to identify patients with symptoms, signs, and findings on common diagnostic tests consistent with AD. The advent of potential disease-modifying therapies emphasizes the need to develop and deploy a practical and efficient approach to diagnose patients with cognitive impairment due to AD. The accumulation and spread of cerebral amyloid plaques and tau tangles in patients with AD leads to synaptic dysfunction, neuronal loss, and the eventual emergence and progression of cognitive impairment. A pragmatic and organized approach is needed to recognize patients with symptomatic AD in clinical practice, stage the level of impairment, confirm the clinical diagnosis, and apply this information to advance therapeutic decision making.

Cerebral Amyloid Angiopathy, Dementia, and Alzheimer Neuropathologic Changes: Findings From the ACT Autopsy Cohort.

Cerebral amyloid angiopathy (CAA) is common in older adults and is associated with dementia. Less is known whether this association is mediated by Alzheimer disease (AD) neuropathologic changes, the examination of which was the objective of this study. This was a retrospective cross-sectional examination of the Kaiser Permanente Washington database of the Adult Changes in Thought (ACT) autopsy cohort with information on CAA, dementia, the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) (amyloid neuritic plaques), and Braak (tau neurofibrillary tangles). CAA was diagnosed by immunohistochemistry and dementia by ACT Consensus Diagnostic Conference. AD neuropathology was categorized by CERAD scores and Braak stages. Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% CIs of the associations of CAA with dementia, adjusting for age at death and sex, and with additional adjustments separately for CERAD scores (moderate-severe vs mild-absent), Braak stages (V-VI vs 0-IV), APOE ε4, and stroke. Formal mediation analyses were conducted to estimate age-sex-adjusted OR (95% CI) for natural indirect effects (NIEs) of CERAD scores and Braak stages. The 848 participants had a mean age of 86.7 ± 4.6 years at death, and 57.6% were female. CAA was present in 322 participants (38.0%), of whom 152, 145, and 25 had mild, moderate, and severe CAA, respectively. Dementia was present in 384 participants (45.3%), of whom 317 had AD. Dementia was more common in those with CAA than without (53.7% vs 40.1%; age-sex-adjusted OR 1.57, 95% CI 1.18-2.10). This association remained significant after separate adjustment for other covariates but lost significance when adjusted for CERAD scores (OR 1.27, 95% CI 0.93-1.71) and Braak stages (OR 0.96, 95% CI 0.69-1.33). Findings from our formal mediation analyses show that ORs (95% CIs) for NIE of CERAD scores and Braak stages were 1.25 (1.13-1.37) and 1.63 (1.38-1.88), respectively, and CERAD scores and Braak stages mediated 53% and 111% of the total association, respectively. We observed a significant association between CAA and dementia that disappeared when adjusted for CERAD or Braak stages. Findings from our mediation analyses suggest that the CAA-dementia association may be potentially mediated by AD neuropathologic changes. This hypothesis needs to be tested in future mechanistic studies in AD accounting for unmeasured confounders.

Prevalence of mixed neuropathologies in age-related neurodegenerative diseases: A community-based autopsy study in China.

Despite extensive studies on mixed neuropathologies, data from China are limited. This study aims to fill this gap by analyzing brain samples from Chinese brain banks. A total of 1142 brains from six Chinese brain banks were examined using standardized methods. Independent pathologists conducted evaluations with stringent quality control. Prevalence and correlations of neurological disorders were analyzed. Significant proportions of brains displayed primary age-related tauopathy (PART, 35%), limbic-predominant age-related TDP-43 encephalopathy (LATE, 46%), and aging-related tau astrogliopathy (ARTAG, 12%). Alzheimer's disease neuropathological change (ADNC, 48%), Lewy body disease (LBD, 13%), and cerebrovascular disease (CVD, 63%) were also prevalent, often co-occurring with regional variations. CVD emerged as the potential most early contributor to neuropathological changes. This analysis highlights the prevalence of PART, LATE, ARTAG, ADNC, LBD, and CVD, with regional differences. The findings suggest CVD may be the earliest contributing factor, potentially preceding other neuropathologies. Highlights The prevalence of primary age-related tauopathy (PART), limbic-predominant age-related TDP-43 encephalopathy (LATE), aging-related tau astrogliopathy (ARTAG), Alzheimer's disease neuropathologic change, Lewy body disease, and cerebrovascular disease (CVD) in China, increasing with age, is comparable to other countries. Significant regional differences in the prevalences of diseases are noted. CVD develops prior to any other disorders, including PART, LATE, and ARTAG.

Medial temporal atrophy predicts the limbic comorbidities in lewy body disease.

Although neuropathological comorbidities, including Alzheimer's disease neuropathological change (AD-NC) and limbic-predominant age-related TAR DNA-binding protein 43encephalopathy neuropathological change (LATE-NC), are associated with medial temporal atrophy in patients with Lewy body disease (LBD), the diagnostic performance of magnetic resonance imaging (MRI)-derived indices remains unclear. This study aimed to investigate the diagnostic performance of MRI-derived indices representing medial temporal atrophy in differentiating between LBD with AD-NC and/or LATE-NC (mixed LBD [mLBD]) and without these comorbidities (pure LBD [pLBD]). This study included 24 and 16 patients with pathologically confirmed mLBD and pLBD, respectively. In addition to the well-known medial temporal atrophy and entorhinal cortex atrophy (ERICA) scores, the cross-sectional areas of the bilateral entorhinal cortices/parahippocampal gyri (ABEP) were segmented manually. Even incorporating various covariates such as age at MRI examination, sex, argyrophilic grain, the MRI-derived indices, especially ABEP, significantly correlated with the severity of AD-NC, and showed a trend of correlation with LATE-NC. For the differentiation between all mLBD and pLBD, the ERICA score and ABEP demonstrated higher diagnostic performance (area under the receiver-operating-characteristic curve [AUC] of 0.80 and 0.87, respectively). Additionally, the highest diagnostic performance for ABEP (AUC, 0.94; sensitivity, 100%; specificity, 88.9%; accuracy, 96%) was observed in differentiating between pLBD and mLBD with two comorbidities (AD-NC and LATE-NC). In patients with pathologically confirmed LBD, medial temporal atrophy was significantly correlated with AD-NC, and showed a trend of correlation with LATE-NC. Moreover, MRI-derived indices indicative of medial temporal atrophy were useful in diagnosing these comorbidities.

Hypertension may associate with cerebral small vessel disease and infarcts through the pathway of intracranial atherosclerosis

Hypertension, a major modifiable risk factor for cardiovascular diseases, is linked to late-life neurocognitive disorders such as vascular dementia and Alzheimer's disease (AD). This study explores the associations between hypertension, intracranial atherosclerotic disease (ICAD), cerebral small vessel disease (cSVD), and Alzheimer's disease neuropathologic change (ADNC) in a large community-based autopsy study.This cross-sectional study used data from the Biobank for Aging Studies of the University of São Paulo Medical School. Sociodemographic and clinical information was gathered from a reliable next-of-kin informant. Neurofibrillary tangles, neuritic plaques, lacunar infarcts, hyaline arteriolosclerosis, and cerebral amyloid angiopathy were evaluated. Causal mediation analyses with natural effect models were performed to examine indirect associations of hypertension with cerebrovascular pathologies and ADNC through morphometric measurements of intracranial artery lumen obstruction.Hypertensive participants (n = 354) presented a higher rate of stenosed arteries (obstruction ≥ 50 %), critically stenosed arteries (obstruction ≥ 70 %), and more severe ICAD, shown by higher maximum and mean obstruction indexes compared to nonhypertensive participants (n = 166). These measurements of atherosclerosis were associated with neurofibrillary tangles and cSVD lesions. Hypertension was indirectly associated with hyaline arteriolosclerosis and lacunar infarcts through the pathway of ICAD. Presenting hypertension indirectly increased the odds of displaying hyaline arteriolosclerosis by 26 % (95 % CI: 1.08, 1.45, p = 0.002) and lacunar infarcts by 17 % (95 % CI: 1.01, 1.35, p = 0.029). Cognitive and APOE ε4 carrier status did not alter the investigated associations. In this community sample, hypertension was indirectly associated with cSVD through ICAD.

Amygdala-predominant α-synuclein pathology is associated with exacerbated hippocampal neuron loss in Alzheimer's disease.

Misfolded α-synuclein protein accumulates in 43-63% of individuals with symptomatic Alzheimer's disease. Two main patterns of comorbid α-synuclein pathology have been identified: caudo-rostral and amygdala-predominant. α-Synuclein aggregates have been shown to interact with the transactive response DNA-binding protein 43 (TDP-43) and abnormally phosphorylated tau protein. All these proteins accumulate in the amygdala, which is anatomically connected with the hippocampus. However, the specific role of amygdala-predominant α-synuclein pathology in the progression of Alzheimer's disease and hippocampal degeneration remains unclear. In this cross-sectional study, we analysed 291 autopsy brains from both demented and non-demented elderly individuals neuropathologically. Neuronal density in the CA1 region of the hippocampus was assessed for all cases. We semiquantitatively evaluated α-synuclein pathology severity across seven brain regions and calculated a ratio of limbic to brainstem α-synuclein pathology severity, which was used to stratify the cases into two distinct spreading patterns. In the 99 symptomatic Alzheimer's disease cases, we assessed severity of limbic-predominant age-related TDP-43 neuropathological changes and CA1 phosphorylated tau density. We performed triple fluorescence staining of medial temporal lobe samples with antibodies against phosphorylated TDP-43, α-synuclein and phosphorylated tau. Finally, we employed path analysis to determine the association network of various parameters of limbic pathology in Alzheimer's disease cases and CA1 neuronal density. We identified an association between the amygdala-predominant αSyn pathology pattern and decreased neuronal density in the CA1 region. We found that Alzheimer's disease cases with an amygdala-predominant α-synuclein pattern exhibited the highest TDP-43 severity and prevalence of TDP-43 inclusions in the dentate gyrus among all groups, while those with the caudo-rostral pattern had the lowest severity of Alzheimer's disease neuropathological changes. We observed colocalization of TDP-43, aggregated α-synuclein and hyperphosphorylated tau in cytoplasmic inclusions within hippocampal and amygdala neurons of Alzheimer's disease cases. Path analysis modelling suggests that the relationship between amygdala-predominant α-synuclein pathology and CA1 neuron loss is partially mediated by hippocampal tau and TDP-43 aggregates. Our findings suggest that Alzheimer's disease cases with amygdala-predominant α-synuclein pathology may constitute a distinct group with more severe hippocampal damage, a higher TDP-43 burden and potential interactions among α-synuclein, TDP-43 and hyperphosphorylated tau.

Amyloid-β predominant Alzheimer's disease neuropathologic change.

Different subsets of Alzheimer's disease neuropathologic change (ADNC), including the intriguing set of individuals with severe/widespread Aβ plaques but no/mild tau tangles (Aβ-predominant ADNC, or AP-ADNC), may have distinct genetic and clinical features. Analyzing National Alzheimer's Coordinating Center data, we stratified 1,187 participants into AP-ADNC (n = 95), low Braak primary age related tauopathy (PART; n = 185), typical-ADNC (n = 832), and high-Braak PART (n = 75). AP-ADNC differed in some clinical features and genetic polymorphisms in the APOE, SNX1, WNT3/MAPT, and IGH genes. We conclude that AP-ADNC differs from classical ADNC with implications for in vivo studies.

Unraveling the interplay of β-amyloid pathology and Parkinson's disease progression: Insights from autopsy-confirmed patients

BackgroundParkinson's disease (PD) is a prevalent neurodegenerative disorder that manifests with both motor and non-motor symptoms, with α-synuclein misfolding recognized as a key contributor. Cognitive decline in advanced PD stages prompts interest in amyloid deposition, a hallmark of Alzheimer's disease (AD), as a potential factor. This study explores the impact of β-amyloid (Aβ) pathology in PD patients on disease progression, aiming to elucidate the role of Aβ in PD development and progression. MethodsThis study included autopsy-confirmed PD patients with post-mortem analyses from the Parkinson's Progression Markers Initiative. Comprehensive clinical assessments, including demographic data, clinical features, CSF markers, and neuroimaging, were conducted. Statistical analyses assessed differences between groups based on the severity of AD neuropathological changes. ResultsAll 16 PD participants exhibited severe Lewy body pathology, with 75 % displaying AD neuropathological changes. At baseline, PD patients with severe or moderate AD neuropathological changes had a lower Aβ42 levels (p = 0.022) and Aβ42/tau ratio (p = 0.001). Longitudinal follow-up data indicated that individuals with severe or moderate AD neuropathological changes exhibited a more rapid decline in MOCA score and BJLOT score, along with a quicker increase in MDS-UPDRS Ⅲ score. ConclusionsThe study underscores the presence of severe Aβ pathology in PD, suggesting a role in accelerated disease progression. Cross-seeding between Aβ and α-synuclein may contribute to rapid clinical symptom progression. Further research is needed for a comprehensive understanding of neurodegenerative disease complexities and exploring potential therapeutic interventions targeting protein aggregation.

The Alzheimer's Disease Neuroimaging Initiative Neuropathology Core: An update.

Biomarkers for Alzheimer's disease neuropathologic change (ADNC) have been instrumental in developing effective disease-modifying therapeutics. However, to prevent/treat dementia effectively, we require biomarkers for non-AD neuropathologies; for this, neuropathologic examinations and annotated tissue samples are essential. We conducted clinicopathologic correlation for the first 100 Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) cases. Clinical syndromes in this cohort showed 95% sensitivity and 79% specificity for predicting high/intermediate ADNC, a 21% false positive rate, and a ∼44% false negative rate. In addition, 60% with high/intermediate ADNC harbored additional potentially dementing co-pathologies. These results suggest that clinical presentation imperfectly predicts ADNC and that accurate prediction of high/intermediate ADNC does not exclude co-pathology that may modify presentation, biomarkers, and therapeutic responses. Therefore, new biomarkers are needed for non-AD neuropathologies. The ADNI NPC supports this mission with well-characterized tissue samples (available through ADNI and the National Institute on Aging) and "gold-standard" diagnostic information (soon to include digital histology). The Alzheimer's Disease Neuroimaging Initiative (ADNI) Neuropathology Core (NPC) brain donation cohort now exceeds 200 cases. ADNI NPC data in National Alzheimer's Coordinating Center format are available through the Laboratory of Neuro Imaging. Digitized slide files from the ADNI NPC will be available in 2025. Requests for ADNI brain tissue samples can be submitted online for ADNI/National Institute on Aging evaluation. Clinical diagnoses of Alzheimer's disease (AD)/AD and related dementias (ADRD) do not always predict post mortem neuropathology. Neuropathology is essential for the development of novel AD/ADRD biomarkers.