Cotton wool plaques (CWPs) have been described as features of the neuropathologic phenotype of dominantly inherited Alzheimer disease (DIAD) caused by some missense and deletion mutations in the presenilin 1 (PSEN1) gene. CWPs are round, eosinophilic amyloid-β (Aβ) plaques that lack an amyloid core and are recognizable, but not fluorescent, in Thioflavin S (ThS) preparations. Amino-terminally truncated and post-translationally modified Aβ peptide species are the main component of CWPs. Tau immunopositive neurites may be present in CWPs. In addition, neurofibrillary tangles coexist with CWPs. Herein, we report the structure of Aβ and tau filaments isolated from brain tissue of individuals affected by DIAD caused by the PSEN1 V261I and A431E mutations, with the CWP neuropathologic phenotype. CWPs are predominantly composed of type I Aβ filaments present in two novel arrangements, type Ic and type Id; additionally, CWPs contain type I and type Ib Aβ filaments. Tau filaments have the AD fold, which has been previously reported in sporadic AD and DIAD. The formation of type Ic and type Id Aβ filaments may be the basis for the phenotype of CWPs. Our data are relevant for the development of PET imaging methodologies to best detect CWPs in DIAD.

Human brain aging is characterized by the production and deposition of β-amyloid (Aβ) in the form of senile plaques and cerebral amyloid angiopathy and the intracellular accumulation of hyper-phosphorylated tau (Hp-tau) to form neurofibrillary tangles (NFTs) and dystrophic neurites of senile plaques. The process progresses for years and eventually manifests as cognitive impairment and dementia in a subgroup of aged individuals. Aβ is produced and deposited first in the neocortex in most aged mammals, including humans; it is usually not accompanied by altered behavior and cognitive impairment. Hp-tau is less frequent than Aβ pathology, and NFTs are rare in most mammals. In contrast, NFTs are familiar from middle age onward in humans; NFTs first appear in the paleocortex and selected brain stem nuclei. NFTs precede for decades or years Aβ deposition and correlate with dementia in about 5% of individuals at the age of 65 and 25% at the age of 85. Based on these comparative data, (a) Aβ deposition is the most common Alzheimer\'s disease neuropathological change (ADNC) in the brain of aged mammals; (b) Hp-tau is less common, and NFTs are rare in most aged mammals; however, NFTs are the principal cytoskeletal pathology in aged humans; (c) NFT in aged humans starts in selected nuclei of the brain stem and paleocortical brain regions progressing to the most parts of the neocortex and other regions of the telencephalon; (d) human brain aging is unique among mammalian species due to the early appearance and dramatic progression of NFTs from middle age onward, matching with cognitive impairment and dementia in advanced cases; (e) neither mammalian nor human brain aging supports the concept of the amyloid cascade hypothesis.

BACKGROUND: TRAILBLAZER-ALZ 4 demonstrated superiority of donanemab versus aducanumab at the 6-month primary endpoint of the percentage of participants achieving amyloid plaque clearance (<24.1 Centiloids [CL]) in patients with early symptomatic AD (Salloway et al. CTAD 2022).
METHODS: Participants (n = 148) were randomized 1:1 to receive donanemab (titration: 700mg IV Q4W [first 3 doses], then 1400mg IV Q4W [subsequent doses]) or aducanumab (titration per USPI: 1mg/kg IV Q4W [first 2 doses], 3mg/kg IV Q4W [next 2 doses], 6mg/kg IV Q4W [next 2 doses] and 10mg/kg IV Q4W [subsequent doses]). The study is ongoing with a total duration of 18 months.
RESULTS: Baseline demographics and characteristics were well-balanced across treatment arms (donanemab [N = 71], aducanumab [N = 69]). Twenty-seven donanemab-treated and 28 aducanumab-treated participants had low/medium (intermediate) tau levels based on screening tau PET scans. In all participants at 12 months, 70.2%±6.3% (least square [LS] mean ± standard error [SE]) donanemab-treated vs. 21.9%±5.9% aducanumab-treated participants achieved amyloid plaque clearance (p<0.001) assessed by florbetapir F18 PET scans. In the low/medium tau subpopulation, 80.0%±9.9% donanemab-treated vs. 9.6%±5.4% aducanumab-treated participants achieved amyloid clearance (p<0.001). The percent change (LS mean ± SE) in brain amyloid levels were -82.8%±3.1% (baseline [LS mean ± standard deviation]: 97.59±28.20 CL) and -57.0%±3.1% (baseline: 102.71±35.30 CL) in donanemab and aducanumab arms, respectively (p<0.001). In the low/medium tau subpopulation, percent change in brain amyloid levels were -82.7%±4.6% (baseline: 104.97±25.68 CL) and -57.0%±4.5% (baseline: 102.99±27.87 CL) in donanemab and aducanumab arms, respectively (p<0.001). Adverse events occurred in 78.9% of donanemab-treated and 82.6% of aducanumab-treated participants, respectively. Amyloid-related imaging abnormalities occurred in 29.6% (1.4% serious [n = 1]) and 40.6% (2.9% serious [n = 2]) of participants in the donanemab and aducanumab arms, respectively, with higher rates in ApoE4 carriers.
CONCLUSIONS: TRAILBLAZER-ALZ 4 provides the first active comparator data on amyloid plaque clearance in patients with early symptomatic AD and demonstrates the higher brain amyloid reduction of donanemab vs. aducanumab at 12 months when drug titration has been completed and the treatment regime has stabilized.

BACKGROUND: Genetic studies of Alzheimer\'s disease (AD) have shown association with microglia in the brain. We probed microglia with markers against amyloid-associated (Clec7a, Axl), inflammatory M1 (CD86), alternatively activated M2 (CD206, CD163), and homeostatic (P2ry12, TMEM119) phenotypes in low plaque/tangle pathology controls (A-T-), high plaque/low tangle pathology controls (A+,T-), high plaque/high tangle pathology controls (HPCs) and late AD samples. We sought to determine how these microglial markers changed with clinical and neuropathological AD. APOE status was also explored as its associated with increased inflammation (suggesting M1 effects) and APOE is highly expressed by amyloid-associated microglia.
METHODS: Samples of parietal cortex from AD patients were cryopreserved in 0.32M sucrose + inhibitors and obtained from the UC Irvine ADRC. The tissue was later thawed, homogenized in 0.32M sucrose + inhibitors and then slow frozen to -80°C. These samples were then processed and probed against targets of interest by western blotting.
RESULTS: Preliminary data shows a 64.7% decrease in P2ry12 signal in late AD compared to A-T- controls that approaches significance, although TMEM119 shows no changes. A similar pattern is seen in APOE4+(APOE3/4 and 4/4) samples compared to ones that are APOE3/3, with P2ry12 showing a significant decrease while TMEM119 showing no change. CD206 shows a 44.8% decrease in late AD samples relative to A-T- controls, though CD163 shows no difference. CD206 and CD163 do not differ between HPC and late AD samples, nor are they modulated by APOE genotype.
CONCLUSIONS: Preliminary data suggests a decrease of homeostatic microglial signature with the presence of neuropathological, not clinical, AD, although one of the markers, TMEM119, showed no change. TMEM119 and P2ry12 are interesting markers of homeostasis that were characterized in mouse models of AD yet may have a more complicated connection to human disease (Zhou et. al., 2020). M2 microglial marker CD206 shows an increase with neuropathological, but not clinical, AD. Again, a complicated picture of M2 markers is seen, with CD206 showing change but not CD163. APOE genotype differences modulated the P2ry12 homeostatic signal, although no M2 changes were seen.

Alzheimer\'s disease is the primary neurodegenerative disease affecting the elderly population. Despite the first description of its pathology over a century ago, its precise cause and molecular mechanism remain unknown. Numerous factors, including beta-amyloid, tau protein, the APOEε4 gene, and different metals, have been extensively investigated in relation to this disease. However, none of them have been proven to have a decisive causal relationship. Furthermore, no single theory has successfully integrated these puzzle pieces thus far. In this review article, we propose the most probable molecular mechanism for AD, which clearly shows the relationship between the main aspects of the disease, and addresses fundamental questions such as: Why is aging the major risk factor for the disease? Are amyloid plaques and tau tangles the causes or consequences of AD? Why are the distributions of senile plaques and tau tangles in the brain different and independent of each other? Why is the APOEε4 gene a risk factor for AD? Finally, why is the disease more prevalent in women?

BACKGROUND: Alzheimer\'s disease (AD) is characterised biologically by beta-amyloid (Aβ) plaques and tau tangles, but autopsy studies reveal that most older adults also present with cerebrovascular disease (CVD) markers. Effects of biological AD on cognition in the context of concurrent CVD remain unclear. In older adults with CVD pathology, this study sought to determine ante-mortem cognitive trajectories associated with Aβ/tau positivity or negativity (+/-) at autopsy.
METHODS: Participants aged 65-95 classified as cognitively unimpaired at baseline from the National Alzheimer\'s Coordinating Center database, with ≥1 follow-up between 2005-2015, and available autopsy/APOE data were included (N = 924). Autopsy indicated that all participants had at least one of six CVD pathology markers. Participants were classified into four groups (A-T-, A+T-, A-T+, A+T+) based on semiquantitative Consortium to Establish a Registry for Alzheimer\'s Disease neuritic plaque staging and Braak staging. Linear mixed models including group × time interactions assessed rate of change in Preclinical Alzheimer\'s Cognitive Composite scores, episodic memory, and executive function. Interactions between age, sex, APOE ε4 × time and the interval between death/the final study visit were included as covariates.
RESULTS: A+T+ adults demonstrated significantly faster cognitive decline on all outcomes in the ∼10 years preceding death compared to A-T-, A+T-, and A-T+ adults (Table 1, Figure 1, d = 0.15 - 0.39). At final visit prior to death, a greater proportion of A+T+ adults (36%) received a dementia diagnosis compared to A-T+ (14%) or A+T- (15%) (p <.001). When analyses were restricted to exclude dementia diagnoses, significantly faster decline on all outcomes (p\'s <.001, d = 0.06 - 0.36) was similarly observed in A+T+ adults compared to A-T-, A+T- and A-T+ adults (Figure 2). Cognitive trajectories were equivalent between A-T- and A+T- for all outcomes (p\'s >.55).
CONCLUSIONS: ln older adults with CVD pathology, A+T+ at autopsy was associated with greater cognitive decline over 10 years preceding death compared to A+T-, A-T+, and A-T- older adults. Faster cognitive decline in this group in the context of low final visit dementia diagnoses may suggest that post-mortem A+T+ is associated with a steep trajectory of cognitive decline ante-mortem, but that dementia progression is not inevitable.

Episodic memory in older adults is varied and perceived to rely on numbers of synapses or dendritic spines. We analyzed 2157 neurons among 128 older individuals from the Religious Orders Study and Rush Memory and Aging Project. Analysis of 55,521 individual dendritic spines by least absolute shrinkage and selection operator regression and nested model cross-validation revealed that the dendritic spine head diameter in the temporal cortex, but not the premotor cortex, improved the prediction of episodic memory performance in models containing β amyloid plaque scores, neurofibrillary tangle pathology, and sex. These findings support the emerging hypothesis that, in the temporal cortex, synapse strength is more critical than quantity for memory in old age.

Asymptomatic Alzheimer\'s disease (AsymAD) describes the status of individuals with preserved cognition but identifiable Alzheimer\'s disease (AD) brain pathology (i.e., beta-amyloid (Aβ) deposits, neuritic plaques, and neurofibrillary tangles) at autopsy. In this study, we investigated the postmortem brains of a cohort of AsymAD subjects to gain insight into the mechanisms underlying resilience to AD pathology and cognitive decline. Our results showed that AsymAD cases exhibit enrichment in core plaques, decreased filamentous plaque accumulation, and increased plaque-surrounding microglia. Less pathological tau aggregation in dystrophic neurites was found in AsymAD brains than in AD brains, and tau seeding activity was comparable to that in healthy brains. We used spatial transcriptomics to characterize the plaque niche further and revealed autophagy, endocytosis, and phagocytosis as the pathways associated with the genes upregulated in the AsymAD plaque niche. Furthermore, the levels of ARP2 and CAP1, which are actin-based motility proteins that participate in the dynamics of actin filaments to allow cell motility, were increased in the microglia surrounding amyloid plaques in AsymAD cases. Our findings suggest that the amyloid-plaque microenvironment in AsymAD cases is characterized by the presence of microglia with highly efficient actin-based cell motility mechanisms and decreased tau seeding compared with that in AD brains. These two mechanisms can potentially protect against the toxic cascade initiated by Aβ, preserving brain health, and slowing AD pathology progression.

BACKGROUND: It is not fully established whether plasma β-amyloid(Aβ)42/Aβ40 and phosphorylated Tau181 (p-Tau181) can effectively detect Alzheimer\'s disease (AD) pathophysiology in older Chinese adults and how these biomarkers correlate with astrocyte reactivity, Aβ plaque deposition, tau tangle aggregation, and neurodegeneration.
METHODS: We recruited 470 older adults and analyzed plasma Aβ42/Aβ40, p-Tau181, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) using the Simoa platform. Among them, 301, 195, and 70 underwent magnetic resonance imaging, Aβ and tau positron emission tomography imaging. The plasma Aβ42/Aβ40 and p-Tau181 thresholds were defined as ≤0.0609 and ≥2.418 based on the receiver operating characteristic curve analysis using the Youden index by comparing Aβ-PET negative cognitively unimpaired individuals and Aβ-PET positive cognitively impaired patients. To evaluate the feasibility of using plasma Aβ42/Aβ40 (A) and p-Tau181 (T) to detect AD and understand how astrocyte reactivity affects this process, we compared plasma GFAP, Aβ plaque, tau tangle, plasma NfL, hippocampal volume, and temporal-metaROI cortical thickness between different plasma A/T profiles and explored their relations with each other using general linear models, including age, sex, APOE-ε4, and diagnosis as covariates.
RESULTS: Plasma A+/T + individuals showed the highest levels of astrocyte reactivity, Aβ plaque, tau tangle, and axonal degeneration, and the lowest hippocampal volume and temporal-metaROI cortical thickness. Lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were independently and synergistically correlated with higher plasma GFAP and Aβ plaque. Elevated plasma p-Tau181 and GFAP concentrations were directly and interactively associated with more tau tangle formation. Regarding neurodegeneration, higher plasma p-Tau181 and GFAP concentrations strongly correlated with more axonal degeneration, as measured by plasma NfL, and lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 were related to greater hippocampal atrophy. Higher plasma GFAP levels were associated with thinner cortical thickness and significantly interacted with lower plasma Aβ42/Aβ40 and higher plasma p-Tau181 in predicting more temporal-metaROI cortical thinning. Voxel-wise imaging analysis confirmed these findings.
CONCLUSIONS: This study provides a valuable reference for using plasma biomarkers to detect AD in the Chinese community population and offers novel insights into how astrocyte reactivity contributes to AD progression, highlighting the importance of targeting reactive astrogliosis to prevent AD.

BACKGROUND: Brain inflammation contributes significantly to the pathophysiology of Alzheimer\'s disease, and it is manifested by glial cell activation, increased production of cytokines/chemokines, and a shift in lipid mediators from a pro-homeostatic to a pro-inflammatory profile. However, whether the production of bioactive lipid mediators is affected at earlier stages, prior to the deposition of Aβ plaques and tau hyperphosphorylation, is unknown. The differential contribution of an evolving amyloid and tau pathology on the composition and abundance of membrane phospholipids and bioactive lipid mediators also remains unresolved.
METHODS: In this study, we examined the cortical levels of DHA- and AA-derived bioactive lipid mediators and of membrane phospholipids by liquid chromatography with tandem mass spectrometry in transgenic rat models of the Alzheimer\'s-like amyloid and tau pathologies at early and advanced pathological stages.
RESULTS: Our findings revealed a complex balance between pro-inflammatory and pro-resolving processes in which tau pathology has a more pronounced effect compared to amyloid pathology. At stages preceding tau misfolding and aggregation, there was an increase in pro-resolving lipid mediators (RVD6 and NPD1), DHA-containing phospholipids and IFN-γ levels. However, in advanced tau pathology displaying NFT-like inclusions, neuronal death, glial activation and cognitive deficits, there was an increase in cytokine and PGD2, PGE2, and PGF2α generation accompanied by a drop in IFN-γ levels. This pathology also resulted in a marked increase in AA-containing phospholipids. In comparison, pre-plaque amyloid pathology already presented high levels of cytokines and AA-containing phospholipids together with elevated RVD6 and NPD1 levels. Finally, Aβ plaque deposition was accompanied by a modest increase in prostaglandins, increased AA-containing phospholipids and reduced DHA-containing phospholipids.
CONCLUSIONS: Our findings suggest a dynamic trajectory of inflammatory and lipid mediators in the evolving amyloid and tau pathologies and support their differing roles on membrane properties and, consequentially, on signal transduction.