Welcome to the AD/PD™ 2022 Interactive Program

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Displaying One Session

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114

APOE ISOFORMS DIFFERENTIALLY MODULATE THE ASSOCIATIONS BETWEEN REGIONAL TAU DEPOSITION AND NEUROINFLAMMATION IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
05:15 PM - 05:30 PM

Abstract

Aims

Apolipoprotein E (APOE) has been recognised as the most important genetic risk factors for sporadic Alzheimer disease (AD), with three allelic variants: APOE ε2, APOE ε3 and APOE ε4 exist. Neuroinflammation is considered one of the hallmarks of AD, and it manifests as the presence of both reactive astrocytes and microglia. Mounting evidence suggests that APOE modulates the brain inflammatory responses in an isoform-dependent manner. The role of APOE ε4 in neuroinflammation was interrogated in previous studies. However, relevance of these mechanisms in relation to other AD pathologies, such as tau deposition, still warrants further investigation.

Methods

This was a cross-sectional study examining a total number of 162 subjects from the TRIAD cohort at McGill University Research Centre for Studies in Aging. Cerebral tau neurofibrillary tangles were assessed using positron emission tomography (PET) radiopharmaceuticals [18F]MK6240. Cerebrospinal fluid (CSF) neuroinflammation biomarkers including soluble triggering receptor expressed on myeloid cells 2 (sTREM2), YKL40 and glial fibrillary acidic protein (GFAP) were also measured. Voxelwise analyses were performed to evaluate the relationships between regional tau burden and neuroinflammation biomarkers.

Results

Voxelwise analyses revealed that subjects with different APOE variants showed different relationships between neuroinflammation biomarkers and tau burden. Noteworthy, in APOE ε4 carriers, a significant correlation between neuroinflammation biomarkers and tau burden was found in medial temporal regions. These associations were absent in APOE ε2 and ε3 subjects, suggested APOE exerts immunomodulatory effects in an isoform-dependent way.

Conclusions

APOE isoforms differentially modulate the associations between regional tau deposition and neuroinflammation.

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APOE MISSENSE VARIANT R145C IS ASSOCIATED WITH INCREASED ALZHEIMER’S DISEASE RISK IN AFRICAN ANCESTRY INDIVIDUALS WITH THE APOE Ε3/Ε4 GENOTYPE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
05:30 PM - 05:45 PM

Abstract

Aims

The APOE gene has two common missense variants that greatly impact the risk of late-onset Alzheimer's disease (AD). Here we examined the risk of a third APOE missense variant, R145C, that is rare in European-Americans but common in African-Americans and always in phase with APOE-ε3 (Table 1).

Methods

We included 11,790 individuals of African ancestry (Table 2). The discovery sample was composed of next generation sequencing data (2,888 cases and 4,957 controls), and the replication was composed of imputed data (1,201 cases and 2,744 controls). In primary analyses, the AD risk associated with R145C was estimated using a linear-mixed-model regression on case-control diagnosis. In secondary analyses, we estimated the influence of R145C on age-at-onset using linear-mixed-model regression, and risk of conversion to AD using competing risk regression.

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Results

In ε3/ε4-stratified meta-analyses (Table 3), R145C carriers had a nearly three-fold increased risk compared to non-carriers (OR=2.75 [1.84; 4.11]; P=8.3x10-7) and had a reported AD age-at-onset nearly 6 years younger (β=-5.72 [7.87; 3.56]; P=2.0x10-7). Competing risk regression showed that the cumulative incidence of AD grows faster with age in R145C carriers compared to non-carriers (HR=2.42 [1.81; 3.25]; P=3.7x10-9; Figure 1).

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Conclusions

The R145C variant is a potent risk factor for AD among African ancestry individuals with the ε3/ε4 genotype. Our findings should enhance AD risk prediction in African ancestry individuals and help elucidate the mechanisms linking the apoE protein to AD pathogenesis. The findings add to the growing body of evidence demonstrating the importance of including ancestrally-diverse populations in genetic studies.

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APOE4 IMPAIRS MICROGLIA RESPONSE TO NEURODEGENERATION IN ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
05:45 PM - 06:00 PM

Abstract

Aims

APOE4 is the strongest genetic risk factor for late-onset Alzheimer’s disease (AD). We previously identified that APOE signaling governs the transcriptional regulation from homeostatic to neurodegenerative microglia (MGnD). However, the underlying mechanism for APOE4-mediated microglial dysregulation and its contribution to increased risk for developing AD, is unknown.

Methods

Here we aimed to dissect the impact of microglial APOE4 on AD pathology, using CX3CR1-CREERT2 mice crossed to APOE-KI(E3 and E4)fl/fl:APP/PS1.

Results

We identified reduced numbers of Clec7a+ MGnD-microglia per plaque in APP/PS1:APOE4-KI mice, despite their increased plaque load, compared with APP/PS1:APOE3-KI mice. Moreover, APOE4-KI mice challenged with labeled apoptotic neurons, failed to respond to acute neurodegeneration, depicted by reduced numbers of phagocytic MGnD-microglia at injection site compared with APOE3-KI mice. Here we show that conditional genetic deletion of APOE4 in microglia resulted in increased numbers of MGnD-microglia in response to acute neurodegeneration and in APP/PS1 mice. scRNAseq analysis showed increased proportion of MGnD-microglia in APP/PS1:APOE4 conditional KO mice, associated with reduced plaque pathology and increased astrocytic recruitment towards plaques. Furthermore, we show impaired induction of MGnD signature in AD brains of APOE4 carriers.

Conclusions

Our findings show that APOE4 is a negative regulator of MGnD-microglia in AD, and that its genetic deletion restores the induction of MGnD signature associated with reduction in plaque pathology. Taken together, these findings identify a cell-intrinsic role of APOE4 in the induction of dysfunctional MGnD microglia and their impaired response to neurodegeneration, which may provide new molecular targets to modulate and restore functional microglia in AD.

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IMPACT OF APOE ON AD/ADRD NEUROPATHOLOGIC LESIONS.

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
06:00 PM - 06:15 PM

Abstract

Aims

Alzheimer disease (AD) is primarily driven by genetics, though much is still unknown. The strongest genetic risk factor for AD is APOE, shown mostly in clinically diagnosed AD. To get closer to the underlying genetics, we investigate the neuropathological changes in the AD brain including neurofibrillary tangles (NFT), neuritic plaques (NP), and diffuse plaques (DP). AD lesions often co-occur with AD-related dementia (ADRD) lesions including Lewy Bodies (LB), cerebral amyloid angiopathy (CAA), arteriolosclerosis (ARTE), hippocampal sclerosis (HS), vascular brain injury (VBI), and TAR DNA-binding protein 43 (TDP-43) inclusions. Previously, we showed that higher lesion comorbidity is associated with more severe cognitive impairment. Herein, we report on the influence of the APOE genotype on AD/ADRD lesions.

Methods

Using the NACC database, we identified 3,787 individuals with neuropathology data and APOE genotype. Lesions were ranked ordinally based on increasing severity. APOE status was categorized by genotype. Ordinal logistic regression models assessed associations between APOE genotypes and lesions, adjusting for age at death and sex.

Results

Regression models show that APOE e4 is strongly associated with severity of NFT, NP, DP, and CAA (p<1.0E-10), and is nominally associated with TDP-43, LB, HS, and VBI (p<0.05), but not with the severity of ARTE (p>0.05).

Conclusions

APOE e2 behaves protectively against lesion severity while APOE e4 has a multiplicative risk effect on the 3 AD lesions, CAA, and TDP-43. The other ADRD lesions are not strongly associated with APOE genotypes and are likely influenced by other genetic factors.

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LOWER CSF APOE GLYCOSYLATION ASSOCIATES WITH MEASURES OF AD BIOMARKERS

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
06:15 PM - 06:30 PM

Abstract

Aims

Background: The mechanisms of how APOE4 allele (APOE4) increases the risk of Alzheimer’s disease (AD) pathology have not been fully elucidated. In cerebrospinal fluid (CSF), apoE is heavily glycosylated but its contributions to AD pathology is not known. ApoE’s glycosylation affects its binding to lipids and abeta peptides.

Methods

Total glycosylation and isoform-specific glycosylation were analyzed in plasma and CSF from a group of older individuals (n=106) from the University of Southern California ADRC cohort, grouped into cognitively normal individuals (n=75), those with mild cognitive impairment (n=14) and with AD dementia (n=17).

Results

In heterozygous individuals, the apoE3/E2, E4/E2, and E4/E3 isoform ratios were all significantly lower in plasma compared to CSF. The ratio of glycosylated to total apoE was greater in CSF compared to plasma for all apoE isoforms. In CSF but not plasma, ApoE4 was 35% and 25% less glycosylated (P<0.001) than ApoE2 and ApoE3, respectively. The % of secondary glycosylation was positively correlated with CSF Ab42 levels (R=0.55, p<0.001) and negatively correlated with CSF total Tau (R=-0.38, p=0.001). Patients with AD dementia had lower apoE % glycosylation than individuals with MCI (p=0.008).

Conclusions

Brain ApoE4 is less glycosylated than ApoE3 or ApoE2, and its degree of glycosylation correlates with markers of AD pathology. Ongoing experiments are delineating the effects of ApoE glycosylation on its functions. ApoE4 glycosylation may represent a newer target of treatment in AD.

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INTERIM RESULTS FROM PHASE 2 BIOMARKER STUDY WITH ORAL ANTI-AMYLOID AGENT ALZ-801: PLASMA BIOMARKERS IN APOE4 CARRIERS WITH EARLY ALZHEIMER’S DISEASE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
06:30 PM - 06:45 PM

Abstract

Abstract Body

Background
The core Alzheimer’s disease (AD) biomarkers, beta-amyloid and hyperphosphorylated tau (Aβ, p-tau), are useful in evaluating disease-modifying agents. ALZ-801, an oral, brain-penetrant, amyloid oligomer inhibitor, is evaluated as a disease-modifying treatment in two ongoing Early AD trials: Phase 2 study in APOE4 carriers and APOLLOE4 Phase 3 study in APOE4/4 homozygotes.

Objectives
Report preliminary 26-week results of plasma biomarkers and cognitive tests of the Phase 2 trial.

Methods
The ongoing Phase 2 biomarker study enrolled APOE4 carrier Early AD subjects (N=84) with A+/T+ CSF biomarkers, who receive ALZ-801 at 265mg BID for 2 years. The pre-specified primary analysis at 13 and 26 weeks is plasma p-tau181, with secondary cognitive outcomes. Biomarker analyses were performed, blinded to clinical information, at the Clinical Neurochemistry Laboratory, Gothenburg University, Sweden.

Results
In 80 patients (69 years, 51% female), who completed 26 weeks of treatment, significant mean reductions from baseline were seen at Week 13 and Week 26 timepoints: p-tau181 18% (p=0.038) and 29% (p=0.028); and p-tau181/Aβ42 21% (p=0.018) and 30% (p=0.022). The Rey Auditory Verbal Learning Test total memory scores (immediate + delayed) improved significantly at Week 26 (p=0.002). In 84 subjects, the most common adverse event was mild nausea, with no drug-related serious events and no evidence of vasogenic edema.

Conclusions
Preliminary analyses from Phase 2 trial show robust reductions in plasma p-tau181 and p-tau181/Aβ42 with memory improvement at 26 weeks. These results confirm target engagement of ALZ-801 in AD brain, and support disease modifying effects of ALZ-801 on core AD pathologies.
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PRE-RECORDED: THE PATHOPHYSIOLOGICAL ROLE OF MICROGLIAL APOE

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
06:45 PM - 07:00 PM
Presenter

Abstract

Abstract Body

Microglia are increasingly implicated in aging and Alzheimer’s disease (AD). Using an isogenic human ES-derived microglia (hMGLs) platform, we recently identified APOE as a convergent pathogenic node for microglial specific late-onset AD risk genes. APOE is abundantly expressed in astrocytes under physiological conditions and dramatically increased in microglia. However, whether microglial APOE exert different functions remains largely elusive. Here, we purified APOE particles derived from primary astrocytes and microglia including hMGLs, and integrate proteomic and lipidomic analysis and neuronal and glial functional test. We found that microglial APOE is more stable than astrocytic APOE, and the size of microglial APOE particles differs from that of astrocytes. In addition, we found that microglial APOE particles are more neurotoxic and more potent in inhibiting microglial migration and phagocytosis of Aβ. Further, microglial APOE particles altered homeostasis of microglia and astrocyte, and impaired mouse cognitive function. Together, our study demonstrates distinct functions of microglial APOE and provides new insights into the contribution of microglial APOE to AD pathogenesis.

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DISCUSSION

Session Type
SYMPOSIUM
Date
Thu, 17.03.2022
Session Time
05:15 PM - 07:15 PM
Room
ONSITE: 114
Lecture Time
07:00 PM - 07:15 PM