PSEN1 E280A Research Articles

Minocycline mitigates Aβ and TAU pathology, neuronal dysfunction, and death in the PSEN1 E280A cholinergic-like neurons model of familial Alzheimer’s disease

Familial Alzheimer’s disease (FAD) presenilin 1 E280A (PSEN1 E280A) is a severe neurological condition due to the loss of cholinergic neurons (ChNs), accumulation of amyloid beta (Aβ), and abnormal phosphorylation of the TAU protein. Up to date, there are no effective therapies available. The need for innovative treatments for this illness is critical. We found that minocycline (MC, 5 μM) was innocuous toward wild-type (WT) PSEN1 ChLNs but significantly (i) reduces the accumulation of intracellular Aβ by −69%, (ii) blocks both abnormal phosphorylation of the protein TAU at residue Ser202/Thr205 by −33% and (iii) phosphorylation of the proapoptotic transcription factor c-JUN at residue Ser63/Ser73 by −25%, (iv) diminishes oxidized DJ-1 at Cys106-SO3 by −29%, (v) downregulates the expression of transcription factor TP53, (vi) BH-3-only protein PUMA, and (vii) cleaved caspase 3 (CC3) by −33, −86, and −78%, respectively, compared with untreated PSEN1 E280A ChLNs. Additionally, MC increases the response to ACh-induced Ca2+ influx by +92% in mutant ChLNs. Oxygen radical absorbance capacity (ORAC) and ferric ion-reducing antioxidant power (FRAP) analysis showed that MC might operate more efficiently as a hydrogen atom transfer agent than a single electron transfer agent. In silico molecular docking analysis predicts that MC binds with high affinity to Aβ (Vina Score −6.6 kcal/mol), TAU (VS -6.5 kcal/mol), and caspase 3 (VS -7.1 kcal/mol). Taken together, our findings suggest that MC demonstrates antioxidant, anti-amyloid, and anti-apoptosis activity and promotes physiological ACh-induced Ca2+ influx in PSEN1 E280A ChLNs. The MC has therapeutic potential for treating early-onset FAD.

Basal forebrain volume and metabolism in carriers of the Colombian mutation for autosomal dominant Alzheimer's disease.

We aimed to study atrophy and glucose metabolism of the cholinergic basal forebrain in non-demented mutation carriers for autosomal dominant Alzheimer's disease (ADAD). We determined thelevel of evidence for or against atrophy and impaired metabolism of the basal forebrain in 167 non-demented carriers of the Colombian PSEN1 E280A mutation and 75 age- and sex-matched non-mutation carriers of the same kindred using a Bayesian analysis framework. We analyzed baseline MRI, amyloid PET, and FDG-PET scans of the Alzheimer's Prevention Initiative ADAD Colombia Trial. We found moderate evidence against an association of carrier status with basal forebrain volume (Bayes factor (BF10) = 0.182). We found moderate evidence against a difference of basal forebrain metabolism (BF10 = 0.167). There was only inconclusive evidence for an association between basal forebrain volume and delayed memory and attention (BF10 = 0.884 and 0.184, respectively), and between basal forebrain volume and global amyloid load (BF10 = 2.1). Our results distinguish PSEN1 E280A mutation carriers from sporadic AD cases in which cholinergic involvement of the basal forebrain is already detectable in the preclinical and prodromal stages. This indicates an important difference between ADAD and sporadic AD in terms of pathogenesis and potential treatment targets.

Neuroprotective Effect of Combined Treatment with Epigallocatechin 3-Gallate and Melatonin on Familial Alzheimer's Disease PSEN1 E280A Cerebral Spheroids Derived from Menstrual Mesenchymal Stromal Cells.

Familial Alzheimer's disease (FAD) is caused by mutations in one or more of 3 genes known as AβPP, PSEN1, and PSEN2. There are currently no effective therapies for FAD. Hence, novel therapeutics are needed. To analyze the effect of treatment with a combination of epigallocatechin-3-gallate (EGCG) and Melatonin (N-acetyl-5-methoxytryptamine, aMT) in a cerebral spheroid (CS) 3D in vitro model of PSEN 1 E280A FAD. We developed a CS in vitro model based on menstrual stromal cells derived from wild-type (WT) and mutant PSEN1 E280A menstrual blood cultured in Fast-N-Spheres V2 medium. Beta-tubulin III, choline acetyltransferase, and GFAP in both WT and mutant CSs spontaneously expressed neuronal and astroglia markers when grown in Fast-N-Spheres V2 medium for 4 or 11 days. Mutant PSEN1 CSs had significantly increased levels of intracellular AβPP fragment peptides and concomitant appearance of oxidized DJ-1 as early as 4 days, and phosphorylated tau, decreased ΔΨm, and increased caspase-3 activity were observed on Day 11. Moreover, mutant CSs were unresponsive to acetylcholine. Treatment with a combination of EGCG and aMT decreased the levels of all typical pathological markers of FAD more efficiently than did EGCG or aMT alone, but aMT failed to restore Ca2+ influx in mutant CSs and decreased the beneficial effect of EGCG on Ca2+ influx in mutant CSs. Treatment with a combination of EGCG and aMT can be of high therapeutic value due to the high antioxidant capacity and anti-amyloidogenic effect of both compounds.

APOE3 Christchurch modulates β-catenin/Wnt signaling in iPS cell-derived cerebral organoids from Alzheimer's cases.

A patient with the PSEN1 E280A mutation and homozygous for APOE3 Christchurch (APOE3Ch) displayed extreme resistance to Alzheimer's disease (AD) cognitive decline and tauopathy, despite having a high amyloid burden. To further investigate the differences in biological processes attributed to APOE3Ch, we generated induced pluripotent stem (iPS) cell-derived cerebral organoids from this resistant case and a non-protected control, using CRISPR/Cas9 gene editing to modulate APOE3Ch expression. In the APOE3Ch cerebral organoids, we observed a protective pattern from early tau phosphorylation. ScRNA sequencing revealed regulation of Cadherin and Wnt signaling pathways by APOE3Ch, with immunostaining indicating elevated β-catenin protein levels. Further in vitro reporter assays unexpectedly demonstrated that ApoE3Ch functions as a Wnt3a signaling enhancer. This work uncovered a neomorphic molecular mechanism of protection of ApoE3 Christchurch, which may serve as the foundation for the future development of protected case-inspired therapeutics targeting AD and tauopathies.

Genetic modifiers of cognitive decline in PSEN1 E280A Alzheimer's disease.

Rate of cognitive decline (RCD) in Alzheimer's disease (AD) determines the degree of impairment for patients and of burden for caretakers. We studied the association of RCD with genetic variants in AD. RCD was evaluated in 62 familial AD (FAD) and 53 sporadic AD (SAD) cases, and analyzed by whole-exome sequencing for association with common exonic functional variants. Findings were validated in post mortem brain tissue. One hundred seventy-two gene variants in FAD, and 227 gene variants in SAD associated with RCD. In FAD, performance decline of the immediate recall of the Rey-Osterrieth figure test associated with 122 genetic variants. Olfactory receptor OR51B6 showed the highest number of associated variants. Its expression was detected in temporal cortex neurons. Impaired olfactory function has been associated with cognitive impairment in AD. Genetic variants in these or other genes could help to identify risk of faster memory decline in FAD and SAD patients.

APOE3 Christchurch heterozygosity delays clinical onset in autosomal dominant Alzheimer’s disease

AbstractBackgroundWe previously reported a case of a homozygous woman with the APOE3 Christchurch (R136S, APOE3Ch) variant who demonstrated extreme resistance to autosomal dominant Alzheimer’s disease (ADAD) caused by the PSEN1 E280A variant. In this study, we examined the potential protective effects of APOE3Ch against ADAD by characterizing the clinical profile of individuals who were heterozygous for the APOE3Ch variant from the Colombian kindred with the PSEN1 E280A variant.MethodsA total of 421 carriers of the PSEN1 E280A variant were included. Of the 421 carriers, 12 were heterozygous for APOE3Ch (including the previously reported homozygous for APOE3Ch). Clinical and neuropsychological assessments were performed in Spanish at the University of Antioquia in Colombia. Four of the APOE3Ch carriers also donated their brains for postmortem studies. A PSEN1 E280A who is heterozygous for the APOE3Ch variant also underwent structural MRI and amyloid and tau PET imaging.ResultsOur findings showed that PSEN1 E280A carriers who are heterozygous carriers of the APOE3Ch variant had a significantly delayed onset for mild cognitive impairment (MCI, median age of 51 vs. 45 years; p = 0.0048) and dementia (52.5 vs. 48 years; p = 0.016), compared to PSEN1 E280A carriers without the APOE3Ch variant. Specifically, APOE3Ch carriers had seven‐time higher odds of developing MCI and three‐time higher odds of developing dementia at a later age than 75% of all the PSEN1 E280A carriers (odds ratio [OR] = 7.6; 95% confidence interval [CI] 1.9, 29.2, p<0.05); dementia OR = 3.07; 95% CI 1.01, 9.33). Initial characterization of brain imaging of a PSEN1 E280A carrier who is heterozygous for the APOE3Ch variant showed levels of medial temporal lobe tau pathology and hippocampal atrophy that were lower than expected for a typical carrier of their age, and similar to our observations in the previously reported APOE3Ch homozygote case.ConclusionsThese clinical, cognitive, and neuroimaging data provide evidence that APOE3Ch heterozygosity delays the onset of cognitive decline and may have a protective, dose‐dependent effect against tau pathology and neurodegeneration. These results provide support for the potential of the APOE3Ch variant as a target for the development of new treatments for AD.

Proteomic characterization of small vessel pathology in PSEN1 E280A familial Alzheimer’s disease

AbstractBackgroundVascular pathology is a main contributor to Alzheimer’s disease (AD) progression and severity. We have previously characterized vascular pathology in the PSEN1E280A Colombian kindred. In postmortem analyses we identified that the occipital cortex (OC) is the most affected region by small vessel disease (SVD), including other cortical areas and basal ganglia. Interestingly, frontal cortex (FC) is spared from tau pathology in protected PSEN1E280A cases, while the OC is not. Here we study the proteome of isolated vessels from frontal and occipital cortices to identify differences in molecular pathways.MethodApproximately 400 mg of FC and OC of postmortem brain tissue from PSEN1E280A familial AD (FAD, n = 10), sporadic AD (SAD, n = 10) and controls (HC, n = 5) were homogenized, centrifuged at 2000 g / 5 minutes before using gradient centrifugation at 10000 g / 15 minutes with dextran to receive the microvessel containing pellet which was retrieved and resuspended in lysis buffer for tandem mass tag (TMT) proteomics. Proteomics spectral data were matched to peptide sequences in the human UniProt protein database using the MaxQuant software package. The MaxQuant output files were analysed by MSstatsTMT using R software for statistical analysis. clusterProfiler package was used to perform Gene Ontology enrichment analyses.ResultMicrovessels isolated from AD OC showed 1597 significantly dysregulated proteins when compared to controls, while FC showed 523. FAD showed the majority of upregulated proteins in FC (181 > 88 in SAD), and OC (428 > 84). This pattern was similar in downregulated proteins in the OC (391>171), but not in the FC (106<156) (Fig. 1A). The comparison between FAD cases and controls was the only one that identified a variety of biological processes (BP) during Protein set enrichment analysis. Notably, FAD FC showed upregulation of BP associated to vessel proliferation (Fig. 1B), while the OC showed downregulation of BP associated to immune system and mRNA regulation (Fig. 1C).ConclusionWe have identified the OC as a critical region of FAD pathology. Proteomic analysis of isolated microvessels from this region point towards a more deleterious profile while the FC microvessel proteome indicates an earlier stage of SVD pathology.

Informed consent process experience in Alzheimer’s Prevention Initiative (API) Autosomal Dominant Alzheimer’s Disease Colombia trial

AbstractBackgroundRecruiting cognitively‐unimpaired volunteers at high genetic risk of developing dementia into the Alzheimer’s Prevention Initiative (API) Colombia trial, and maintaining study adherence for at least 5 years has been a monumental challenge. Major barriers included inclusion criteria, protocol visit schedule, long informed consent form (ICF), low levels of education of participants, misconceptions about participating in a clinical trial, and blinding to genetic status and treatment arm. We explain how our group went out of the conventional and traditional schemes of informed consent while adhering to good clinical practice and developed a novel approach to the consent process for potential candidates.MethodThe identification, community education, and follow‐up of affected PSEN1 E280A families for the past three decades was the initial fundamental step to initiate a proper ICF process for the study. Then the launch of API Colombia Registry in 2010 was the base for appropriate preparation for the prevention trial. The process for API Colombia trial included step by step strategies, such as: a pre‐screening process developed by the team, pre‐consent informational meeting with the principal investigator in small groups of potential candidates, illustrated materials like a booklet titled “What I should know about informed consent and my decision to participate”, and detailed infographics as a complementary material to main study ICF, use of a voluntary pre‐selection survey. The screening visit was divided in parts: discussion with the sub‐investigator about clinical trial participation, review of participant’s questions, and signatures according to regulatory requirements.ResultFrom 623 potentially eligible registrants for pre‐screening, 319 were consented and underwent full eligibility screening and 252 were randomized. After eight years of study duration, 94% of participants completed the protocol, 90.5% completed the trial on treatment. Most participants who dropped out of the study did it due to incompatibility with work, unexpected pregnancy, or the decision to have children.ConclusionWe attribute successful trial adherence to the consent process that led to a well‐informed, voluntary, and responsible decision, and the participant’s understanding of the unique contribution they can make to change the world by participating in clinical research.

Longitudinal effects of sex on pathology accumulation, neurodegeneration and cognitive decline in Presenilin‐1 E280A mutation carriers: preliminary findings from the Colombia‐Boston (COLBOS) biomarker study

AbstractBackgroundPrevious work showed that females at risk for autosomal dominant Alzheimer’s disease (AD) due to a single mutation (E280A) in the Presenilin‐1 gene (PSEN1) may have greater cognitive resilience to AD‐pathology and neurodegeneration than males. However, more research is needed to clarify the effect of sex on AD risk and progression. We investigated the effects of sex on rates of amyloid and tau accumulation, neurodegeneration, and memory decline in PSEN1 mutation carriers with and without cognitive impairment, who are genetically determined to develop early‐onset dementia.MethodA total of 66 cognitively unimpaired mutation carriers (mean age of 34.41 +/‐ 4.86 years; 38 females), and 23 cognitively impaired mutation carriers (mean age of 44.91 +/‐ 2.83 years; 17 females) from the Colombia‐Boston Biomarker (COLBOS) study completed baseline cognitive assessments. A subset of 52 participants also completed florbetapir‐ and flortaucipir‐PET, and structural MRI. Cognitive and neuroimaging follow‐up visits were completed at 2‐ (n = 29) and 4‐year (n = 13) intervals. We used linear mixed‐effects models, with random intercepts, to predict rate of change in MMSE scores, CERAD word list delayed recall, cortical amyloid burden, tau in the entorhinal, inferior temporal, and precuneus cortices, and hippocampal volume by sex, controlling for education.ResultOver time, carriers exhibited greater cortical amyloid burden (p<.001), inferior temporal tau (p = .019), precuneus tau (p = .003), lower hippocampal volume (p = .005), and showed a trend towards lower MMSE scores (p = .059) and word list delayed recall (p<.080); entorhinal tau did not significantly increase (p = .137). Female carriers showed a steeper decline in word list delayed recall than male carriers (p = .021). There were no sex differences in the rate of accumulation of mean cortical amyloid or regional tau, hippocampal atrophy, or change in MMSE scores (all ps>.05).ConclusionPreliminary findings of this ongoing study suggest that despite similar rates of pathology accumulation or atrophy between female and male PSEN1 E280A carriers, female mutation carriers may have faster memory decline. Future analyses with additional participants and follow‐up intervals are needed to characterize sex differences in ADAD risk and resilience, as well as inform development of treatments and interventions.

Statistical innovations in the API ADAD Colombia trial: a randomized, double‐blind, placebo‐controlled, parallel‐group study in cognitively unimpaired PSEN1 E280A mutation carriers evaluating efficacy and safety of crenezumab

AbstractBackgroundA number of extended families in Colombia with early‐onset ADAD have a PSEN1 mutation at codon 280 (E280A), comprise the largest ADAD kindred in the world. Trial participants have been treated with crenezumab (an experimental anti‐amyloid monoclonal antibody) or placebo. Topline results were presented in August, 2022 at AAIC. Although the trial did not demonstrate a statistically significant clinical benefit in either of its co‐primary endpoints, multiple statistical innovations were incorporated into this trial.MethodThe API ADAD Colombia trial is a randomized, double‐blind, placebo‐controlled, parallel‐group phase 2b study evaluating the efficacy, safety, and tolerability of crenezumab in cognitively unimpaired ADAD PSEN1 E280A mutation carriers in Colombia (NCT01998841). Due to under enrollment and concerns with the sensitivity of the primary endpoint, the protocol was amended mid‐trial to change from 260 weeks of treatment to a common‐close design whereby treatment continued in the double‐blind portion until the last enrolled participant received 260 weeks of treatment. Because of the change in trial design and power considerations, the primary analysis was adapted from a traditional mixed model with repeated measures (MMRM) based analysis to a random coefficient regression model (RCRM) based analysis. To quantitatively examine the adequacy of the RCRM assumptions, a robust variance estimator (Huber 1967; White 1982) was prespecified as a sensitivity analysis to calculate the standard errors and p‐values of the co‐primary endpoints. This study used a type‐I‐error‐controlled statistical procedure to identify and elevate the Free and Cued Selective Reminding Test (FCSRT) cueing index to a co‐primary endpoint. To comprehensively assess the crenezumab effect across primary and secondary endpoints, the prespecified relative reduction point estimates along with the bootstrapped 95% confidence intervals were generated.ResultInnovative statistical methods in this trial will be presented.ConclusionAlthough the API Colombia study did not meet its co‐primary endpoints, statistical learnings from this trial can benefit development of future AD trials. To further maximize the value of this unique trial dataset, participant‐level data will be made publicly available, including clinical, imaging, and biomarker data.Funding: NIA grants RF1‐AG041705, R01‐AG055444, Genentech, Roche, philanthropic contributions to Banner Alzheimer’s Foundation. FlorbetapirPET was partly supported by Avid and Lilly.

Functional and structural changes of cholinergic basal forebrain in asymptomatic PSEN1 E280A mutation carriers compared with non‐mutation carriers from the API ADAD Colombia cohort

AbstractBackgroundImaging studies showed early atrophy of the cholinergic basal forebrain in prodromal sporadic Alzheimer’s disease (AD) and alterations of the posterior basal forebrain functional connectivity in amyloid positive, but cognitively normal people. Similar investigations in familial cases of AD are still lacking. Here we investigated whether basal forebrain volume, metabolism, and posterior connectivity were already reduced in preclinical stages of autosomal dominant AD.MethodWe analyzed baseline data from 242 cognitively unimpaired subjects (69% PSEN1 E280A mutation carriers; mean age = 38 years; 62% female; mean education = 9 years) enrolled in the API ADAD Colombia Trial including available MRI, FDG‐PET and cognitive measures. We determined volume and metabolism of the basal forebrain, and of the hippocampus as a comparison region. In addition, we created connectivity maps from resting state fMRI data using anterior and posterior BF seed regions. We carried out Bayesian ANCOVA to determine evidence in favor or against an effect of carriers’ status on volumes, metabolism, functional connectivity and cognitive scores.ResultWe found inconclusive to moderate evidence in favor of no effect of carrier status on basal forebrain (BF10 = 0.884) and hippocampal volumes (BF10 = 0.964) or metabolism (BF10 = 0.187) (see Figure) in preclinical (CDR = 0) and prodromal (CDR = 0.5) subjects. However, we found extreme evidence that delayed memory was decreased already in preclinical mutation carriers (BF10 = 4066.73). Yet, we found no conclusive evidence that this subtle memory impairment was associated with basal forebrain (BF10 = 0.582) or hippocampal (BF10 = 0.906) atrophy.ConclusionOur findings indicate absence of basal forebrain and hippocampus atrophy or metabolic impairment in preclinical mutation carriers. Interestingly, memory impairment was already present in preclinical mutation carriers. This is consistent with results of the Dominantly Inherited Alzheimer Network (DIAN) cohort showing early cognitive impairment in mutation carriers, but no significant group differences in hippocampal volume until later stages of the disease. These previous and our findings may suggest that different brain regions and networks are affected in preclinical stages of familial AD than in preclinical sporadic AD, which should be investigated in future studies.

Prevalence and pathological correlates of unawareness of memory impairment in non‐demented individuals with autosomal dominant Alzheimer’s disease: an item‐level investigation of the Memory Complaints Scale

AbstractBackgroundAwareness of memory was previously found to be reduced in the pre‐dementia stages, reaching unawareness/anosognosia 6‐years before dementia onset in individuals who carry the PSEN1 E280A mutation for autosomal dominant Alzheimer’s disease (Vannini et al.,2021). Whether there are potential differences in awareness for specific types of situations involving memory as well as their association with molecular markers of AD disease progression in preclinical AD is unknown. Here, we investigated memory awareness on an item‐level basis as well as its relationship to neocortical amyloid and regional tau levels in non‐demented mutation carriers and non‐carrier family members.MethodA total of 119 Colombian kindred members, 56 carriers (7 mildly impaired) and 63 non‐carriers were included (Table.1). Awareness indexes were calculated using participant and study‐partner discrepancy scores for each of the 15 questions of the Memory Complaint Scale (Spanish version). A score of ≥0 indicates that the participant is aware and <0 unaware. A subset of 67 kindred members (N = 31 carriers, 1 impaired) underwent amyloid (PiB) and tau (FTP) scans. For each question, odds ratio and Fisher’s exact test were used to evaluate prevalence of awareness/unawareness in carriers and non‐carriers. Pearson correlations, corrected for multiple comparisons, were used to assess the associations between awareness and pathology in the mutation carriers.ResultMutation carriers had significantly decreased overall awareness (p = 0.03), increased mean cortical amyloid (p<0.001) and inferior temporal tau (p = 0.001), compared to non‐carriers. Two questions (items 10 and 15), showed significantly lower awareness in the carriers than non‐carriers (both p = 0.002, Table.2). These results remained significant after removing impaired carriers. In carriers, decreased awareness was related to increased tau for 5/15 (33%) questions (Table.3 and Figure.1). No significant associations were found between awareness and amyloid.ConclusionOur results support previous findings that awareness is decreased in pre‐dementia stages of AD and related to tau, and not to amyloid pathology (Gagliardi et al.,2021). Importantly, we found that loss of awareness of specific memory items could differentiate carriers from non‐carriers. These findings support the usefulness of study‐partner‐reported cognitive decline. Individuals who become unaware of cognitive changes may represent a specific risk group to harbor pathology and develop AD dementia.

PSEN1 E280A Cholinergic-like Neurons and Cerebral Spheroids Derived from Mesenchymal Stromal Cells and from Induced Pluripotent Stem Cells Are Neuropathologically Equivalent.

Alzheimer's disease (AD) is a chronic neurological condition characterized by the severe loss of cholinergic neurons. Currently, the incomplete understanding of the loss of neurons has prevented curative treatments for familial AD (FAD). Therefore, modeling FAD in vitro is essential for studying cholinergic vulnerability. Moreover, to expedite the discovery of disease-modifying therapies that delay the onset and slow the progression of AD, we depend on trustworthy disease models. Although highly informative, induced pluripotent stem cell (iPSCs)-derived cholinergic neurons (ChNs) are time-consuming, not cost-effective, and labor-intensive. Other sources for AD modeling are urgently needed. Wild-type and presenilin (PSEN)1 p.E280A fibroblast-derived iPSCs, menstrual blood-derived menstrual stromal cells (MenSCs), and umbilical cord-derived Wharton Jelly's mesenchymal stromal cells (WJ-MSCs) were cultured in Cholinergic-N-Run and Fast-N-Spheres V2 medium to obtain WT and PSEN 1 E280A cholinergic-like neurons (ChLNs, 2D) and cerebroid spheroids (CSs, 3D), respectively, and to evaluate whether ChLNs/CSs can reproduce FAD pathology. We found that irrespective of tissue source, ChLNs/CSs successfully recapitulated the AD phenotype. PSEN 1 E280A ChLNs/CSs show accumulation of iAPPβ fragments, produce eAβ42, present TAU phosphorylation, display OS markers (e.g., oxDJ-1, p-JUN), show loss of ΔΨm, exhibit cell death markers (e.g., TP53, PUMA, CASP3), and demonstrate dysfunctional Ca2+ influx response to ACh stimuli. However, PSEN 1 E280A 2D and 3D cells derived from MenSCs and WJ-MSCs can reproduce FAD neuropathology more efficiently and faster (11 days) than ChLNs derived from mutant iPSCs (35 days). Mechanistically, MenSCs and WJ-MSCs are equivalent cell types to iPSCs for reproducing FAD in vitro.

Effects of APOE4 and education on the clinical onset of autosomal dominant Alzheimer’s disease due to the PSEN1 E280A mutation (S39.004)

<h3>Objective:</h3> Determine the impact of APOE4 genotype and education on the clinical onset of autosomal dominant Alzheimer’s disease. <h3>Background:</h3> Autosomal dominant Alzheimer’s disease (ADAD) is genetically determined, but variability in age of symptom onset suggests it may be influenced by additional genetic and environmental risk factors. Although the e4 allele of the apolipoprotein E (APOE4) gene and education level both influence clinical onset of dementia in sporadic Alzheimer’s disease (AD), it is unclear whether APOE4 affects onset of ADAD. Here, we investigated the effects of APOE4 and education on the clinical onset of ADAD. <h3>Design/Methods:</h3> We analyzed retrospective data from 675 presenilin-1 (<i>PSEN1</i>) E280A mutation carriers (141 APOE4 carriers, 534 APOE4 non-carriers) and 594 <i>PSEN1</i> non-carriers (148 APOE4 carriers, 446 APOE4 non-carriers) from a Colombian kindred with ADAD. We used the Mini-Mental State Examination (MMSE) as a proxy for clinical impairment. Model parameters in both <i>PSEN1</i> carriers and non-carriers were estimated using a Hamiltonian Markov chain Monte Carlo method. The age-related trajectories of APOE4 carriers versus non-carriers were compared in both <i>PSEN1</i> carriers and non-carriers. <h3>Results:</h3> In <i>PSEN1</i> carriers, lower MMSE scores began to significantly differentiate APOE4 carriers from non-carriers at age 45, the average age of mild cognitive impairment onset in this kindred. Years of education moderated the effect of APOE such that APOE4 carriers with lower educational levels had lower average MMSE scores in comparison to APOE4 non-carriers. <h3>Conclusions:</h3> Our findings suggest 1) age-related changes in global cognitive function may be accelerated in ADAD mutation carriers who are APOE4 carriers, compared to APOE4 non-carriers; and 2) higher educational levels may have a protective effect against cognitive impairment, even in the presence of genetic risk factors. Further longitudinal studies are necessary to clarify the impact of both education and APOE4 genotype on ADAD clinical progression. <b>Disclosure:</b> Mr. Barksdale has nothing to disclose. The institution of Dr. Langella has received research support from Alzheimer’s Association. Dr. Vasquez has nothing to disclose. David Fernando Aguillon, Sr. has nothing to disclose. Yinghua Chen has nothing to disclose. Dr. Su has nothing to disclose. Dr. ACOSTA-BAENA has nothing to disclose. Juliana Acosta Uribe has nothing to disclose. Ana Baena has nothing to disclose. Gloria Garcia-Ospina has nothing to disclose. Margarita Giraldo-Chica has nothing to disclose. Victoria Tirado has nothing to disclose. Mrs. Munoz has nothing to disclose. Miss Guzman Martinez has nothing to disclose. Dr. Rios Romenets has nothing to disclose. Mr. Oliveira has nothing to disclose. Dr. Yang has received personal compensation in the range of $500-$4,999 for serving as a invited speaker with Genentech, Inc.. The institution of Clara Vila-Castelar has received research support from Alzheimer’s Association. The institution of Clara Vila-Castelar has received research support from NIA . The institution of Dr. Pruzin has received research support from Alzheimer’s Association. Dr. Ghisays has received personal compensation for serving as an employee of Banner Alzheimer’s Institute. Joseph Arboleda-Velasquez has nothing to disclose. Dr. Kosik has received personal compensation in the range of $50,000-$99,999 for serving as an officer or member of the Board of Directors for Rainwater Foundation. The institution of Dr. Kosik has received research support from National Institute of Health. The institution of Dr. Kosik has received research support from Hillblom Foundation. The institution of Dr. Kosik has received research support from Adelson Medical Foundation. The institution of Dr. Kosik has received research support from Alzheimer Association/Rainwater Foundation. The institution of Dr. Kosik has received research support from Thome Memorial FOundation. Dr. Reiman has received personal compensation in the range of $50,000-$99,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Denali, Green Valley, Zinfandel, and Takeda. Dr. Reiman has received stock or an ownership interest from Alkahest, Alzheon, Aural Analytics, Denali, and United Neuroscience.. Dr. Reiman has received intellectual property interests from a discovery or technology relating to health care. Dr. Reiman has received personal compensation in the range of $500-$4,999 for serving as a Member, National Advisory Council on Aging (NACA) with NIA. Francisco Lopera has nothing to disclose. Dr. Quiroz has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Quiroz has received intellectual property interests from a discovery or technology relating to health care.

Genetic associations with age at dementia onset in the PSEN1 E280A Colombian kindred.

Genetic associations with Alzheimer's disease (AD) age at onset (AAO) could reveal genetic variants with therapeutic applications. We present a large Colombian kindred with autosomal dominant AD (ADAD) as a unique opportunity to discover AAO genetic associations. A genetic association study was conducted to examine ADAD AAO in 340 individuals with the PSEN1 E280A mutation via TOPMed array imputation. Replication was assessed in two ADAD cohorts, one sporadic early-onset AD study and four late-onset AD studies. 13 variants had p<1×10-7 or p<1×10-5 with replication including three independent loci with candidate associations with clusterin including near CLU. Other suggestive associations were identified in or near HS3ST1, HSPG2, ACE, LRP1B, TSPAN10, and TSPAN14. Variants with suggestive associations with AAO were associated with biological processes including clusterin, heparin sulfate, and amyloid processing. The detection of these effects in the presence of a strong mutation for ADAD reinforces their potentially impactful role.

Evaluation of Strategies Based on Wavelet-ICA and ICLabel for Artifact Correction in EEG Recordings

In quantitative electroencephalography, it is of vital importance to eliminate non-neural components, as these can lead to an erroneous analysis of the acquired signals, limiting their use in diagnosis and other clinical applications. In light of this drawback, preprocessing pipelines based on the joint use of the Wavelet Transform and the Independent Component Analysis technique (wICA) were proposed in the 2000s. Recently, with the advent of data-driven methods, deep learning models were developed for the automatic labeling of independent components, which constitutes an opportunity for the optimization of ICA-based techniques. In this paper, ICLabel, one of these deep learning models, was added to the wICA methodology in order to explore its improvement. To assess the usefulness of this approach, it was compared to different pipelines which feature the use of wICA and ICLabel independently and a lack thereof. The impact of each pipeline was measured by its capacity to highlight known statistical differences between asymptomatic carriers of the PSEN-1 E280A mutation and a healthy control group. Specifically, the between-group effect size and the P-values were calculated to compare the pipelines. The results show that using ICLabel for artifact removal can improve the effect size (ES) and that, by leveraging it with wICA, an artifact smoothing approach that is less prone to the loss of neural information can be built.

Effect of APOE4 on Plasma Phospho‐tau 217 and Neurofilament Light in the PSEN1 E280A Autosomal Dominant Alzheimer’s Disease Colombian Kindred

AbstractBackgroundThe Colombian kindred affected by the autosomal dominant AD causative mutation PSEN1 E280A are an invaluable population in determining the utility of blood biomarkers (BB) and how additional risk factors may affect BB years to decades prior to symptom onset. Neurofilament light (NfL) (Quiroz et al., 2020) and phospho‐tau 217 (p‐tau217) (Palmqvist et al., 2020) diverge about 20 years prior to onset of clinical symptoms in carriers compared to non‐carriers. How APOE4 carriage may influence NfL and p‐tau217 in the kindred is unknown. We assessed cross‐sectional effects of APOE4 carriage on plasma NfL and p‐tau217 in the PSEN1 E280A kindred.MethodWe used a single molecule array immunoassay to quantify plasma NfL and a Meso Scale Discovery based plasma immunoassay to quantify p‐tau217. 1428 persons (age 18 to 75, mean 35.8, 23% APOE4 carriers, 54% PSEN1 E280A carriers) had available data for NfL analyses. A total of 612 persons (age 18 to 60, mean 35.9, 25% APOE4 carriers, 62% PSEN1 E280A carriers) had available data for p‐tau217 analyses. Age related trajectories were derived from cross‐sectional log‐transformed p‐tau217 and NfL concentrations modelled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method in E280A mutation and APOE4 carriage defined groups. The primary comparison was made between APOE4 carrier and noncarriers within E280A carriers and noncarriers separately.ResultIn PSEN1 E280A mutation carriers, plasma NfL concentrations begin to differentiate those who were APOE4 carriers from non‐carriers at age 47.4 (figure 1). Plasma NfL concentrations did not differentiate APOE4 carriers versus non‐carriers in those without the PSEN1 E280A mutation though concentration of NfL trended higher in APOE4 carriers in the higher age range of the sample. Plasma p‐tau217 concentrations did not differentiate APOE4 carriers from non‐carriers in PSEN1 E280A mutation carriers or non‐carriers.ConclusionAPOE4 carriage results in accelerated NfL plasma increases in PSEN1 E280A mutation carriers starting at about the age of symptom onset. The inability to detect APOE4‐related ptau217 and NfL differences in the other groups may be related to the younger age of participants and limitations in statistical power.

APOE ε4 and global cognitive functioning in individuals with autosomal dominant Alzheimer’s disease due to the PSEN1 E280A variant

AbstractBackgroundAPOE‐ε4 allele (APOE4) increases the risk for sporadic Alzheimer’s disease (AD) and is associated with an earlier onset of AD dementia. However, previous studies have shown conflicting results on the association of APOE4 with the age of dementia onset in individuals with autosomal dominant AD (ADAD). Here, we examined the impact of APOE4 genotype on the age‐related trajectory of global cognitive function in mutation carriers and non‐carriers from the Colombian ADAD kindred.MethodData were obtained from a retrospective cohort of individuals from the largest known early‐onset ADAD kindred, residing in Antioquia, Colombia. Analyses included 675 PSEN1 E280A carriers (ages 18 to 75; 141 with an APOE4 allele: APOE4+, and 534 without an APOE4 allele: APOE4‐) and 594 non‐carriers. The Mini‐Mental State Examination (MMSE) was used to assess global cognitive functioning. Age‐related trajectories were derived from cross‐sectional log‐transformed MMSE scores modeled using a restricted cubic spline model. Model parameters were estimated using a Hamiltonian Markov chain Monte Carlo method to compare APOE4+ versus APOE4‐ trajectories in the mutation carrier and non‐carrier groups and estimate the age at onset of differences in global cognitive functioning.ResultLower MMSE scores distinguished PSEN1 E280A mutation carriers from non‐carriers at age 31.4, approximately 14 years before the average age of mild cognitive impairment (MCI) onset in this cohort. Among PSEN1 E280A mutation carriers, lower scores in MMSE began to significantly differentiate APOE4+ from APOE4‐ at age 45, the estimated average age of MCI onset in this kindred (figure 1). MMSE scores did not differentiate APOE4+ from APOE4‐ in those without the PSEN1 E280A mutation.ConclusionOur findings suggest that age‐related changes in cognitive function, as measured by the MMSE, are accelerated in ADAD mutation carriers who are APOE4+, compared to those who are APOE4‐. Future longitudinal studies of PSEN1 mutation carriers are needed to further clarify the impact of APOE4 genotype on rates of cognitive decline, heterogeneity of clinical presentation, and clinical progression in the preclinical, MCI, and dementia stages.

Machine learning assisted neuropathological assessment of 126 brains from PSEN1 E280A familial Alzheimer’s disease

AbstractBackgroundDuring the last 25 years we have collected 126 brains from the largest family in the world carrying PSEN1 mutation E280A and suffering from familial Alzheimer’s disease (FAD). Classical neuropathology scales rate all FAD cases as severe, overlooking the degree of heterogeneity observed in these cases. Here we present a new approach involving High Throughput Digital Neuropathology (HTDNp), Machine Learning (ML) classification of pathology, and multidimensional data analysis.MethodFrontal, Temporal, Parietal, and Occipital cortices, and cerebellum of all 126 brains were processed for H&amp;E staining and immunohistochemistry (IHC) for amyloid beta (Ab) and hyperphosphorylated tau (pTau). Cases were diagnosed, and staged according to CERAD, Braak and Thal systems. All slides were digitally scanned and processed for ML classification. Ab pathology was classified as core and diffuse plaques, and cerebral amyloid angiopathy (CAA), using a previously trained convolutional neural network (CNN). pTau pathology was classified as neurofibrillary tangles, dystrophic neurites, and diffuse pathology, by training a new CNN. ML was used for data dimensionality reduction, using self‐organizing maps (SOM). Clinical profiles were identified in the pathological clusters, analyzing presence and onset of specific symptoms.ResultPSEN1 E280A cases showed high degree of heterogeneity regarding ages of onset, disease duration, brain weight, and ApoE haplotype. Clinically, memory and language impairment were prevalent, while depression, insomnia, gait disorders and behavioral symptoms presented only in some cases. All cases were classified as CERAD C, Thal 5, and Braak VI. ML‐assisted classification and quantification of Ab and pTau pathology showed a high degree of variability among patients and brain areas. SOM analysis identified four distinct pathological clusters, each one with a characteristic clinical profile, indicating a clinical correlate for FAD pathological presentation in these cases.ConclusionCurrent neuropathological diagnosis of Alzheimer’s disease is not sensitive enough to differentiate among disease subtypes or heterogeneity. This can be detected by using HTDNp and ML tools, allowing the identification of clinically relevant pathological subtypes even in PSEN1 E280A brains, an otherwise uniform sample. This approach can be explored further in other FAD and sporadic Alzheimer’s disease cases, aiming for a more precise diagnosis, and a better understanding of the disease.

White matter hyperintensities are a prominent feature of autosomal dominant Alzheimer’s disease that emerge prior to dementia

BackgroundTo promote the development of effective therapies, there is an important need to characterize the full spectrum of neuropathological changes associated with Alzheimer’s disease. In line with this need, this study examined white matter abnormalities in individuals with early-onset autosomal dominant Alzheimer’s disease, in relation to age and symptom severity.MethodsThis is a cross-sectional analysis of data collected in members of a large kindred with a PSEN1 E280A mutation. Participants were recruited between September 2011 and July 2012 from the Colombian Alzheimer’s Prevention Initiative registry. The studied cohort comprised 50 participants aged between 20 and 55 years, including 20 cognitively unimpaired mutation carriers, 9 cognitively impaired mutation carriers, and 21 non-carriers. Participants completed an MRI, a lumbar puncture for cerebrospinal fluid collection, a florbetapir PET scan, and neurological and neuropsychological examinations. The volume of white matter hyperintensities (WMH) was compared between cognitively unimpaired carriers, cognitively impaired carriers, and non-carriers. Relationships between WMH, age, and cognitive performance were further examined in mutation carriers.ResultsThe mean (SD) age of participants was 35.8 (9.6) years and 64% were women. Cardiovascular risk factors were uncommon and did not differ across groups. Cognitively impaired carriers [median, 6.37; interquartile range (IQR), 9.15] had an increased volume of WMH compared to both cognitively unimpaired carriers [median, 0.85; IQR, 0.79] and non-carriers [median, 1.07; IQR, 0.71]. In mutation carriers, the volume of WMH strongly correlated with cognition and age, with evidence for an accelerated rate of changes after the age of 43 years, 1 year earlier than the estimated median age of symptom onset. In multivariable regression models including cortical amyloid retention, superior parietal lobe cortical thickness, and cerebrospinal fluid phospho-tau, the volume of WMH was the only biomarker independently and significantly contributing to the total explained variance in cognitive performance.ConclusionsThe volume of WMH is increased among individuals with symptomatic autosomal-dominant Alzheimer’s disease, begins to increase prior to clinical symptom onset, and is an independent determinant of cognitive performance in this group. These findings suggest that WMH are a key component of autosomal-dominant Alzheimer’s disease that is closely related to the progression of clinical symptoms.