Early-onset Alzheimer's Disease Research Articles

White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). Cerebrospinal fluid (CSF) concentrations of Aβ1-40, Aβ1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. Biomarkers were correlated with one another. Levels of CSF Aβ42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aβ42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

BACE2: A Promising Neuroprotective Candidate for Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia that affects millions of predominantly elderly individuals worldwide. Despite intensive research over several decades, controversies still surround the etiology of AD and the disease remains incurable. Meanwhile, new molecular players of the central amyloid cascade hypothesis have emerged and among these is a protease known as β-site APP cleavage enzyme 2 (BACE2). Unlike BACE1, BACE2 cleaves the amyloid-β protein precursor within the Aβ domain that accordingly prevents the generation of Aβ42 peptides, the aggregation of which is commonly regarded as the toxic entity that drives neurodegeneration in AD. Given this non-amyloidogenic role of BACE2, it is attractive to position BACE2 as a therapeutic target for AD. Indeed, several groups including ours have demonstrated a neuroprotective role for BACE2 in AD. In this review, we discuss emerging evidence supporting the ability of BACE2 in mitigating AD-associated pathology in various experimental systems including human pluripotent stem cell-derived cerebral organoid disease models. Alongside this, we also provide an update on the identification of single nucleotide polymorphisms occurring in the BACE2 gene that are linked to increased risk and earlier disease onset in the general population. In particular, we highlight a recently identified point mutation on BACE2 that apparently leads to sporadic early-onset AD. We believe that a better understanding of the role of BACE2 in AD would provide new insights for the development of viable therapeutic strategies for individuals with dementia.

Alzheimer’s disease-associated complement gene variants influence plasma complement protein levels

BackgroundAlzheimer’s disease (AD) has been associated with immune dysregulation in biomarker and genome-wide association studies (GWAS). GWAS hits include the genes encoding complement regulators clusterin (CLU) and complement receptor 1 (CR1), recognised as key players in AD pathology, and complement proteins have been proposed as biomarkers.Main bodyTo address whether changes in plasma complement protein levels in AD relate to AD-associated complement gene variants we first measured relevant plasma complement proteins (clusterin, C1q, C1s, CR1, factor H) in a large cohort comprising early onset AD (EOAD; n = 912), late onset AD (LOAD; n = 492) and control (n = 504) donors. Clusterin and C1q were significantly increased (p < 0.001) and sCR1 and factor H reduced (p < 0.01) in AD plasma versus controls. ROC analyses were performed to assess utility of the measured complement biomarkers, alone or in combination with amyloid beta, in predicting AD. C1q was the most predictive single complement biomarker (AUC 0.655 LOAD, 0.601 EOAD); combining C1q with other complement or neurodegeneration makers through stepAIC-informed models improved predictive values slightly. Effects of GWS SNPs (rs6656401, rs6691117 in CR1; rs11136000, rs9331888 in CLU; rs3919533 in C1S) on protein concentrations were assessed by comparing protein levels in carriers of the minor vs major allele. To identify new associations between SNPs and changes in plasma protein levels, we performed a GWAS combining genotyping data in the cohort with complement protein levels as endophenotype. SNPs in CR1 (rs6656401), C1S (rs3919533) and CFH (rs6664877) reached significance and influenced plasma levels of the corresponding protein, whereas SNPs in CLU did not influence clusterin levels.ConclusionComplement dysregulation is evident in AD and may contribute to pathology. AD-associated SNPs in CR1, C1S and CFH impact plasma levels of the encoded proteins, suggesting a mechanism for impact on disease risk.

Clinical characteristics of early-onset versus late-onset Alzheimer's disease: a systematic review and meta-analysis.

A number of studies have compared Alzheimer's disease (AD), the commonest form of dementia, based on their age of onset, i.e. before the age of 65 years (early-onset AD, EO-AD) tothose developing after 65 years of age (late-onset AD, LO-AD), but the differences are not clear. We performed a systematic review and meta-analysis to compare clinical characteristics between EO-AD and LO-AD. Medline, Embase, PsycINFO, and CINAHL databases were systematically searched for studies comparing time to diagnosis, cognitive scores, annual cognitive decline, activities of daily living (ADLs), neuropsychiatric symptoms (NPS), quality of life (QoL), and survival time for EO-AD and LO-AD patients. Forty-two studies were included (EO-AD participants n = 5,544; LO-AD participants n = 16,042). An inverse variance method with random effects models was used to calculate overall effect estimates for each outcome. People with EO-AD had significantly poorer baseline cognitive performance and faster cognitive decline but longer survival times than people with LO-AD. There was no evidence that EO-AD patients differ from people with LO-AD in terms of symptom onset to diagnosis time, ADLs, and NPS. There were insufficient data to estimate overall effects of differences in QoL in EO-AD compared to LO-AD. Our findings suggest that EO-AD differs from LO-AD in baseline cognition, cognitive decline, and survival time but otherwise has similar clinical characteristics to LO-AD. Larger studies using standardized questionnaires focusing on the clinical presentations are needed to better understand the impact of age of onset in AD.

The Early-Onset Alzheimer's Disease Whole-Genome Sequencing Project: Study design and methodology.

Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations, resulting in a lack of understanding of its molecular etiology. Whole-genome sequencing and harmonization of clinical, neuropathological, and biomarker data of over 5000 EOAD cases of diverse ancestries. A publicly available genomics resource for EOAD with extensive harmonized phenotypes. Primary analysis will (1) identify novel EOAD risk loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. This novel resource complements over 50,000 control and late-onset AD samples generated through the Alzheimer's Disease Sequencing Project (ADSP). The harmonized EOAD/ADSP joint call will be available through upcoming ADSP data releases and will allow for additional analyses across the full onset range. Sequencing efforts to identify genetic variants and pathways underlying Alzheimer's disease (AD) have largely focused on late-onset AD although early-onset AD (EOAD), accounting for ∼10% of cases, is largely unexplained by known mutations. This results in a significant lack of understanding of the molecular etiology of this devastating form of the disease. The Early-Onset Alzheimer's Disease Whole-genome Sequencing Project is a collaborative initiative to generate a large-scale genomics resource for early-onset Alzheimer's disease with extensive harmonized phenotype data. Primary analyses are designed to (1) identify novel EOAD risk and protective loci and druggable targets; (2) assess local-ancestry effects; (3) create EOAD prediction models; and (4) assess genetic overlap with cardiovascular and other traits. The harmonized genomic and phenotypic data from this initiative will be available through NIAGADS.

Developments in understanding early onset Alzheimer's disease.

On September 25 and 26, 2021, the Alzheimer's Association hosted the first meeting focused on people with early-onset Alzheimer's disease (EOAD)-sometimes referred to as younger onset Alzheimer's disease (AD). Though a diagnosis of AD can be devastating at any age, those with a younger onset-defined as symptoms developing prior to 65 years of age-face unique challenges. EOAD occurs when people are in the prime of their lives, often with multiple responsibilities including careers, community activities, and raising children and caring for older family members. These challenges warrant special consideration and study, yet people with EOAD are often excluded from AD research because of their atypical age of onset. To help fill this gap, we designed and launched the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) to enroll and follow 500 people with EOAD from > 15 sites in the United States, which the National Institute on Aging funded in 2018. The September 2021 meeting was designed to inform people with EOAD and their family members and caregivers about the latest research on the biology of EOAD, treatments in the pipeline, practical considerations about legal and financial arrangements for families, and the support networks available to them. More than 217 registrants attended.

Pathogenic Aβ production by heterozygous PSEN1 mutations is intrinsic to the mutant protein and not mediated by conformational hindrance of wild-type PSEN1

Presenilin-1 (PSEN1) is the catalytic subunit of the intramembrane protease γ-secretase and undergoes endoproteolysis during its maturation. Heterozygous mutations in the PSEN1 gene cause early-onset familial Alzheimer's disease (eFAD) and increase the proportion of longer aggregation-prone amyloid-β peptides (Aβ42 and/or Aβ43). Previous studies had suggested that PSEN1 mutants might act in a dominant-negative fashion by functional impediment of wild-type PSEN1, but the exact mechanism by which PSEN1 mutants promote pathogenic Aβ production remains controversial. Using dual recombinase-mediated cassette exchange (dRMCE), here we generated a panel of isogenic embryonic and neural stem cell lines with heterozygous, endogenous expression of PSEN1 mutations. When catalytically inactive PSEN1 was expressed alongside the wild-type protein, we found the mutant accumulated as a full-length protein, indicating that endoproteolytic cleavage occurred strictly as an intramolecular event. Heterozygous expression of eFAD-causing PSEN1 mutants increased the Aβ42/Aβ40 ratio. In contrast, catalytically inactive PSEN1 mutants were still incorporated into the γ-secretase complex but failed to change the Aβ42/Aβ40 ratio. Finally, interaction and enzyme activity assays demonstrated the binding of mutant PSEN1 to other γ-secretase subunits, but no interaction between mutant and wild-type PSEN1 was observed. These results establish that pathogenic Aβ production is an intrinsic property of PSEN1 mutants and strongly argue against a dominant-negative effect in which PSEN1 mutants would compromise the catalytic activity of wild-type PSEN1 through conformational effects.

Transcriptomic Downregulation of APOE, Polymorphic Variations of APOE, Diet, Social Isolation, and Co-morbidities as Contributing Factors to Alzheimer's Disease: a Case-Control Study of Kashmiri Population.

Alzheimer's disease (AD) is the most common form of dementia, generally affecting elderly people in the age group of above 60-65 years. Amyloid deposition has been found to be a possible cause and a characteristic feature of Alzheimer's disease. Mutations, variant genotypes, or downregulation that reduce amyloid clearance or accelerate amyloid accumulation can lead to Alzheimer's disease. This study involved clinically confirmed AD patients, age matched controls of similar ethnicity, and patients who had no history of cancer or any other chronic disease. DNA and RNA extractions of samples were done as per Saguna et al. [45] and TRIzol method, respectively. Frequencies of variant genotypes were observed using the RFLP technique, whereas, for expression analysis, qPCR was performed. The association between diet, smoking status, family history, and co-morbidities was calculated using statistical tools. Expression analysis showed downregulation in more than 65% of AD cases. Hypertension and diabetes also had a significant association with AD. Allelic isoforms ε2:ε2 and ε2:ε3 tend to be less frequent among AD cases compared to controls (2.85% vs 26.15% and 11.42% vs 21.43%, respectively). Among individuals (AD cases) with ε2:ε3 and ε2:ε4, 37.5% of the patients were having severe dementia and 62.5% were having mild to moderate dementia, whereas, among individuals with ε3:ε4 and ε4:ε4, 57% were having severe dementia and 43% were having mild to moderate dementia. Besides this, all early-onset Alzheimer's patients were found to have at least one ε4 allele. The percentage of individuals with family history (cases vs controls) was 34.17% vs 3.75%, without family history 64.55% vs 95%. On comparing AD cases against controls for smoking status, the results observed are the following: chain smokers, 12.65% vs 18.75%; moderate smokers, 16.45% vs 6.25%; ex-smokers, 36.70% vs 22.50%; non-smokers, 34.17% vs 52.50%. On comparing dietary habits in AD cases against controls, the results were as follows: individuals with generally fatty diet 26.58% vs 11.25%, with mixed diet 36.70% vs 78.75%, with generally vegetarian diet 34.17% vs 10.00%, data not available 2.53% among AD cases. Family history, dietary habits, genetics, and socioeconomic status are strongly associated with the development of Alzheimer disease. Although family history or genetic makeup cannot be changed, eating habits can be changed quite easily. We simply need to go from a high-fat diet to one that is lower in fat. Regarding socioeconomic status, which includes stress of both kinds, including economic stress, stress brought on by the loss of loved ones through death or separation, and co-morbidities (hypertension and diabetes), all are manageable and even modifiable through counseling, positive behavior, and physical activity like exercise, walking, cycling, and playing games.

COULD ALZHEIMER'S DISEASE PATHOLOGY BE ASSOCIATED WITH METALS RELEASED FROM TOTAL HIP ARTHROPLASTY?

Both total joint arthroplasty (TJA) and Alzheimer's Disease (AD) are prevalent in elderly populations. It is the goal of this study to determine if the presence of implant metals originating from TJA correlates with the onset with higher implant metal content in the brain and AD pathology.Tissue samples from four brain regions of 701 (229 with TJA) participants from an ongoing longitudinal cohort study (Rush Memory and Aging Project) was analyzed including the inferior-temporal-cortex (ITC), which is associated with early onset of AD. Implant metal (Co, Cr, Mo, Ti, Al) content was determined by ICP-MS. Comparisons were conducted between the no-TJA-group and a TJA group. Due to the higher likelihood of Co release the TJA group was further differentiated in a THA (N=146) and a TKA/TSA (N=83) group. Diffuse and neuritic amyloid plaques and phosphorylated tau were assessed and summarized as standard measures of AD pathology. We used separate linear regression models adjusted for age, sex, education, and APOɛ4-status for the associations of all metals (log-transformed) with global AD pathology, amyloid plaques, and phosphorylated tau.The THA group had higher cobalt content across all brain regions (p=0.003) and within the ITC (p=0.051) compared to the no-TJA group, whereas the TKA/TSA group did not. Across all tissue samples, Co was associated with higher amyloid load (β=0.35, p=0.027), phosphorylated tau (β=0.47, p=0.011), and global AD pathology (β=0.19, 0.0004) in the ITC. The presence of TJA itself was not associated with AD pathology.We showed that only Co content was higher within the ITC in persons with THA. We found among all tested metals that Co was consistently associated with AD pathology. Although we found an association of cobalt with AD pathology, the cross-sectional nature of this study does not allow the determination of cause and effect.

Distinct cerebral small vessel disease impairment in early-and late-onset Alzheimer's disease.

This study investigated cerebral small vessel disease (CSVD) damage patterns in early-onset and late-onset Alzheimer's disease (EOAD and LOAD) and their effects on cognitive function. This study included 93 participants, 45 AD patients (14 EOAD and 31 LOAD), and 48 normal controls (13 YNC and 35 ONC) from the ADNI database. All participants had diffusion tensor imaging data; some had amyloid PET and plasma p-tau181 data. The study used peak width of skeletonized mean diffusivity (PSMD) to measure CSVD severity and compared PSMD between patients and age-matched controls. The effect of age on the relationship between PSMD and cognition was also examined. The study also repeated the analysis in amyloid-positive AD patients and amyloid-negative controls in another independent database (31 EOAD and 38 LOAD), and the merged database. EOAD and LOAD showed similar cognitive function and disease severity. PSMD was validated as a reliable correlate of cognitive function. In the ADNI database, PSMD was significantly higher for LOAD and showed a tendency to increase for EOAD; in the independent and merged databases, PSMD was significantly higher for both LOAD and EOAD. The impact of PSMD on cognitive function was notably greater in the younger group (YNC and EOAD) than in the older group (ONC and LOAD), as supported by the ADNI and merged databases. EOAD has less CSVD burden than LOAD, but has a greater impact on cognition. Proactive cerebrovascular prevention strategies may have potential clinical value for younger older adults with cognitive decline.

PSEN1/SLC20A2 double mutation causes early-onset Alzheimer’s disease and primary familial brain calcification co-morbidity

Primary familial brain calcification (PFBC; formerly Fahr’s disease) and early-onset Alzheimer’s disease (EOAD) may share partially overlapping pathogenic principles. Although the heterozygous loss-of-function mutation c.1523 + 1G > T in the PFBC-linked gene SLC20A2 was detected in a patient with asymmetric tremor, early-onset dementia, and brain calcifications, CSF β-amyloid parameters and FBB-PET suggested cortical β-amyloid pathology. Genetic re-analysis of exome sequences revealed the probably pathogenic missense mutation c.235G > A/p.A79T in PSEN1. The SLC20A2 mutation segregated with mild calcifications in two children younger than 30 years. We thus describe the stochastically extremely unlikely co-morbidity of genetic PFBC and genetic EOAD. The clinical syndromes pointed to additive rather than synergistic effects of the two mutations. MRI data revealed the formation of PFBC calcifications decades before the probable onset of the disease. Our report furthermore exemplifies the value of neuropsychology and amyloid PET for differential diagnosis.

The Adult Neurogenesis Theory of Alzheimer's Disease.

Alzheimer's disease starts in neural stem cells (NSCs) in the niches of adult neurogenesis. All primary factors responsible for pathological tau hyperphosphorylation are inherent to adult neurogenesis and migration. However, when amyloid pathology is present, it strongly amplifies tau pathogenesis. Indeed, the progressive accumulation of extracellular amyloid-β deposits in the brain triggers a state of chronic inflammation by microglia. Microglial activation has a significant pro-neurogenic effect that fosters the process of adult neurogenesis and supports neuronal migration. Unfortunately, this "reactive" pro-neurogenic activity ultimately perturbs homeostatic equilibrium in the niches of adult neurogenesis by amplifying tau pathogenesis in AD. This scenario involves NSCs in the subgranular zone of the hippocampal dentate gyrus in late-onset AD (LOAD) and NSCs in the ventricular-subventricular zone along the lateral ventricles in early-onset AD (EOAD), including familial AD (FAD). Neuroblasts carrying the initial seed of tau pathology travel throughout the brain via neuronal migration driven by complex signals and convey the disease from the niches of adult neurogenesis to near (LOAD) or distant (EOAD) brain regions. In these locations, or in close proximity, a focus of degeneration begins to develop. Then, tau pathology spreads from the initial foci to large neuronal networks along neural connections through neuron-to-neuron transmission.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n=212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n=70). Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Genetic protection from early-onset familial Alzheimer's disease.

Genetic protection from early-onset familial Alzheimer's disease.

Cross‐species evidence of differential expression of S100A6 and SLC11A1 in the hippocampus of Alzheimer’s disease patients and mouse models

AbstractBackgroundThe evaluation of similarities and differences between mouse models and human Alzheimer’s disease (AD) provides invaluable insights on disease pathophysiology. We compared hippocampal transcriptomic profiles of human late‐onset AD (LOAD) and early‐onset AD (EOAD) individuals with three mouse models (hAβ‐KI, APP/PS1 and 5xFAD) in an exploratory analysis. Afterwards, we validated the intersection of genes consistently altered in all groups using hippocampal tissue from APP/PS1 mice, and EOAD and LOAD patients.MethodsFive publicly available human AD/cognitively unimpaired (CU) transcriptomic profiles were collected from GEO (https://www.ncbi.nlm.nih.gov/geo/), merged and submitted to differential expression analysis (DEA) using R. APP/PS1 mouse model RNAseq data from two datasets (GSE149661 and GSE145907) were also collected. Finally, RNAseq data of 5xFAD and hAβ‐KI mouse models were obtained from AMP‐AD Knowledge Portal (https://www.synapse.org/) using synapser and synapserutils packages. All animal models were also submitted to DEA. Validation of selected genes was performed by qRT‐PCR. Target mRNA levels were normalized using β‐actin as a housekeeper gene. The results were expressed relative to wild‐type (WT) animals or CU controls using the 2−ΔΔCt method.ResultsDEA identified 1164, 3261 and 1782 differentially expressed genes (DEGs) for the comparisons between hAβ‐KI, 5xFAD and APP/PS1 mutants versus WT controls, respectively. hAβ‐KI, APP/PS1, and 5xFAD mice exhibited more DEGs in common with LOAD than with EOAD patients. Interestingly, APP/PS1 and 5xFAD mice also presented more DEGs in common with LOAD than with EOAD patients. However, 5xFAD showed significantly higher DEGs intersection with EOAD than with hAβ‐KI and APP/PS1. Additionally, we identified S100A6, C1QB, SST, CD14, CD33, SLC11A1 and KCNK1 genes altered in both EOAD and LOAD as well as the three mouse models evaluated. qRT‐PCR analysis of these genes in EOAD, LOAD and APP/PS1 model revealed S100A6 and SLC11A1 consistently altered in human pathology and mouse model.ConclusionAnimal models seek to better simulate AD pathology, making the evaluation of their molecular overlap with human disease greatly important. S100A6, a calcium‐binding protein modulating several biological activities, and SLC11A1, a metal transporter associated with inflammatory processes, were consistently altered in our transcriptomics exploratory analyses and experimental validation, making them promising targets for further investigation.

Tau‐PET imaging with 18F‐PI‐2620 reveals lateralized distribution of tau pathology in critical language regions in patients with early onset of Alzheimer’s Disease and patients with primary progressive aphasia

AbstractBackgroundLanguage disorders are frequent in patients in advanced and early stages of dementia (Goth &amp; Strøm, 2018) together with the deterioration of other cognitive domains (e.g., memory) (Taler &amp; Phillips, 2008). The first complaint in people with dementia often is language impairment, even preceding other cognitive declines (Ferris &amp; Farlow, 2013). Logopenic variant primary progressive aphasia (lvPPA) and non‐fluent/agrammatic variant PPA (nf/avPPA) are rare neurodegenerative disorders being language impairment the main feature (Gono‐Tempini, 2011). Both β‐amyloid (Aβ) and tau appear to occur in Alzheimer disease (AD). Moreover, Aβ and tau aggregates also represent the underlying pathology in lvPPA (Montembeault et al. 2018) while nf/avPPA resembles a pure tau‐pathology. The purpose of this study is to explore the distribution of tau‐pathology in critical language regions in patients with early‐onset AD (EOAD) and patients diagnosed with primary progressive aphasia (PPA).MethodEight participants (55‐77y): 4 with EOAD, 3 with lvPPA (these first seven patients additionally had a positive 18F‐Florbetaben Amyloid PET), 1 with nf/avPPA, and 14 healthy controls (HC) (age range 54‐76y) underwent dynamic PET scans with 18F‐PI‐2620 to examine the distribution of tau‐pathology in the following cortical language regions: inferior frontal gyrus (IFG), superior temporal gyrus (STG), supramarginal and angular gyrus (PL). Group differences in language regions were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum.ResultCompared to HC, 3/4 patients with EOAD showed elevated levels of 18F‐PI‐2620 binding, mainly in the right IFG and IPL and left STG, while 3/4 patients with PPA (2 lvPPA and 1 nf/avPPA) showed left lateralized elevated uptake of 18F‐PI‐2620 in all language regions. All PPA patients showed increased binding of 18F‐PI‐2620 predominantly in the left parietal regions.ConclusionOur preliminary results reveal a lateralized distribution pattern of 18F‐PI‐2620 in language regions in patients with EOAD and particularly in those with PPA. These findings suggest that 18F‐PI‐2620 PET imaging is a promising tool to visualize tau aggregations in patients with EOAD and PPA. However, further studies are needed to confirm these preliminary results.

Epidemiological profile of early‐onset Alzheimer’s mortality in Brazil from 2010 to 2019

AbstractBackgroundEarly‐onset Alzheimer disease (EOAD) is not just late‐onset AD (LOAD) at a younger age; there are substantial differences between these 2 categories of AD (Mendez, 2017). Therefore, the first step is to understand its population context. In this way, we sought in this study to determine the socio‐epidemiological aspects of Early‐onset Alzheimer disease (EOAD) mortality in Brazil. This is the first study that analyzes the epidemiology of EOAD in Brazilian territory.MethodData from the Ministry of Health’s Mortality Information System (SIM) were analyzed for the epidemiological characterization of deaths from Alzheimer’s (ICD‐10 code G30.0) between 2010 and 2019, considering the variables available on the death certificates. EOAD mortality was considered as death from Alzheimer’s in patients younger than 60 years of age. The sociodemographic variables chosen were sex, race/color, marital status, education and region of the country.ResultBetween 2010 and 2019, SIM recorded 804 cases of EOAD. Of these, 50.62% were male and 49.37% were female. As for race, 63.6% were white, 26.6% brown, 4.97% black, 0.62% yellow, and in 4.10% this information was ignored on the death certificate. It was found that 45% were married, 25% single, 10.9% widowed, 8.2% divorced, 2.2% other and 8.45% were ignored. The level of education was 1 to 3 years in 21.3%, 21% for 4 to 7 years, 15.9% for 8 to 11 years, 7.8% for more than 12 years, 12.4% none and in 21.39% we did not obtain this data. It was also observed 48.8% cases in the Southeast, 21.2% in the South, 20.1% in the Northeast, 6.84% in the Midwest and 2.8% in the North.ConclusionThe prevalence of early Alzheimer’s mortality was higher in male, white, married patients, from the Southeast region, with 1 to 3 years of schooling. The epidemiological profile is a fundamental part for the elaboration of programs of preventive actions and health promotion. Strengths of this study include the production of information on mortality from early Alzheimer’s disease in Brazil, in a context of lack of research of this type in the country.

Comparison of white matter hyperintensities between early‐onset Alzheimer’s disease participants and their cognitively normal and early‐onset nonAD peers from LEADS

AbstractBackgroundThe Longitudinal Early‐onset Alzheimer Disease study (LEADS) aims to robustly characterize biomarkers of early‐onset AD (EOAD). Here we quantified white matter hyperintensities (WMH) in EOAD and compared the volume of WMH with that of cognitively normal (CN) and amyloid‐negative early‐onset dementia (EOnonAD) groups.MethodsWe compared WMH of 194 amyloid‐positive EOAD, 59 amyloid‐negative EOnonAD, and 88 cognitively normal participants. WMH in left and right frontal, temporal, parietal, and occipital regions was compared between the group, as well as the sum total in each hemisphere. For distributional considerations, the logarithm of the WMHs was used in the analyses. Group comparisons were performed using t‐tests. Analyses of variance were used to compare the groups after correcting for the effects of age, sex, and education. Linear regression analyses were used to investigate the association between cognitive impairment and WMH using age, sex, and education as covariates. Cognitive impairment was measured using the Mini‐Mental State Exam (MMSE) and Clinical Dementia Rating (CDR) scale sum of boxes (CDR‐sb). All p‐values were corrected for multiple comparisons using the false discovery rate method.ResultsEOAD showed greater WMH compared with both CN and EOnonAD groups across all regions. This relationship holds after correcting for the effects of age, sex, and education (see Figure 1 and Table 1, all p‐values &lt; 0.05). No significant differences were observed between WMHs of CN and EOnonAD groups. Higher WMH values were associated with greater cognitive impairment: MMSE (b = ‐1.69, p‐value &lt;0.0001) and CDR‐sb (b = 0.45, p‐value &lt;0.0001).ConclusionsEOAD consistently show higher WMH compared to their CN and EOnonAD peers. The extent of WMH in CN and EOnonAD groups is similar. No differences in regional distribution were observed, with EOAD having higher WMH across all brain regions. Higher WMHs were associated with worse cognitive impairment measured both using MMSE and CDR sum of boxes.

Microbiome‐associated metabolic determinants of neurodegeneration and cognitive resilience

AbstractBackgroundType 2 diabetes (T2D) is a common antecedent of pathological neurodegeneration and accompanying dementia, including Alzheimer’s Disease (AD); however, the mechanistic link between metabolic and neurodegenerative disorders remains unresolved (1‐3). Study of a small cohort of dementia patients revealed divergent gut microbiota composition, increased gut permeability, and inflammation, implicating a microbial determinant in neuroimmune dysregulation (4), an emerging player in neurodegeneration (5). Notably, the microbiome is a source of neuroprotective metabolites (6), highlighting the need to elucidate the role of the microbiome and realize the potential for its therapeutic modulation in AD. We recently began a clinical trial focusing on individuals of Mexican descent living in Southern Texas, a population with increased prevalence of co‐morbid T2D and early onset AD (7‐8), with the working hypothesis that diet‐driven shifts in gut microbiome composition contribute to T2D and AD pathophysiology in this population (9‐11).MethodWe will perform metagenomic 16S rRNA gene amplicon sequencing and compare within (alpha) and between (beta) sample diversity as well as quantitative phylogenetic and taxonomic comparisons. Using 3xTg‐AD and hTau mouse models, we will determine the impact of microbial depletion via broad spectrum antibiotics on AD pathology and cognitive function. Data will be analyzed separately for each sex using nested t‐tests, nested one‐way ANOVA, or a mixed effects model to account for litter effects.ResultData resulting from our preclinical animal and clinical human studies will inform future experiments in which we will transplant fecal microbiota samples derived from T2D versus non‐diabetic human subjects into microbially‐depleted, “humanized” AD mice. We will then perform metabolomic, molecular, electrophysiological, and behavioral analyses to determine the impact(s) of T2D gut microbiota on host AD‐like pathology and behavioral phenotypes.ConclusionCharacterizing gut microbiome signatures of T2D individuals of Mexican descent living in Southern Texas could identify key actors among “disease state” microbiota which may exacerbate or accelerate neurodegenerative disorders, as well as gut microbiota present in healthy controls lost in the T2D population which contribute to molecular mechanisms of cognitive resilience. Consequently, our approach may lead to novel immunotherapeutic approaches to target or limit neuroinflammation in AD.