Early-onset Alzheimer's Disease Patients Research Articles

Choriocapillaris reduction accurately discriminates against early-onset Alzheimer's disease.

This study addresses the urgent need for non-invasive early-onset Alzheimer's disease (EOAD) prediction. Using optical coherence tomography angiography (OCTA), we present a choriocapillaris model sensitive to EOAD, correlating with serum biomarkers. Eighty-four EOAD patients and 73 controls were assigned to swept-source OCTA (SS-OCTA) or the spectral domain OCTA (SD-OCTA) cohorts. Our hypothesis on choriocapillaris predictive potential in EOAD was tested and validated in these two cohorts. Both cohorts revealed diminished choriocapillaris signals, demonstrating the highest discriminatory capability (area under the receiver operating characteristic curve: SS-OCTA 0.913, SD-OCTA 0.991; P<0.001). A sparser SS-OCTA choriocapillaris correlated with increased serum amyloid beta (Aβ)42, Aβ42/40, and phosphorylated tau (p-tau)181 levels (all P<0.05). Apolipoprotein E status did not affect choriocapillaris measurement. The choriocapillaris, observed in both cohorts, proves sensitive to EOAD diagnosis, and correlates with serum Aβ and p-tau181 levels, suggesting its potential as a diagnostic tool for identifying and tracking microvascular changes in EOAD. Optical coherence tomography angiography may be applied for non-invasive screening of Alzheimer's disease (AD). Choriocapillaris demonstrates high sensitivity and specificity for early-onset AD diagnosis. Microvascular dynamics abnormalities are associated with AD.

Generation and characterization of an iPS cell line (PUMCi006-A) from skin fibroblasts of a patient with an M239T mutation in PSEN2 gene

Presenilin-2 (PSEN2) mutation is one of the pathogenic factors of autosomal dominant early-onset Alzheimer's disease (EOAD). We generated a human induced pluripotent stem cell (iPSC) line from fibroblasts of an EOAD patient carrying PSEN2 mutation (c.716 T > C) utilizing Sendai reprogramming kit. The resulting iPSC line carried patient-specific point mutation, exhibited typical iPSC morphology, retained a normal karyotype, expressed pluripotency markers, and could form embryoid bodies. Established iPSC line serve as valuable resource for EOAD disease pathogenesis modelling and drug screening.

Correlation between serum biomarkers, brain volume, and retinal neuronal loss in early-onset Alzheimer's disease.

To compare the peripapillary retinal nerve fiber layer (pRNFL), retinal nerve fiber layer (RNFL), and ganglion cell complex (GCC) thickness measurement in early-onset Alzheimer's disease (EOAD) and controls using spectral domain optical coherence tomography (SD-OCT). We also assessed the relationship between SD-OCT measurements and cognitive measures, serum biomarkers for Alzheimer's disease (AD), and cerebral microstructural volume. pRNFL, RNFL, and GCC thicknesses were measured in 43 EOAD and 42 controls using SD-OCT. Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE) were used to assess cognitive status, magnetic resonance imaging (MRI) tool was used to quantify cerebral microstructural volume, and serum biomarkers were quantified from peripheral blood. EOAD patients had thinner pRNFL (P < 0.001), RNFL (P = 0.008), and GCC (P = 0.018) thicknesses compared to controls after adjusting for multiple factors. pRNFL thickness correlated (P = 0.016) with serum t-tau level. Serum Aβ42 (P < 0.05) concentration correlated with RNFL thickness. Importantly, occipital lobe volume (P = 0.010) correlated with GCC thicknesses in EOAD patients. Our findings suggest that retinal thickness may be useful markers for assessing neurodegenerative processin EOAD.

The rs‐gamma connectivity alterations related to the atrophy pattern and CSF p‐tau in early‐onset AD

AbstractBackgroundAmong the other frequencies, the gamma frequency has received the least attention in the study of Alzheimer’s disease (AD). Previous studies point to association between amyloid accumulation and gamma alterations, suggesting that gamma activity may serve as a potential biomarker for the pathophysiology of AD. The goal of the current study is to examine changes in resting‐state (rs) gamma activity in patients with CSF‐proven early‐onset AD (EOAD) and their relationship to structural pathology associated with the disease.MethodDrug‐naive CSF‐proven EOAD patients [mean age: 57.92 (4.35) years] and age‐, gender, and education‐matched healthy controls (HC) [mean age: 57.58 (4.01) years] were included. Gamma imaginary part of coherency (ICoh) was measured in total gamma (30‐48 Hz), gamma‐1 (30‐35 Hz), gamma‐2 (35‐40 Hz), and gamma‐3 (40‐48 Hz) frequencies. Gray matter volumes compared between groups. The rsEEG gamma activity was used for discriminant analysis. The relationships between rsEEG, MRI, and CSF p‐tau measurements were investigated.ResultIn the EOAD group, gray matter volume in temporal, parietal, and occipital areas were decreased by over 20%. We discovered that the volume of frontal and neighboring regions, that were intact in this patient group, was negatively correlated with F8‐TP8 and F4‐C4 ICoh of sub‐gamma bands. On the contrary, the volume of temporal and parietal regions where the atrophy was prominent, was positively correlated with P8‐O2 and C3‐O1 ICoh of sub‐gamma bands. In the EOAD, executive function and F7‐TP7, P3‐O1 sub‐gamma bands were negatively correlated.Regarding CSF, p‐Tau and C3‐C4 gamma‐1 showed strong positive correlation (r = 0.615). Lastly, a set of gamma ICoh measurements displayed a correct classification rate of 83% between groups.ConclusionGamma coherence follows pair‐specific alterations related to atrophy pattern in EOAD. The gamma connectivity becomes greater where atrophy is increased and when CSF p‐tau is higher in EOAD. This study establishes the significance of sub‐gamma oscillations as a non‐invasive biomarker candidate with achieving an 83% correct classification rate between groups.

High burdens of phosphorylated tau protein and distinct precuneus atrophy in sporadic early-onset Alzheimer’s disease

Early-onset Alzheimer’s disease (EOAD) is a rare devastating subclassification of Alzheimer’s disease (AD). EOAD affects individuals <65 years old, and accounts for 5%–10% of all AD cases. Previous studies on EOAD primarily focused on familial forms, whereas research on sporadic EOAD (sEOAD), which represents 85%–90% of EOAD cases, is limited. In this prospective cohort study, participants were recruited between 2018 and 2023 and included patients with sEOAD (n = 110), late-onset AD (LOAD, n = 89), young controls (YC, n = 50), and older controls (OC, n = 25). All AD patients fulfilled the diagnostic criteria based on biomarker evidence. Familial EOAD patients or non-AD dementia patients were excluded. Single molecule array technology was used to measure fluid biomarkers, including cerebrospinal fluid (CSF) and plasma amyloid beta (Aβ) 40, Aβ42, phosphorylated tau (P-tau) 181, total tau (T-tau), serum neurofilament light chain and glial fibrillary acidic protein (GFAP). Patients with sEOAD exhibited more severe executive function impairment and bilateral precuneus atrophy (P < 0.05, family-wise error corrected) than patients with LOAD. Patients with sEOAD showed elevated CSF and plasma P-tau181 levels (154.0 ± 81.2 pg/mL, P = 0.002; and 6.1 ± 2.3 pg/mL, P = 0.046). Moreover, precuneus atrophy was significantly correlated with serum GFAP levels in sEOAD (P < 0.001). Serum GFAP levels (area under the curve (AUC) = 96.0%, cutoff value = 154.3 pg/mL) displayed excellent diagnostic value in distinguishing sEOAD patients from the control group. These preliminary findings highlight the crucial role of tau protein phosphorylation in the pathogenesis and progression of sEOAD.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n=25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n=211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Early-onset Alzheimer's disease explained by polygenic risk of late-onset disease?

Early-onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early-onset AD patients without an identified autosomal dominant cause, we hypothesized that their early-onset disease reflects further enrichment of the common risk-conferring single nucleotide polymorphisms associated with late-onset AD. We applied a previously validated polygenic hazard score for late-onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early-onset AD. For comparison, we included 179 participants with late-onset AD and 70 healthy controls. Polygenic hazard scores were similar in early- versus late-onset AD. The polygenic hazard score was not associated with age-of-onset or disease biomarkers within early-onset AD. Early-onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late-onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights: There is a unique genetic architecture of early- versus late-onset Alzheimer's disease (AD).Late-onset AD polygenic risk is not an explanation for early-onset AD.Polygenic risk of late-onset AD does not predict early-onset AD biology.Unique genetic architecture of early- versus late-onset AD parallels AD heterogeneity.

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.

Octapeptide repeat alteration mutations of the prion protein gene in clinically diagnosed Alzheimer's disease and frontotemporal dementia.

Studies focusing on octapeptide repeat alteration mutations in PRNP in Alzheimer's disease (AD) and frontotemporal dementia (FTD) cohorts have been rare. We aim to screen sporadic AD and FTD patients with unknown etiology for the octapeptide repeat insertions and deletions in PRNP. Two hundred and six individuals were screened for alterations to the repeat region in the PRNP gene, including 146 sporadic AD and 60 sporadic FTD patients. Our study showed a 1.5% (3/206) occurrence of the octapeptide repeat alteration mutations in PRNP in a Chinese cohort of sporadic dementia. One late-onset FTD patient and one early-onset AD patient each had a two-octapeptide repeat deletion in PRNP, while one early-onset AD patient had a five-octapeptide repeat insertion mutation. PRNP octapeptide repeat alteration mutations are present in sporadic AD and FTD patients. The genetic investigation for PRNP octapeptide repeat alteration mutations in sporadic dementia patients should be carried out in future clinical studies.

Ethnic Disparities in Clinical Presentation of Patients with Early-Onset Alzheimer’s Disease (P14-6.002)

<h3>Objective:</h3> N/A <h3>Background:</h3> Early-onset Alzheimer’s Disease (EOAD) affects patients younger than age 65 and may present with non-amnestic features. Black patients are half as likely to be diagnosed despite twice as many risk factors. Ethnic disparities in EOAD have not been fully characterized. <h3>Design/Methods:</h3> We retrospectively identified EOAD patients February 2017–February 2022 and collected data on ethnicity, level of education, Montreal Cognitive Assessment (MoCA) scores and clinical presentation. <h3>Results:</h3> Of 88 total patients, 60 (68.8%) identified as Caucasian/White and 28 (31.8%) identified as African American/Black. Age at diagnosis (years) was (57.3 ± 5.24) in Black patients compared to (55.9 ± 5.69) in White patients. Time to diagnosis (years) was on average longer in Black patients (5 ± 9.21) compared with White patients (3.5 ± 6.44) and Black patients were on average more advanced (total MOCA scores) at presentation (12.17 ± 6.91) compared with White patients (15.15 ± 5.92) despite similar education level (in years) among Black patients (14.71 ± 2.30) and White patients (15.21±3.00). An amnestic profile was more common in Black patients (19 or 67.9%) than non-amnestic presentations (9 or 32.1%), although 2 patients (7.14%) presented with visual symptoms suggestive of posterior cortical atrophy (PCA), 5 (17.9%) patients had prominent language symptoms suggestive of logopenic primary progress aphasia (l-PPA) and 1 (3.6%) patient had an executive presentation, suggestive of frontal variant of AD (fAD). Comparatively, non-amnestic presentations were more commonly diagnosed in White patients, with 11 (18.3%) PCA diagnoses, 10 (16.7%) patients with fAD and 8 (13.3%) patients with l-PPA. <h3>Conclusions:</h3> In our cohort, Black patients with EOAD are on average older, more advanced and experience longer delays in diagnosis than their White counterparts. Non-amnestic presentations are more common in White patients. Further work is needed to further characterize the barriers to diagnosis accessibility of care for Black patients with EOAD. <b>Disclosure:</b> Ms. Yang has nothing to disclose. Dr. Yoon has nothing to disclose. Ms. Covaciu has nothing to disclose. The institution of Dr. Seibert has received research support from Retirement Research Foundation. The institution of Dr. Seibert has received research support from Center for Healthcare Delivery Science and Innovation.

Characterizing Early-Onset Alzheimer Disease Using Multiprobe PET/MRI: An AT(N) Framework-Based Study.

Early-onset Alzheimer disease (EOAD) is rare, highly heterogeneous, and associated with poor prognosis. This AT(N) Framework-based study aimed to compare multiprobe PET/MRI findings between EOAD and late-onset Alzheimer disease (LOAD) patients and explore potential imaging biomarkers for characterizing EOAD. Patients with AD who underwent PET/MRI in our PET center were retrospectively reviewed and grouped according to the age at disease onset: EOAD, younger than 60 years; and LOAD, 60 years or older. Clinical characteristics were recorded. All study patients had positive β-amyloid PET imaging; some patients also underwent 18 F-FDG and 18 F-florzolotau PET. Imaging of the EOAD and LOAD groups was compared using region-of-interest and voxel-based analysis. Correlation of onset age and regional SUV ratios were also evaluated. One hundred thirty-three patients were analyzed (75 EOAD and 58 LOAD patients). Sex ( P = 0.515) and education ( P = 0.412) did not significantly differ between groups. Mini-Mental State Examination score was significantly lower in the EOAD group (14.32 ± 6.74 vs 18.67 ± 7.20, P = 0.004). β-Amyloid deposition did not significantly differ between groups. Glucose metabolism in the frontal, parietal, precuneus, temporal, occipital lobe, and supramarginal and angular gyri was significantly lower in the EOAD group (n = 49) than in the LOAD group (n = 44). In voxel-based morphometry analysis, right posterior cingulate/precuneus atrophy was more obvious in the EOAD ( P < 0.001), although no voxel survived family-wise error correction. Tau deposition in the precuneus, parietal lobe, and angular, supramarginal, and right middle frontal gyri was significantly higher in the EOAD group (n = 18) than in the LOAD group (n = 13). Multiprobe PET/MRI showed that tau burden and neuronal damage are more severe in EOAD than in LOAD. Multiprobe PET/MRI may be useful to assess the pathologic characteristics of EOAD.

Regional Comparison of Imaging Biomarkers in the Striatum between Early- and Late-onset Alzheimer’s Disease

Striatal changes in the pathogenesis of Alzheimer's disease (AD) is not fully understood yet. We compared structural and functional image differences in the striatum between patients with early onset AD (EOAD) and late onset AD (LOAD) to investigate whether EOAD harbors autosomal dominant AD like imaging findings. The clinical, neuropsychological and neuroimaging biomarkers of 77 probable AD patients and 107 elderly subjects with normal cognition (NC) from the Alzheimer's Disease Neuroimaging Initiative (ADNI)-2 dataset were analyzed. Enrolled each subject completed a 3-Tesla MRI, baseline 18F-FDG-PET, and baseline 18F-AV-45 (Florbetapir) amyloid PET studies. AD patients were divided into two groups based on the onset age of clinical symptoms (EOAD <65 yrs; LOAD ≥65 yrs). A standardized uptake value ratio of the striatum and subcortical structures was obtained from both amyloid and FDG-PET scans. Structural MR imaging analysis was conducted using a parametric boundary description protocol, SPHARM-PDM. Of the 77 AD patients, 18 were EOAD and 59 were LOAD. Except for age of symptom onset, there were no statistically significant differences between the groups in demographics and detailed neuropsychological test results. 18F-AV-45 amyloid PET showed marked β-amyloid accumulation in the bilateral caudate nucleus and left pallidum in the EOAD group. Intriguingly, the caudate nucleus and putamen showed maintained glucose metabolism in the EOAD group compared to the LOAD group. Our image findings in the striatum of EOAD patients suggest that sporadic EOAD may share some pathophysiological changes noted in autosomal dominant AD.

The role of ethnicity, biological sex, and psychotropic agents in early and late onset Alzheimer's disease.

This study investigates differences in pharmacological and demographic factors among male and female patients with Late-onset Alzheimer's disease (LOAD) and Early-onset Alzheimer's disease (EOAD). Data are from 10,126 AD patients, 9,290 were diagnosed with LOAD, while 836 were diagnosed with EOAD. Data were collected from the Prisma Health Upstate Alzheimer's patients' registry between 2016 and 2021. The logistic regression analysis was used to assess the association between pharmacological and demographic factors in males and females with LOAD and EOAD. In the adjusted analysis for males, patients that were administered memantine [odd ratio (OR) = 1.588, 95% CI, 1.175-2.145, p = 0.003], and buspirone [OR = 1.971, 95% CI, 1.221-3.183, p = 0.006] were more likely to be associated with EOAD, while increasing age [OR = 0.816, 95% CI, 0.799-0.834, p < 0.001] was associated with LOAD. Female patients with a history of alcohol (ETOH) use were more likely to be associated with EOAD while increasing age [OR = 0.845, 95% CI, 0.834-0.857, p < 0.001], treatment with memantine [OR = 0.774, 95% CI, 0.627-0.956, p = 0.017], African Americans [OR = 0.621, 95% CI, 0.462-0.835, p = 0.002] and tobacco use [OR = 0.529, 95% CI, 0.424-0.660, p < 0.001] were associated with LOAD. Our findings identified specific demographic and pharmacological factors associated with males and females with LOAD and EOAD. These findings suggest the need to develop strategies to eliminate disparity in the care of LOAD or EOAD patients.

Age‐at‐Onset and APOE Related Heterogeneity in the Clinical, Plasma Biomarker, and Neuropathologic Presentation of Alzheimer’s Disease (AD)

AbstractBackgroundPatients with sporadic early‐onset AD (EOAD) show less pronounced memory impairment, faster cognitive decline, and greater likelihood of focal cortical syndromes than those with later onset (LOAD), while often lacking the APOE ε4 allele classically associated with younger onset. This heterogeneity could arise from differences in the distribution of AD pathology or presence of concomitant pathologies.MethodWe examined clinical and cognitive heterogeneity in relation to age‐at‐onset, APOE genotype, and concomitant neuropathology (Lewy body, TDP‐43, and vascular) in patients with autopsy‐confirmed severe AD from the National Alzheimer’s Coordinating Center database (N=1750). In patients from the UCSD Alzheimer’s Disease Research Center (N=121) we examined how age‐related heterogeneity relates to differences in distribution of neurofibrillary tangle (NFT) pathology and plasma biomarkers of AD.ResultAge‐at‐onset distribution in APOE ε4‐ patients was bimodal with best separation at age 63. Patients with EOAD (age ≤63) had faster cognitive and functional decline than LOAD regardless of APOE genotype; and were more likely to present with nonmemory cognitive complaints (OR=5.56, 99%CI: 3.32‐9.39), show greater executive dysfunction (β=2.59 SD, 99%CI: 2.10‐3.09), and receive a non‐AD clinical diagnosis (OR=1.54, 99%CI: 1.19‐1.97), particularly for ε4‐ EOAD (p’s&lt;0.01, APOE × age‐at‐onset interactions). Despite this atypicality, groups did not differ in their high rates of AD biomarker positivity, and ε4‐ EOAD patients were most likely to have pure AD without concomitant pathology. TDP‐43 (OR=0.37; 99%CI: 0.18–0.72) and microvascular (OR=0.65; 99%CI: 0.47–0.88) pathology were less common in EOAD, while Lewy pathology was more common in ε4+ (OR=1.48; 99% CI, 1.02–2.17). Midfrontal NFT density was higher in EOAD than LOAD (β= 0.87 SD, 99%CI: 0.44‐1.29). Greater hippocampal NFT density was associated with APOE ε4+ (β=0.49 SD, 99%CI: 0.02‐0.96). Mediation analyses suggest that differences in midfrontal/hippocampal NFT ratio, rather than concomitant neuropathology, mediate the atypical cognitive profiles and decline of EOAD (p&lt;0.01).ConclusionA relatively more neocortical NFT distribution, rather than concomitant non‐AD pathology, accounts for the atypical, non‐memory dominant clinical presentation and rapid progression in EOAD. This suggests that selective cortical vulnerability may explain the earlier‐than‐expected onset and atypical profile in these individuals without the APOE ε4 risk allele.

Hyperconnectivity matters in early-onset Alzheimer's disease: a resting-state EEG connectivity study

ObjectivesThe aim of this study was to differentiate individuals with early-onset Alzheimer's disease (EOAD) and identify differences of functional connectivity in resting-state EEG between individuals with EOAD and late-onset AD (LOAD) in comparison with both healthy young and elderly individuals. MethodsForty EOAD and 56 LOAD patients were included along with 51 demographically matched young, and 54 elderly healthy individuals as controls to the EOAD and LOAD groups. Four minutes of resting-state EEG were recorded during the eyes-closed condition. The absolute value of imaginary coherence (ICoh) was measured for connectivity. The maximum values of ICoh were measured at delta (0.5-3.5 Hz), theta (4-7.5Hz), alpha (8-13 Hz), alpha-1 (8-10 Hz), alpha-2 (10.5-13 Hz), beta (13-30 Hz), beta-1 (13-20 Hz), and beta-2 (20.5-30 Hz) frequency bands. ResultsIndividuals with EOAD showed higher coherence values in all frequency bands than LOAD patients. Compared to young healthy controls (YHC), EOAD had increased ICoh values in theta and beta-2 bands, whereas LOAD had lower ICoh values in the alpha-1 band than elderly healthy controls (EHC). Lastly, patients with EOAD demonstrated negative moderate correlations between language domains and beta-1 ICoh values. ConclusionTo the authors’ knowledge, this is the first study evaluating coherence alterations among early-and late-onset AD patients and the diagnostic value of coherence measures. It was suggested that EOAD patients had more severe pathological changes compared with LOAD.

Presenilin 1 gene mutations: a potential marker to help diagnose early onset Alzheimer’s disease

Alzheimer’s disease is a prevalent neurodegenerative disorder that affects millions of people worldwide with a substantial healthcare expenditure of almost $500 billion dollars. Alzheimer’s is primarily considered a disease of the aging population, with 95% of cases being diagnosed in patients over 65. Alzheimer’s in patients under 65 years of age are termed early onset Alzheimer’s disease (EOAD). The clinical presentation and disease mechanism of EOAD are quite distinct from typical Alzheimer’s. For example, EOAD patients often experience more rapid cognitive decline and have cortical region atrophy as opposed to temporal region atrophy. The atypical nature of EOAD frequently leads to delayed diagnosis and treatment. This delay is especially problematic for EOAD patients because they are at a stage of life with significant responsibilities such as maintaining their careers and families. This case study examines a previously healthy 32-year-old man that was mistakenly suspected of having frontotemporal dementia. Alzheimer’s was not considered as a correct diagnosis due to the atypical symptoms and weak family history for the disease. For these reasons, genetic analysis was not used to help make a diagnosis. The patient died at the age of 36 and autopsy revealed markers of Alzheimer’s including neuritic plaques and tau neurofibrillary tangles. Genetic analysis revealed no presenilin 1 (PSEN1) mutations which has been associated with EOAD. However, this patient may have had deletion mutations that could not be investigated due to the lack of frozen tissue for RNA analysis. This case illustrates the importance of genetic testing for EOAD diagnosis.

Dementia-related genetic variants in an Italian population of early-onset Alzheimer's disease.

Early-onset Alzheimer’s disease (EOAD) is the most common form of early-onset dementia. Although three major genes have been identified as causative, the genetic contribution to the disease remains unsolved in many patients. Recent studies have identified pathogenic variants in genes representing a risk factor for developing Alzheimer’s disease (AD) and in causative genes for other degenerative dementias as responsible for EOAD. To study them further, we investigated a panel of candidate genes in 102 Italian EOAD patients, 45.10% of whom had a positive family history and 21.74% with a strong family history of dementia. We found that 10.78% of patients carried pathogenic or likely pathogenic variants, including a novel variant, in PSEN1, PSEN2, or APP, and 7.84% showed homozygosity for the ε4 APOE allele. Additionally, 7.84% of patients had a moderate risk allele in PSEN1, PSEN2, or TREM2 genes. Besides, we observed that 12.75% of our patients carried only a variant in genes associated with other neurodegenerative diseases. The combination of these variants contributes to explain 46% of cases with a definite familiarity and 32% of sporadic forms. Our results confirm the importance of extensive genetic screening in EOAD for clinical purposes, to select patients for future treatments and to contribute to the definition of overlapping pathogenic mechanisms between AD and other forms of dementia.

Galectin-3 is elevated in CSF and is associated with Aβ deposits and tau aggregates in brain tissue in Alzheimer’s disease

Galectin-3 (Gal-3) is a beta-galactosidase binding protein involved in microglial activation in the central nervous system (CNS). We previously demonstrated the crucial deleterious role of Gal-3 in microglial activation in Alzheimer’s disease (AD). Under AD conditions, Gal-3 is primarily expressed by microglial cells clustered around Aβ plaques in both human and mouse brain, and knocking out Gal-3 reduces AD pathology in AD-model mice. To further unravel the importance of Gal-3-associated inflammation in AD, we aimed to investigate the Gal-3 inflammatory response in the AD continuum. First, we measured Gal-3 levels in neocortical and hippocampal tissue from early-onset AD patients, including genetic and sporadic cases. We found that Gal-3 levels were significantly higher in both cortex and hippocampus in AD subjects. Immunohistochemistry revealed that Gal-3+ microglial cells were associated with amyloid plaques of a larger size and more irregular shape and with neurons containing tau-inclusions. We then analyzed the levels of Gal-3 in cerebrospinal fluid (CSF) from AD patients (n = 119) compared to control individuals (n = 36). CSF Gal-3 levels were elevated in AD patients compared to controls and more strongly correlated with tau (p-Tau181 and t-tau) and synaptic markers (GAP-43 and neurogranin) than with amyloid-β. Lastly, principal component analysis (PCA) of AD biomarkers revealed that CSF Gal-3 clustered and associated with other CSF neuroinflammatory markers, including sTREM-2, GFAP, and YKL-40. This neuroinflammatory component was more highly expressed in the CSF from amyloid-β positive (A+), CSF p-Tau181 positive (T+), and biomarker neurodegeneration positive/negative (N+/−) (A + T + N+/−) groups compared to the A + T−N− group. Overall, Gal-3 stands out as a key pathological biomarker of AD pathology that is measurable in CSF and, therefore, a potential target for disease-modifying therapies involving the neuroinflammatory response.

Evolution of Clinical-Pathological Correlations in Early-Onset Alzheimer's Disease Over a 25-Year Period in an Academic Brain Bank.

Early onset Alzheimer's disease (EOAD) represents a diagnostic challenge and is associated with a high diagnostic delay and misdiagnosis. To describe clinical and pathological data from a pathologically confirmed EOAD cohort and evaluate evolving trends in clinical-pathological correlation accuracy. Retrospective review of clinical and neuropathological data of pathologically confirmed EOAD patients (age at onset [AAO] < 60). Comparison between two periods: 1994- 2009 and 2010- 2018. Eighty brain donors were included. Mean AAO, age at death, and diagnostic delay was 55, 66, and 3 years, respectively. Twenty-nine percent had a nonamnestic presentation. Sixteen percent were given a non-AD initial clinical diagnosis (initial misdiagnosis) and 14% received a final misdiagnosis. Nonamnestic presentation patients received more misdiagnoses than amnestic presentation ones (39% versus 7% and 39% versus 3.5%, on initial and final misdiagnosis, respectively). When comparing both time periods, a trend towards a higher diagnostic accuracy in the 2010- 2018 period was observed, mainly on initial misdiagnosis in nonamnestic presentation patients (53% versus 13%, p = 0.069). Diagnostic delay was similar between both periods. Cerebral amyloid angiopathy (96%) and Lewy body co-pathology (55%) were very frequent, while limbic-predominant age-related TDP-43 encephalopathy pathologic changes were only present in 12.5%. In the last decade, there has been a trend towards improved diagnostic accuracy in EOAD, which might be explained by improved diagnostic criteria, increasing experience on EOAD and the beginning of the use of biomarkers, although diagnostic delay remains similar. Concomitant neuropathology was very frequent despite the relatively young age of brain donors.

PSEN2 Mutation Spectrum and Novel Functionally Validated Mutations in Alzheimer's Disease: Data from PUMCH Dementia Cohort.

Background:The established causative mutations in the APP, PSEN1, and PSEN2 can explain less than 1%,Alzheimer’s disease (AD) patients. Of the identified variants, the PSEN2 mutations are even less common.Objective:With the genetic study from the dementia cohort of Peking Union Medical College Hospital (PUMCH), we aim to illustrate the PSEN2 mutation spectrum and novel functionally validated mutations in Chinese AD patients.Methods:702 AD participants, aged 30–85, were identified in PUMCH dementia cohort. They all received history inquiry, physical examination, biochemical test, cognitive evaluation, brain CT/MRI, and next-generation DNA sequencing. Functional analysis was achieved by transfection of the HEK293 cells with plasmids harboring the wild-type PSEN2 or candidate mutations.Results:Nine PSEN2 rare variants were found, including two reported (M239T, R62C) and seven novel variants (N141S, I368F, L396I, G117X, I146T, S147N, H220Y). The HEK293 cells transfected with the PSEN2 N141S, M239T, I368F plasmids showed higher Aβ42 and Aβ42/Aβ40 levels relative to the wild-type PSEN2. The PSEN2 L396I, G117X, S147N, H220Y, and R62C did not alter Aβ42, Aβ40 levels, or Aβ42/Aβ40 ratio. 1.9%,(13/702) subjects harbored rare PSEN2 variants. 0.4%,(3/702) subjects carried pathogenic/likely pathogenic PSEN2 mutations. The three subjects with the functionally validated PSEN2 mutations were all familial early-onset AD patients. The common symptoms included amnesia and mental symptom. Additionally, the M239T mutation carrier presented with dressing apraxia, visuospatial agraphia, dyscalculia and visual mislocalization.Conclusion:The PSEN2 N141S, M239T, and I368F are functionally validated mutations.