Young-onset Alzheimer Research Articles

Gray matter reserve determines glymphatic system function in young-onset Alzheimer's disease: Evidenced by DTI-ALPS and compared with age-matched controls.

The diffusion tensor imaging analysis along the perivascular space (ALPS)-index can be used to model the glymphatic system in vivo. This study explores putative mechanisms between prediction of ALPS-index and cognitive outcomes in young-onset Alzheimer's disease (YOAD) and age-matched controls (CTLs) and analyzes whether the link was mediated by the integrity of ALPS-index-anchored cerebral gray matter (GM). We enrolled 130 patients with YOAD and 137 CTLs. All participants underwent three-dimensional T1 -weighted MRI, diffusion tensor imaging and cognitive tests. We constructed GM regions correlated with the ALPS-index in the YOAD and CTL groups. For the GM regions significantly correlated with the ALPS-index and cognitive measures, we extracted a 4-mm radius sphere. In the YOAD and CTL groups, we used mediator analysis to explore the ALPS-index as predictor, GM partitions as mediators, and significant cognitive test scores as outcomes. Patient group had significantly lower ALPS-index. The ALPS-index was associated with GM volume in the cerebellar gray, dorsolateral prefrontal, thalamus, superior frontal, amygdala and hippocampus, and these coherent regions coincided with those showing GM atrophy in the YOAD group. Mediation analysis of the YOAD group suggested that the relationships between the ALPS-index and cognitive performance were fully mediated by the integrity of ALPS-index coherent GM areas. Reserved GM mediates the link between the glymphatic system and cognition. Our findings suggest that GM integrity rather than the glymphatic system could serve as a direct cognitive test scores predictor in patients with YOAD.

Journey to Diagnosis of Young-Onset Dementia: A Qualitative Study of People with Young-Onset Dementia and their Family Caregivers in Australia.

This study aims to explore the journey to dementia diagnosis and reaction to the diagnosis from the perspective of people with young-onset dementia living in the community from diverse areas in Australia (metropolitan, regional, rural) and their family caregivers. Semi-structured interviews were conducted with community-dwelling people with early to moderate young-onset Alzheimer's disease (n = 8) or frontotemporal dementia (n = 5) and one person with both Alzheimer's disease and frontotemporal dementia, and family caregivers of community-dwelling people with young-onset Alzheimer's disease and/or frontotemporal dementia (n = 28). This study employed interpretive description. Thematic analysis was conducted for emergent themes, comparisons and interplay between themes. The journey to the diagnosis is characterised as involving an extensive period of the gradual worsening of symptoms, drawn out investigations, and difficulties facing the prospect of a diagnosis of young-onset dementia. Participants with young-onset dementia struggled to manage their symptoms and the process of seeking a diagnosis was often slow due to difficulties during the course of their medical investigations and feeling reluctance to face the possibility of having dementia. Once participants finally received the diagnosis of young-onset dementia, participants with young-onset dementia and their family caregivers experienced feelings of devastation and shock, in some cases denial and avoidance, and even, confirmation and relief at having received a diagnosis. In some instances, participants experienced more than one of these reactions. There was a profound realisation by participants that a diagnosis of young-onset dementia had serious implications on their life and future. The journey to diagnosis was found to be a drawn-out process and receiving the diagnosis was a shock for both people with young-onset dementia and their family caregivers. The findings highlight the significance of the role healthcare professionals play in both the diagnostic and post-diagnostic journey, particularly in terms of supporting patients with young-onset dementia and their family caregivers.

Brain Amyloid in Sporadic Young Onset Alzheimer's Disease.

Controversy exists as to the role of the amyloid-β (Aβ) peptide in the pathophysiology of Alzheimer's disease (AD). To clarify the effect of age on Aβ deposition in sporadic AD by exploring the degree of amyloid burden in patients with sporadic young onset AD (YOAD). Patients were diagnosed with YOAD with dementia starting before the age of 65 years (N = 42; males = 20, females = 22). A cross-sectional analysis of amyloid binding using positron emission tomography (PET) imaging was performed using the C-Pittsburgh Compound B (PiB). The global standardized uptake value ratios (gSUVR) were examined using the Wilcoxon two-sample test, as were the cognitive scores between disease and healthy control populations. Differences in PiB retention in different anatomical areas were compared using the Kruskal-Wallis test. The contrast in APOE genotyping between groups was calculated with Fisher's Exact Test. Women had a median gSUVR = 2.68±0.73 and 73% had at least one APOE ɛ4 allele. Men had gSUVR = 2.37±0.54, with 80% having at least one APOE ɛ4 allele. The gSUVRs were significantly higher than the control populations for men and women and had significantly greater frequency of APOE ɛ4. Men and women analyzed together had significantly greater amyloid burden and APOE ɛ4 allele frequencies than controls, but no differences existed between them in gSUVR nor in the anatomical distribution of amyloid uptake. Men and women with YOAD have greater amyloid uptake than controls and have more APOE ɛ4 alleles. Our findings suggest that the Aβ peptide is operational in young onset dementia and driven by the APOE ɛ4 allele.

Cortical tau is associated with microstructural imaging biomarkers of neurite density and dendritic complexity in Alzheimer's disease.

In Alzheimer's disease (AD), hyperphosphorylated tau is closely associated with focal neurodegeneration, but the mechanism remains uncertain. We quantified cortical microstructure using neurite orientation dispersion and density imaging in 14 individuals with young onset AD. Diffusion tensor imaging measured mean diffusivity (MD). Amyloid beta and tau positron emission tomography were acquired and associations with microstructural measures were assessed. When regional volume was adjusted for, in the medial temporal lobe there was a significant negative association between neurite density and tau (partial R2 =0.56, p=0.008) and between orientation dispersion and tau (partial R2 =0.66, p=0.002), but not between MD and tau. In a wider cortical composite, there was an association between orientation dispersion and tau (partial R2 =0.43, p=0.030), but not between other measures and tau. Our findings are consistent with tau causing first dendritic pruning (reducing dispersion/complexity) followed by neuronal loss. Advanced magnetic resonance imaging (MRI) microstructural measures have the potential to provide information relating to underlying tau deposition.

Carer burden and behavioral disturbance is similar between younger-onset Alzheimer's disease and behavioral variant frontotemporal dementia.

Carer burden is common in younger-onset dementia (YOD), often due to the difficulty of navigating services often designed for older people with dementia. Compared to Alzheimer's disease (AD), the burden is reported to be higher in behavioral variant frontotemporal dementia (bvFTD). However, there is little literature comparing carer burden specifically in YOD. This study hypothesized that carer burden in bvFTD would be higher than in AD. Retrospective cross-sectional study. Tertiary neuropsychiatry service in Victoria, Australia. Patient-carer dyads with YOD. We collected patient data, including behaviors using the Cambridge Behavioral Inventory-Revised (CBI-R). Carer burden was rated using the Zarit Burden Inventory-short version (ZBI-12). Descriptive statistics and Mann-Whitney U tests were used to analyze the data. Carers reported high burden (ZBI-12 mean score = 17.2, SD = 10.5), with no significant difference in burden between younger-onset AD and bvFTD. CBI-R stereotypic and motor behaviors, CBI-R everyday skills, and total NUCOG scores differed between the two groups. There was no significant difference in the rest of the CBI-R subcategories, including the behavior-related domains. Carers of YOD face high burden and are managing significant challenging behaviors. We found no difference in carer burden between younger-onset AD and bvFTD. This could be due to similarities in the two subtypes in terms of abnormal behavior, motivation, and self-care as measured on CBI-R, contrary to previous literature. Clinicians should screen for carer burden and associated factors including behavioral symptoms in YOD syndromes, as they may contribute to carer burden regardless of the type.

An Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger-Onset Alzheimer's.

An Innovative Approach to Empowering Care Partners Living with A Loved One Diagnosed with Younger-Onset Alzheimer's Our innovative approach at Lorenzo's House, a nonprofit in Chicago, empowers care partners living with a loved one with younger-onset Alzheimer's. Lorenzo's Angels is a proven model designed to create one-on-one mentor matches between care partners. This personalized match offers connection with someone who shares a similar profile and understands. Families living with a younger-onset diagnosis are often underserved and under-discussed in the Alzheimer's community. With this diagnosis comes a dramatic shift in a younger family's dynamic and they are often alienated from popular Alzheimers' resources geared towards people who are diagnosed later in life. These care partner spouses are in a uniquely important and difficult position as they are responsible for being the primary care partner to their spouse, breadwinner for the household, and for parenting independently - all while navigating the complexities of the diagnosis. A family culture changes after a younger-onset Alzheimer's diagnosis, and there is a need for innovative care and personal connection. We recognize that the best guidance and support for care partners often comes from people who have or are still walking the path. We empower families by cultivating a care partner-to-care partner mentor model, building an International network of care partners matches. Our framework emphasizes social emotional wellness, practical information and resourcefulness so that families turn isolation to connectedness and darkness to light, living this journey together - never alone. By creating this framework through digital and in-person platforms, we provide sustenance to care partners everywhere living with a loved one with younger-onset Alzheimer's.

Supporting Youth With A Parent Who Is Living Younger-Onset Alzheimer's: A Crucial Component In Integrated Care.

Supporting Youth With A Parent Who Is Living Younger-Onset Alzheimer's: A Crucial Component In Integrated Care Lorenzo's House, a nonprofit in Chicago, focuses on a transformative approach that supports children and young adults who are living with a parent with younger-onset Alzheimer's. Youth are often affected by a parent's diagnosis at a neurobiologically vulnerable time in their lives. Youth frequently don't know how to explain their experience as a care partner with their peers, leaving them isolated and managing the ongoing change by themselves. By creating spaces specifically catered towards these young care partners, we are radically shifting the journey of what younger-onset Alzheimer's looks like for children and young adults. We focus on the relationship between the parent diagnosed and their children, what children need as care partners, and what issues and struggles they face at a variety of ages in this journey. Our three youth programs focus on innovation to support youth living with a parent with younger-onset Alzheimer's: Lorenzo's Camp, a camp designed by youth care partners, therapists, medical professionals - intended to share common stories and build an alliance; the Light Club, a virtual youth care partner group injected with team building and relationship development; and lastly youth-led advocacy work. Our model shifts the narrative for how youth experience being a member of a family that is navigating a younger-onset Alzheimer's diagnosis.

Importance of the Genetic Diagnosis of Young Onset Alzheimer's Disease: Presenilin Presented in Still Alice

Alice in the movie Still Alice suffers from Juvenile Alzheimer's disease. Incidences of Alzheimer's disease tend to be sporadic cases in which clinical manifestations begin after 65 years of age. However, the majority of the Juvenile type of Alzheimer's disease occurs at 50-60 years of age, and is usually induced by genetic mutations, such as amyloid β, and the presenilin 1 or 2 genes. Genetic examination revealed that Alice possessed a mutation of the presenilin gene. This movie presents her conflicting emotions around the genetic testing of her three children.

The Development of Videoconference-Based Support for People Living With Rare Dementias and Their Carers: Protocol for a 3-Phase Support Group Evaluation.

BackgroundPeople living with rarer dementias face considerable difficulty accessing tailored information, advice, and peer and professional support. Web-based meeting platforms offer a critical opportunity to connect with others through shared lived experiences, even if they are geographically dispersed, particularly during the COVID-19 pandemic.ObjectiveWe aim to develop facilitated videoconferencing support groups (VSGs) tailored to people living with or caring for someone with familial or sporadic frontotemporal dementia or young-onset Alzheimer disease, primary progressive aphasia, posterior cortical atrophy, or Lewy body dementia. This paper describes the development, coproduction, field testing, and evaluation plan for these groups.MethodsWe describe a 3-phase approach to development. First, information and knowledge were gathered as part of a coproduction process with members of the Rare Dementia Support service. This information, together with literature searches and consultation with experts by experience, clinicians, and academics, shaped the design of the VSGs and session themes. Second, field testing involved 154 Rare Dementia Support members (people living with dementia and carers) participating in 2 rounds of facilitated sessions across 7 themes (health and social care professionals, advance care planning, independence and identity, grief and loss, empowering your identity, couples, and hope and dementia). Third, a detailed evaluation plan for future rounds of VSGs was developed.ResultsThe development of the small groups program yielded content and structure for 9 themed VSGs (the 7 piloted themes plus a later stages program and creativity club for implementation in rounds 3 and beyond) to be delivered over 4 to 8 sessions. The evaluation plan incorporated a range of quantitative (attendance, demographics, and geography; pre-post well-being ratings and surveys; psycholinguistic analysis of conversation; facial emotion recognition; facilitator ratings; and economic analysis of program delivery) and qualitative (content and thematic analysis) approaches. Pilot data from round 2 groups on the pre-post 3-word surveys indicated an increase in the emotional valence of words selected after the sessions.ConclusionsThe involvement of people with lived experience of a rare dementia was critical to the design, development, and delivery of the small virtual support group program, and evaluation of this program will yield convergent data about the impact of tailored support delivered to geographically dispersed communities. This is the first study to design and plan an evaluation of VSGs specifically for people affected by rare dementias, including both people living with a rare dementia and their carers, and the outcome of the evaluation will be hugely beneficial in shaping specific and targeted support, which is often lacking in this population.International Registered Report Identifier (IRRID)DERR1-10.2196/35376

CSF biomarkers in patients with epilepsy in Alzheimer's disease: a nation-wide study.

Alzheimer’s disease is the most common neurodegenerative dementia. A subset of Alzheimer’s disease patients develop epilepsy. The risk is higher in young-onset Alzheimer’s disease, but pathophysiological mechanisms remain elusive. The purpose of this study was to assess biomarkers reflecting neurodegeneration in Alzheimer’s disease patients with and without epilepsy. By cross-referencing the largest national laboratory database with Swedish National Patient Register, we could identify CSF biomarker results from 17901 Alzheimer’s disease patients, and compare levels of neurofilament light, glial fibrillary acidic protein, total tau, phosphorylated tau and amyloid beta 42 in patients with (n = 851) and without epilepsy. The concentrations of total tau and phosphorylated tau were higher in Alzheimer’s disease patients with epilepsy than Alzheimer’s disease patients without epilepsy and amyloid beta 42 levels were significantly lower in Alzheimer’s disease patients with epilepsy. No differences in the levels of neurofilament light and glial fibrillary acidic protein were observed. Our study suggests that epilepsy is more common in Alzheimer’s disease patients with more pronounced Alzheimer’s pathology, as determined by the CSF biomarkers. Further studies are needed to investigate the biomarker potential of these CSF markers as predictors of epilepsy course or as indicators of epileptogenesis in Alzheimer’s disease.

Functional Connectivity Group Differences in Young-Onset Alzheimer's Disease as Investigated by Volume- And Surface-Based fMRI Analysis Strategies

Functional Connectivity Group Differences in Young-Onset Alzheimer's Disease as Investigated by Volume- And Surface-Based fMRI Analysis Strategies

Disentangling axonal loss and demyelination using multi‐modal imaging: Application to young onset Alzheimer’s disease

AbstractBackgroundMapping axonal loss in young‐onset Alzheimer’s disease (YOAD) can provide a clearer picture of neurodegenerative processes. Axonal loss has been estimated using metrics derived from diffusion MRI (dMRI). However, these measures are also sensitive to myelin, thus cannot unambiguously disentangle axon loss and demyelination. Here, we address this with multi‐modal imaging, combining dMRI with magnetisation transfer saturation (MTsat) MRI, a technique sensitive specifically to myelin.MethodNeurite density index (NDI), a dMRI estimate from NODDI, relates to axon volume fraction (AVF), an axon density estimate unconfounded by myelin: AVF=(1‐MVF)(1‐FWF)NDI (Stikov et al. Neuroimage; 118:397‐405, 2015). MVF is the myelin volume fraction, an estimate of myelin density, and FWF the free water fraction from NODDI. MVF is estimated from MTsat imaging (Mohammadi et al. Frontiers in Neuroscience; 9, 9:441, 2015). Maps of AVF, MVF and NDI were computed for 21 healthy controls and 30 YOAD patients who underwent NODDI‐compatible dMRI and MTsat MRI. Tract‐based spatial statistics (TBSS) was used to map significant changes (p<0.05, FWE‐corrected) along white matter (WM) skeleton (Fig. 2, lower) of the population template.ResultFigure 1 shows the population‐averaged AVF and MVF of each point along the WM skeleton, demonstrating NDI is influenced by both AVF and MVF. While AVF and NDI correlate strongly (R2=0.46, p<5e‐10), suggesting NDI is primarily a marker of axon density, MVF also contributes to the observed NDI variation (R2=0.16, p<5e‐10).Figure 2 shows TBSS group differences in these metrics. MVF reductions in fronto‐occipital regions, indicating demyelination, overlap with NDI reductions but not AVF changes (Fig. 2A). AVF reductions in the splenium, indicating axonal loss, did not overlap with NDI changes (Fig. 2B). This demonstrates sub‐optimal specificity and sensitivity of NDI to axonal loss. Most AVF reductions; in the posterior tracts, fornix and the corpus callosum splenium, areas associated with symptoms of YOAD; were accompanied by decreased NDI. Concomitant MVF reductions occurred in posterior areas (Fig 2C).ConclusionThis study presents a multi‐modal imaging approach to disambiguate markers of axonal loss and demyelination, effects previously entangled in single modality DWI analysis. This technique may provide new insight into in vivo pathological processes in neurodegenerative diseases.

Not all voxels are created equal: Reducing estimation bias in regional NODDI metrics using tissue-weighted means

Neurite orientation dispersion and density imaging (NODDI) estimates microstructural properties of brain tissue relating to the organisation and processing capacity of neurites, which are essential elements for neuronal communication. Descriptive statistics of NODDI tissue metrics are commonly analyzed in regions-of-interest (ROI) to identify brain-phenotype associations. Here, the conventional method to calculate the ROI mean weights all voxels equally. However, this produces biased estimates in the presence of CSF partial volume. This study introduces the tissue-weighted mean, which calculates the mean NODDI metric across the tissue within an ROI, utilising the tissue fraction estimate from NODDI to reduce estimation bias. We demonstrate the proposed mean in a study of white matter abnormalities in young onset Alzheimer's disease (YOAD). Results show the conventional mean induces significant bias that correlates with CSF partial volume, primarily affecting periventricular regions and more so in YOAD subjects than in healthy controls. Due to the differential extent of bias between healthy controls and YOAD subjects, the conventional mean under- or over-estimated the effect size for group differences in many ROIs. This demonstrates the importance of using the correct estimation procedure when inferring group differences in studies where the extent of CSF partial volume differs between groups. These findings are robust across different acquisition and processing conditions. Bias persists in ROIs at higher image resolution, as demonstrated using data obtained from the third phase of the Alzheimer's disease neuroimaging initiative (ADNI); and when performing ROI analysis in template space. This suggests that conventional ROI means of NODDI metrics are biased estimates under most contemporary experimental conditions, the correction of which requires the proposed tissue-weighted mean. The tissue-weighted mean produces accurate estimates of ROI means and group differences when ROIs contain voxels with CSF partial volume. In addition to NODDI, the technique can be applied to other multi-compartment models that account for CSF partial volume, such as the free water elimination method. We expect the technique to help generate new insights into normal and abnormal variation in tissue microstructure of regions typically confounded by CSF partial volume, such as those in individuals with larger ventricles due to atrophy associated with neurodegenerative disease.

Loss and dispersion of superficial white matter in Alzheimer's disease: a diffusion MRI study.

Pathological cerebral white matter changes in Alzheimer’s disease have been shown using diffusion tensor imaging. Superficial white matter changes are relatively understudied despite their importance in cortico-cortical connections. Measuring superficial white matter degeneration using diffusion tensor imaging is challenging due to its complex organizational structure and proximity to the cortex. To overcome this, we investigated diffusion MRI changes in young-onset Alzheimer’s disease using standard diffusion tensor imaging and Neurite Orientation Dispersion and Density Imaging to distinguish between disease-related changes that are degenerative (e.g. loss of myelinated fibres) and organizational (e.g. increased fibre dispersion). Twenty-nine young-onset Alzheimer’s disease patients and 22 healthy controls had both single-shell and multi-shell diffusion MRI. We calculated fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index and tissue fraction (1-free water fraction). Diffusion metrics were sampled in 15 a priori regions of interest at four points along the cortical profile: cortical grey matter, grey/white boundary, superficial white matter (1 mm below grey/white boundary) and superficial/deeper white matter (2 mm below grey/white boundary). To estimate cross-sectional group differences, we used average marginal effects from linear mixed effect models of participants’ diffusion metrics along the cortical profile. The superficial white matter of young-onset Alzheimer’s disease individuals had lower neurite density index compared to controls in five regions (superior and inferior parietal, precuneus, entorhinal and parahippocampus) (all P < 0.05), and higher orientation dispersion index in three regions (fusiform, entorhinal and parahippocampus) (all P < 0.05). Young-onset Alzheimer’s disease individuals had lower fractional anisotropy in the entorhinal and parahippocampus regions (both P < 0.05) and higher fractional anisotropy within the postcentral region (P < 0.05). Mean diffusivity was higher in the young-onset Alzheimer’s disease group in the parahippocampal region (P < 0.05) and lower in the postcentral, precentral and superior temporal regions (all P < 0.05). In the overlying grey matter, disease-related changes were largely consistent with superficial white matter findings when using neurite density index and fractional anisotropy, but appeared at odds with orientation dispersion and mean diffusivity. Tissue fraction was significantly lower across all grey matter regions in young-onset Alzheimer’s disease individuals (all P < 0.001) but group differences reduced in magnitude and coverage when moving towards the superficial white matter. These results show that microstructural changes occur within superficial white matter and along the cortical profile in individuals with young-onset Alzheimer’s disease. Lower neurite density and higher orientation dispersion suggests underlying fibres undergo neurodegeneration and organizational changes, two effects previously indiscernible using standard diffusion tensor metrics in superficial white matter.

Sex differences in the incidence and prevalence of young-onset Alzheimer's disease: A meta-analysis.

ObjectivesThe lifetime incidence of Alzheimer's disease is higher in women than in men, but it remains unclear if similar sex differences exist in young‐onset Alzheimer's disease (YOAD). This systematic review test the hypothesis that women have a higher prevalence and incidence of YOAD than men.MethodsWe searched Pubmed and Embase (inception to 11 June 2020) for original publications of population‐based observational studies with data on the prevalence and/or incidence of YOAD, defined as a medical diagnosis of Alzheimer's disease before the age of 65 years. Data on cross‐sectional and/or prospective numbers, percentages, incidences, and incidence rates (in person‐years) were derived from included studies. Quality assessment was done using the Nottingham Ottawa Scale. Meta‐analyses were done to test the hypothesis that women have a higher prevalence and incidence of YOAD than men.ResultsAfter screening of 3252 titles, 12 articles were included. The pooled prevalence was 0.4% (confidence interval [CI] = 0.1–2.1) in women and 0.2% (CI = 0–1.2) in men (six studies, relative risk [RR] = 1.54, CI = 0.69–3.44, I 2 = 38%). The pooled incidence was 0.02% (CI = 0.01–0.08) in women and 0.01% (CI = 0–0.05) in men (five studies, RR = 1.50, CI = 0.91‐2.48, I 2 = 0%). The incidence rates per 100,000 person‐years ranged from 0 to 132 in women and from 0 to 42 in men.ConclusionsGiven the low prevalence and wide CIs, no firm conclusions can be drawn. Large‐scale studies are required to verify that women are more likely than men to develop YOAD.

Time to Diagnosis in Young Onset Alzheimer's Disease: A Population-Based Study from Central Norway.

Background:Young onset dementia is associated with a longer time to diagnosis compared to late onset dementia. Earlier publications have indicated that atypical presentation is a key contributing factor to the diagnostic delay. Our hypothesis was that even the most common presentation of Alzheimer’s disease is associated with a substantial diagnostic delay in patients < 65 years.Objective:To determine the time to diagnosis, and time lags in the diagnostic pathway in typical young onset Alzheimer’s disease in central Norway.Methods:The main sources of patients were the databases at the Department of Neurology, University Hospital of Trondheim (St. Olav’s Hospital), and Department of Psychiatry, Levanger Hospital. Other sources included key persons in the communities, collaborating hospital departments examining patients with suspected cognitive impairment, and review of hospital records of all three hospitals in the area. Information on the time lags, and the clinical assessment, including the use of biomarkers, was collected from hospital notes. Caregivers were interviewed by telephone.Results:Time from first symptom to diagnosis in typical young onset Alzheimer’s disease was 5.5 years (n = 223, SD 2.8). Time from onset to contact with healthcare services (usually a general practitioner) was 3.4 years (SD 2.3). Time from contact with healthcare services to the first visit at a hospital was 10.3 months (SD 15.5). Time from first visit at a hospital to diagnosis was 14.8 months (SD 22.6). The analysis of cerebrospinal fluid core biomarkers was performed after 8.3 months (SD 20.9).Conclusion:Typical Alzheimer’s disease is associated with a substantial diagnostic delay in younger patients. Raising public awareness, and education of healthcare professionals on the aspects of young onset Alzheimer’s disease is warranted. CSF core biomarkers should be performed earlier in the hospital evaluation process.

A systematic review of atypical Alzheimer's disease including behavioural and psychological symptoms.

Alzheimer's disease (AD) is the commonest cause of dementia, characterized by the clinical presentation of progressive anterograde episodic memory impairment. However, atypical presentation of patients is increasingly recognized. These atypical AD include logopenic aphasia, behavioural variant AD, posterior cortical atrophy, and corticobasal syndrome. These atypical AD are more common in patients with young onset AD before the age of 65 years old. Since medical needs (including the behavioural and psychological symptoms of dementia) of atypical AD patients could be different from typical AD patients, it is important for clinicians to be aware of these atypical forms of AD. In addition, disease modifying treatment may be available in the future. This review aims at providing an update on various important subtypes of atypical AD including behavioural and psychological symptoms.

Genetic study of young-onset dementia using targeted gene panel sequencing in Taiwan.

Recent genetic progress allows the molecular diagnosis of young-onset dementia, including Alzheimer's disease (AD) and frontotemporal dementia (FTD). We aimed to identify the mutational and clinical spectra of causal genes in a Taiwanese cohort of young-onset dementia. Ninety-one patients with young-onset dementia and 22 age/gender-matched controls were recruited. Genetic causes were identified by a targeted panel containing 90 causative genes for AD, FTD, and related neurodegenerative disorders. Plasma biomarkers, including total tau, Aβ42, and Aβ40, were assayed. Molecular amyloid and tau PET scans were performed in some patients carrying mutations. Nine of 52 patients (17.3%) with young-onset AD had mutations: 2 (22.2%), 4 (44.5%), 2 (22.2%), and 1 (11.1%) in APP, PSEN1, PSEN2, and TREM2, respectively. Two of 33 patients (6.1%) with young-onset FTD had mutations in MAPT and LRRK2. Three of the 6 patients (50.0%) with possible FTD combined with other neurodegenerative disorders had individual mutations in APP, PSEN2, or MAPT. Patients with PSEN1 mutations had earlier onset of disease than those without mutations (p = .02). Plasma level of total tau was increased and Aβ42 and Aβ40 levels decreased in all groups of dementia patients compared to controls. Our findings provide a genetic spectrum of young-onset dementia in our population.

Non-memory cognitive symptom development in Alzheimer's disease.

Memory is known to be the most common first symptom in Alzheimer's disease (AD). Assessing non-memory cognitive symptom development in AD is important for understanding disease progression and the potential identification of treatment-responsive subtypes. Data from the National Alzheimer's Coordinating Center were examined. Logistic regression models were fitted evaluating the development of judgement, language, visuospatial and attention symptoms at first and second visits to Alzheimer's Disease Centers. Predictors were age and prior symptoms, adjusting for symptom length and sex. The models were then refitted assessing apolipoprotein E ε4 (APOE-ε4) effects. Each decade reduction in presentation age increased the odds of language, visuospatial and attention symptom development at both visits by 8%-18% (P<0.05, all tests), and judgement symptoms at the second visit by 13% (P<0.05). Prior symptoms were not equally predictive of symptom development. For example, having first predominant language symptoms carried the lowest risk of developing other first-visit symptoms and having memory symptoms was a stronger predictor of developing judgement than other symptoms. The APOE-ε4 gene showed little impact on symptom development when included as a predictor. Our findings provide support for the concept that younger-onset AD is associated with the progressive development of more non-memory symptoms beyond the first time point. Associations between symptoms were evident, which may reflect that pathology can remain isolated in a network for some time. APOE-ε4 status had little influence on cognitive symptom development which may indicate that the effect it has occurs very early in the disease course.

Selective Vulnerability of the Nucleus Basalis of Meynert Among Neuropathologic Subtypes of Alzheimer Disease

Corticolimbic patterns of neurofibrillary tangle (NFT) accumulation define neuropathologic subtypes of Alzheimer disease (AD), which underlie the clinical heterogeneity observed antemortem. The cholinergic system, which is the target of acetylcholinesterase inhibitor therapy, is selectively vulnerable in AD. To investigate the major source of cholinergic innervation, the nucleus basalis of Meynert (nbM), in order to determine whether there is differential involvement of NFT accumulation or neuronal loss among AD subtypes. In this cross-sectional study, retrospective abstraction of clinical records and quantitative assessment of NFTs and neuron counts in the nbM was completed in January 2019 at the Mayo Clinic using the Florida Autopsied Multi-Ethnic (FLAME) cohort, which had been accessioned from 1991 until 2015. The FLAME cohort is derived from the deeded autopsy program funded throughout the State of Florida's memory disorder clinic referral services. Of the 2809 consecutively accessioned FLAME cohort, 1464 were identified as neuropathologically diagnosed AD cases and nondemented normal controls available for clinicopathologic assessment. Quantification of NFTs and neuronal density in the anterior nbM was performed blinded to neuropathologic groupings. Demographic and clinical characteristics, including cognitive decline measured using the Mini-Mental State Examination score (range, 0-30), were evaluated. The anterior nbM was investigated quantitatively for neuronal loss and NFT accumulation. In total, 1361 AD subtypes and 103 nondemented controls were assessed. The median (interquartile range) age at death was 72 (66-80) years in hippocampal sparing (HpSp) AD, 81 (76-86) years in typical AD, and 86 (82-90) years in limbic predominant AD. The median (interquartile range) count per 0.125 mm2 of thioflavin S-positive NFTs was highest in the nbM of HpSp AD (14 [9-20]; n = 163), lower in typical AD (10 [5-16]; n = 937), and lowest in limbic predominant AD (8 [5-11], n = 163) (P < .001). The median (interquartile range) neuronal density per millimeters squared was lowest in HpSp AD cases (22 [17-28]; n = 148), higher in typical AD (25 [19-30]; n = 727), and highest in limbic predominant AD (26 [19-32]; n = 127) (P = .002). Multivariable regression modeling of clinical and demographic variables was performed to assess overlap in NFT accumulation and neuronal density differences among AD subtypes. Higher NFT accumulation in the nbM was associated with younger age at onset for HpSp AD (β, -1.5; 95% CI, -2.9 to -0.15; P = .03) and typical AD (β, -3.2; 95% CI, -3.9 to -2.4; P < .001). In addition, higher NFT accumulation in the nbM of typical AD cases was associated with female sex (β, 2.5; 95% CI, 1.4-3.5; P < .001), apolipoprotein E ε4 allele (β, 1.3; 95% CI, 0.15-2.5; P = .03), and lower Mini-Mental State Examination scores (β, -1.8; 95% CI, -3.2 to -0.31; P = .02). Demographic and clinical progression variables were not associated with NFT accumulation in the nbM of limbic predominant AD cases. These data provide supportive evidence that NFT accumulation in the nbM may underlie more widespread and severe cholinergic deficits in young-onset AD, in particular in patients with HpSp AD. Moreover, these findings underscore the importance of considering age at onset, sex, and apolipoprotein E genotype when assessing outcomes in AD.