Variant Alzheimer Research Articles

Human iPSC-Derived Hippocampal Spheroids: An Innovative Tool for Stratifying Alzheimer Disease Patient-Specific Cellular Phenotypes and Developing Therapies.

SummaryThe hippocampus is important for memory formation and is severely affected in the brain with Alzheimer disease (AD). Our understanding of early pathogenic processes occurring in hippocampi in AD is limited due to tissue unavailability. Here, we report a chemical approach to rapidly generate free-floating hippocampal spheroids (HSs), from human induced pluripotent stem cells. When used to model AD, both APP and atypical PS1 variant HSs displayed increased Aβ42/Aβ40 peptide ratios and decreased synaptic protein levels, which are common features of AD. However, the two variants differed in tau hyperphosphorylation, protein aggregation, and protein network alterations. NeuroD1-mediated gene therapy in HSs-derived progenitors resulted in modulation of expression of numerous genes, including those involved in synaptic transmission. Thus, HSs can be harnessed to unravel the mechanisms underlying early pathogenic changes in the hippocampi of AD patients, and provide a robust platform for the development of therapeutic strategies targeting early stage AD.

Pathogenic PSEN1 Glu184Gly Mutation in a Family from Thailand with Probable Autosomal Dominant Early Onset Alzheimer's Disease.

A pathogenic mutation in PSEN1 p.Glu184Gly was discovered in a Thai family with early onset Alzheimer’s disease (EOAD) as the first case in Asia. Proband patient presented memory impairment and anxiety at the age of 41 years. Family history was positive, since several family members were also diagnosed with dementia (father and grandfather). MRI in the patient revealed global cortical atrophy without specific lesions or lacuna infarctions. Extensive genetic profiling for 50 neurodegenerative disease related genes was performed by next generation sequencing (NGS) on the patient. PSEN1 Glu184Gly was previously reported in French families with frontal variant Alzheimer’s disease (AD). Interestingly, this mutation is located near the splicing site and could possibly result in abnormal cleavage of PSEN1 transcript. Furthermore, 3D models from protein structural predictions revealed significant structural changes, since glycine may result in increased flexibility of TM-III helix. Inter/intra-helical interactions could also be altered. In the future, functional studies should be performed to verify the probable role PSEN1 Glu184Gly in amyloid beta processing and pathogenicity.

Word retrieval across the biomarker-confirmed Alzheimer's disease syndromic spectrum

Alzheimer's disease (AD) is now conceptualized as a biological entity defined by amyloid and tau deposition and neurodegeneration, with heterogeneous clinical presentations. With the aid of in vivo biomarkers, clinicians are better poised to examine clinical syndromic variability arising from a common pathology. Word retrieval deficits, measured using verbal fluency and confrontation naming tests, are hallmark features of the early clinical stages of the amnestic presentations of AD, specifically in category fluency and naming with relatively spared letter fluency. As yet, there is no consensus regarding performance on these tests in atypical clinical phenotypes of AD, including posterior cortical atrophy (PCA) and logopenic primary progressive aphasia (lvPPA), in individuals who are amyloid-positive (Aβ+) but present with different clinical profiles and patterns of neurodegeneration compared to amnestic AD. The goal of the current study is to determine how Aβ+ individuals across the syndromic spectrum of AD perform on three different word retrieval tasks. A secondary goal is to determine the neuroanatomical substrates underlying word retrieval performance in these Aβ+ individuals. Thirty-two Aβ+ participants with the amnestic presentation, 16 with Aβ+ PCA, 22 with Aβ+ lvPPA, and 99 amyloid-negative (Aβ-) control participants were evaluated with verbal fluency and visual confrontation naming tests as well as high-resolution MRI. The Aβ+ patient groups were rated at very mild or mild levels of severity (CDR 0.5 or 1) and had comparable levels of global cognitive impairment (average MMSE = 23.7 ± 3.9). Behaviorally, we found that the word retrieval profile of PCA patients is comparable to that of amnestic patients, characterized by intact letter fluency but impaired category fluency and visual confrontation naming, while lvPPA patients demonstrated impairment across all tests of word retrieval. Across all AD variants, we observed that letter fluency was associated with cortical thickness in prefrontal, central precuneus, lateral parietal and temporal cortex, while category fluency and naming were associated with cortical thickness in left middle frontal gyrus, posterior middle temporal gyrus, and lateral parietal cortex. Visual confrontation naming was uniquely associated with atrophy in inferior temporal and visual association cortex. We conclude that a better understanding of the word retrieval profiles and underlying neurodegeneration across the AD syndromic spectrum will help improve interpretation of neuropsychological profiles with regard to the localization of neurodegeneration, particularly in the atypical AD variants.

Immunological variants of amnestic mild cognitive impairment

Amnestic mild cognitive impairment (aMCI) is considered as a possible earliest pre-dementia clinical stage of Alzheimer's disease (AD). Taking into account the prominent role of neuroinflammation in the pathogenesis of AD, it is quite important to study possible immunological markers of the risk of aMCI progression and the changes in immune parameters in patients. To study the immunological variants of aMCI and AD based on the parameters of humoral and cell immunity, levels of key cytokines and presence of systemic inflammation, and to explore the link between changes in the immune parameters and clinical prognosis. One hundred patients with a diagnosis of aMCI, 45 patients with AD at the stage of mild to moderate dementia and 40 people without cognitive impairment (the control group) were enrolled into the study. Immunological assessment included determination of the concentration of key cytokines, C-reactive protein, circulating immune complexes and immunoglobulins (Ig A, M, G) in blood serum by ELISA, determination of the main subpopulations of lymphocytes by flow cytometry. Four main immunological variants of aMCI syndrome associated with clinical prognosis were identified. The detected changes in immune parameters are important for further studies to assess an effect of viral and bacterial infections, intestinal microflora disorders on a clinical prognosis in patients with different immunological variants of aMCI syndrome.

NEUROPSYCHOLOGICAL ASSESSMENT OF POSTERIOR CORTICAL ATROPHY: A CASE STUDY

The following case study examines the presentation of Mr. Fraser*, an older adult African American male diagnosed with Posterior Cortical Atrophy (PCA) following neuropsychological evaluation. PCA is a rare variant of Alzheimer’s Disease (AD) that results in visuospatial and perceptual deficits. Unlike other forms of neurocognitive degeneration, PCA tends to present at a relatively young age and may progress rapidly. There is currently a lack of studies examining PCA from a neuropsychological perspective, which may contribute to low awareness of this condition, as well as delayed diagnosis. It has been estimated that approximately 5% of patients with AD exhibit the PCA variant, implying that this a rare but serious condition. The following case study focuses on Mr. Fraser, a 65-year-old who was referred for neuropsychological assessment to assess his cognitive functioning. Mr. Fraser was administered a comprehensive assessment battery, and his overall results were suggestive of severe deficits in delayed memory and visuospatial skills. In the case of Mr. Fraser, these observed deficits, along with identification of visual complaints noted by his geriatrician, ultimately led to a diagnosis of PCA. While this was supported by neurological testing, the DSM-5 does not currently recognize PCA as a diagnosis. As a result, Mr. Fraser was given a diagnosis of possible AD with potential PCA, which may contribute to underestimates of the prevalence of this disorder. Future research and practice should focus on common neuropsychological presentations of this condition. *Identifying information changed in accordance with HIPAA guidelines

Sleep symptoms in syndromes of frontotemporal dementia and Alzheimer's disease: A proof-of-principle behavioural study.

Sleep disruption is a key clinical issue in the dementias but the sleep phenotypes of these diseases remain poorly characterised. Here we addressed this issue in a proof-of-principle study of 67 patients representing major syndromes of frontotemporal dementia (FTD) and Alzheimer's disease (AD), in relation to 25 healthy older individuals. We collected reports on clinically-relevant sleep characteristics - time spent overnight in bed, sleep quality, excessive daytime somnolence and disruptive sleep events. Difficulty falling or staying asleep at night and excessive daytime somnolence were significantly more frequently reported for patients with both FTD and AD than healthy controls. On average, patients with FTD and AD retired earlier and patients with AD spent significantly longer in bed overnight than did healthy controls. Excessive daytime somnolence was significantly more frequent in the FTD group than the AD group; AD syndromic subgroups showed similar sleep symptom profiles while FTD subgroups showed more variable profiles. Sleep disturbance is a significant clinical issue in major FTD and AD variant syndromes and may be even more salient in FTD than AD. These preliminary findings warrant further systematic investigation with electrophysiological and neuroanatomical correlation in major proteinopathies.

Does the Right Focal Variant of Alzheimer's Disease Really Exist? A Literature Analysis.

Alzheimer's disease (AD) is a clinically heterogeneous disease. Multiple atypical syndromes, distinct from the usual amnesic phenotype, have been described. In this context, the existence of a right variant of AD (RAD), characterized by enduring visuospatial impairment associated with right-sided asymmetric brain damage, has been proposed. However, to date, this phenotype remains controversial. In particular, its peculiar characteristics and the independence from more prevalent cases (especially the posterior cortical atrophy syndrome) have to be demonstrated. To explore the existence of focal RAD on the basis of existing literature. We performed a literature search for the description of atypical AD presentations, potentially evoking cases of focal RAD. To be considered as affected by RAD, the described cases had to present: 1) well documented right-sided asymmetry at neuroimaging; 2) predominant cognitive deficits localizable on the right hemisphere; 3) no specific diagnosis of a known variant of AD. Twenty-one cases were found in the literature, but some of them were subsequently excluded because some features of a different clinical syndrome were overlapped with the clinical features of RAD. Thirteen positive cases, three of them with pathologically confirmed AD, remained. A common right clinical-radiological syndrome, characterized by memory and visuospatial impairment with temporal and parietal involvement, consistently emerged. However, the heterogeneity among the reports prevented a definitive and univocal description of the syndrome. Even if sporadic observations strongly support the existence of a focal RAD, no definitive conclusions can still be drawn about it as an independent condition.

A screen of 1,049 schizophrenia and 30 Alzheimer's-associated variants for regulatory potential.

Recent genome-wide association studies (GWAS) identified numerous schizophrenia (SZ) and Alzheimer's disease (AD) associated loci, most outside protein-coding regions and hypothesized to affect gene transcription. We used a massively parallel reporter assay to screen, 1,049 SZ and 30 AD variants in 64 and nine loci, respectively for allele differences in driving reporter gene expression. A library of synthetic oligonucleotides assaying each allele five times was transfected into K562 chronic myelogenous leukemia lymphoblasts and SK-SY5Y human neuroblastoma cells. One hundred forty eight variants showed allelic differences in K562 and 53 in SK-SY5Y cells, on average 2.6 variants per locus. Nine showed significant differences in both lines, a modest overlap reflecting different regulatory landscapes of these lines that also differ significantly in chromatin marks. Eight of nine were in the same direction. We observe no preference for risk alleles to increase or decrease expression. We find a positive correlation between the number of SNPs in linkage disequilibrium and the proportion of functional SNPs supporting combinatorial effects that may lead to haplotype selection. Our results prioritize future functional follow up of disease associated SNPs to determine the driver GWAS variant(s), at each locus and enhance our understanding of gene regulation dynamics.

<p>Early-onset Alzheimer’s disease patient with prion <em>(PRNP)</em> p.Val180Ile mutation</p>

Background: In this study, a known PRNP mutation, Val180Ile (c.G538A), was reported in a 58 years old female patient, clinically diagnosed with Alzheimer’s disease (AD).Case report: The patient presented slowly progressive cognitive decline in memory and visuospatial domain. Neuroimaging showed hippocampal atrophy in MRI and mild amyloid positivity in PET scan. Even though her cerebrospinal fluid (CSF) was positive for 14–3-3 protein, no sign of Creutzfeldt-Jakob diseases symptoms was observed. In addition, reduced Aβ42 and elevated total-Tau and phospho-Tau in CSF also proved the AD diagnosis. The mutation may disturb the hydrophobic core of prion protein, and result in abnormal intramolecular interactions. Due to 23andMe, PRNP Val180Ile could not be categorized either as a mutation with complete penetrance, or as neutral variant, and could have a possible role in neurodegeneration. Pathological overlap was observed between prion diseases and other neurodegenerative diseases, including AD or frontotemporal dementia.Conclusion: Whole exome sequencing and pathway analysis of patient revealed rare or possible risk variants in AD associated genes, such as SORL1 or ABCA7. Along with PRNP, AD risk genes may play a role in negative regulation of amyloid formation. Dysfunctions in these genes could possibly be associated in reduced neuroprotection and amyloid clearance.

037 Frontotemporal dementia or frontal variant alzheimer’s disease? A case series

IntroductionAccurate prediction of the underlying neuropathology in behavioural variant frontotemporal dementia (bvFTD) is essential for future targeted therapy trials and prognostication. Alzheimer’s disease (AD) pathology has been reported in a significant proportion of patients with clinical bvFTD. We sought to determine whether detailed clinical and neuroradiological assessment was sufficient to distinguish bvFTD with AD pathology from bvFTD with frontotemporal lobar degeneration (FTLD).MethodsTwo patients with clinically diagnosed probable bvFTD but AD pathology at autopsy, were identified. The clinical, neuropsychological and imaging features of these patients were compared with those of ten patients with clinically probable bvFTD and proven FTLD pathology (tau, TDP-43, FUS).ResultsBoth patients with AD pathology presented with behavioural symptoms typical of bvFTD as well as memory impairment. Executive function, memory and visuospatial skills were impaired in both pathologic groups. Language skills were relatively spared in those with AD pathology. Neuropsychiatric symptoms were frequent in both groups but significant depression and anxiety were seen only in those with FTLD pathology. Dementia severity and caregiver burden were similar. The degree or topographical distribution of atrophy on MRI did not differ.ConclusionsAlzheimer’s pathology may cause bvFTD symptoms which are otherwise indistinguishable to those caused by FTLD pathology. While there may be subtle differences in patterns of cognitive deficits, standard neuropsychological testing is insufficient to discern the underlying pathology. Similarly, structural imaging cannot be used to reliably identify AD pathology. Better access to amyloid biomarkers may be needed to more accurately define bvFTD caused by AD pathology.

SORL1 genetic variants and Alzheimer disease risk: a literature review and meta-analysis of sequencing data.

Massive parallel sequencing recently allowed the identification of three genes carrying a higher burden of rare, protein-truncating and missense predicted damaging variants in Alzheimer disease (AD) casesas compared to controls: TREM2, SORL1, and ABCA7. SORL1 encodes SorLA, a key protein involved in the processing of the amyloid-beta (Aβ) precursor protein (APP) and the secretion of the Aβ peptide, the aggregation of which triggers AD pathophysiology. Common SORL1 single nucleotide polymorphisms had originally been associated with AD with modest odds ratios (ORs). The association of AD with rare SORL1 coding variants has been demonstrated at the gene level by aggregating protein-truncating (PTV) and rare predicted damaging missense variants. In addition to the loss of SorLA function induced by PTVs, a few missense variants were studied in vitro, showing diverse degrees of decreased SorLA function andleading to increased Aβ secretion. However, the exact functional consequences of most of the missense variants remain to be determined as well as corresponding levels of AD risk. Hereby we review the evidence of the association of SORL1 common and rare variants with AD risk and conduct a meta-analysis of published data on SORL1 rare variants in five large sequencing studies. We observe a significant enrichment in PTVs with ORs of 12.29 (95% confidence interval = [4.22-35.78]) among all AD cases and 27.50 [7.38-102.42] among early-onset cases. Rare [minor allele frequency (MAF) < 1%] and ultra-rare (MAF < 10-4) missense variants that are predicted damaging by 3/3 bioinformatics tools also show significant associations with corresponding ORs of 1.87 [1.54-2.28] and 3.14 [2.30-4.28], respectively. Per-domain analyses show significant association with the APP-binding CR cluster class A repeats and the Aβ-binding VPS10P domains, as well as the fibronectin type III domain, the function of which remains to be specified. These results further support a critical role for SORL1 rare coding variants in AD, although functional and segregation analyses are required to allow an accurate use in a clinical setting.

Exploring quantitative group-wise differentiation of Alzheimer\u2019s disease and behavioural variant frontotemporal dementia using tract-specific microstructural white matter and functional connectivity measures at multiple time points

ObjectivesThis study explored group-wise quantitative measures of tract-specific white matter (WM) microstructure and functional default mode network (DMN) connectivity to establish an initial indication of their clinical applicability for early-stage and follow-up differential diagnosis of Alzheimer’s disease (AD) and behavioural variant frontotemporal dementia (bvFTD).MethodsEleven AD and 12 bvFTD early-stage patients and 18 controls underwent diffusion tensor imaging and resting state functional magnetic resonance imaging at 3 T. All AD and 6 bvFTD patients underwent the same protocol at 1-year follow-up. Functional connectivity measures of DMN and WM tract-specific diffusivity measures were determined for all groups. Exploratory analyses were performed to compare all measures between the three groups at baseline and between patients at follow-up. Additionally, the difference between baseline and follow-up diffusivity measures in AD and bvFTD patients was compared.ResultsFunctional connectivity of the DMN was not different between groups at baseline and at follow-up. Diffusion abnormalities were observed widely in bvFTD and regionally in the hippocampal cingulum in AD. The extent of the differences between bvFTD and AD was diminished at follow-up, yet abnormalities were still more pronounced in bvFTD. The rate of change was similar in bvFTD and AD.ConclusionsThis study provides a tentative indication that quantitative tract-specific microstructural WM abnormalities, but not quantitative functional connectivity of the DMN, may aid early-stage and follow-up differential diagnosis of bvFTD and AD. Specifically, pronounced microstructural changes in anterior WM tracts may characterise bvFTD, whereas microstructural abnormalities of the hippocampal cingulum may characterise AD.Key Points• The clinical applicability of quantitative brain imaging measures for early-stage and follow-up differential diagnosis of dementia subtypes was explored using a group-wise approach.• Quantitative tract-specific microstructural white matter abnormalities, but not quantitative functional connectivity of the default mode network, may aid early-stage and follow-up differential diagnosis of behavioural variant frontotemporal dementia and Alzheimer’s disease.• Pronounced microstructural white matter (WM) changes in anterior WM tracts characterise behavioural variant frontotemporal dementia, whereas microstructural WM abnormalities of the hippocampal cingulum in the absence of other WM changes characterise Alzheimer’s disease.

Shared genes between Alzheimer's disease and ischemic stroke.

SummaryAimsAlthough converging evidence from experimental and epidemiological studies indicates Alzheimer's disease (AD) and ischemic stroke (IS) are related, the genetic basis underlying their links is less well characterized. Traditional SNP‐based genome‐wide association studies (GWAS) have failed to uncover shared susceptibility variants of AD and IS. Therefore, this study was designed to investigate whether pleiotropic genes existed between AD and IS to account for their phenotypic association, although this was not reported in previous studies.MethodsTaking advantage of large‐scale GWAS summary statistics of AD (17,008 AD cases and 37,154 controls) and IS (10,307 IS cases and 19,326 controls), we performed gene‐based analysis implemented in VEGAS2 and Fisher's meta‐analysis of the set of overlapped genes of nominal significance in both diseases. Subsequently, gene expression analysis in AD‐ or IS‐associated expression datasets was conducted to explore the transcriptional alterations of pleiotropic genes identified.Results16 AD‐IS pleiotropic genes surpassed the cutoff for Bonferroni‐corrected significance. Notably, MS4A4A and TREM2, two established AD‐susceptibility genes showed remarkable alterations in the spleens and brains afflicted by IS, respectively. Among the prioritized genes identified by virtue of literature‐based knowledge, most are immune‐relevant genes (EPHA1, MS4A4A, UBE2L3 and TREM2), implicating crucial roles of the immune system in the pathogenesis of AD and IS.ConclusionsThe observation that AD and IS had shared disease‐associated genes offered mechanistic insights into their common pathogenesis, predominantly involving the immune system. More importantly, our findings have important implications for future research directions, which are encouraged to verify the involvement of these candidates in AD and IS and interpret the exact molecular mechanisms of action.

Frontal variant of Alzheimer’s disease masquerading as behavioural-variant frontotemporal dementia: a case study comparison

ABSTRACTThe current clinical diagnostic criteria for Alzheimer’s disease (AD) recognize an atypical, non-amnestic presentation of AD, characterized by prominent executive dysfunction. Increasing evidence, however, indicates that the clinical phenotype of this so-called “frontal-variant” of AD (fv-AD) includes behavioral symptoms and deficits in social cognition, together with disproportionate frontal lobe atrophy. As these features resemble those characteristic of behavioral-variant frontotemporal dementia (bvFTD), differential diagnosis can be challenging. Here, we report a case of fv-AD who met clinical diagnostic criteria bvFTD, but had in vivo amyloid neuroimaging evidence of AD pathology. We compare this case against two individuals who were clinically diagnosed with bvFTD and early-onset AD, with in vivo amyloid neuroimaging confirmation of pathology. We highlight the challenges in differential diagnosis by contrasting their behavioral, cognitive and structural neuroimaging findings.

The Effects of Common Disease-Causing Variations on the Structure and Stability of TREM2: An In Silico Examination

Single nucleotide variations in TREM2 are associated with both a late-onset form of Alzheimer's disease (AD) and a severe, early-onset demyelinating dementia, which can present in isolation as a variant of frontotemporal dementia (FTD) or with cystic bone lipomas in a condition called Nasu-Hakola disease (NHD). Published X-ray crystallography models of the TREM2 Ig domain have suggested that homozygous NHD- or FTD-causing mutations are grossly inactivating while variations associated with increased risk of AD in heterozygous patients are centered on a prominent surface patch of positively charged residues. This surface patch, which is not present in other members of the TREM family, has been proposed as the primary binding site for various polyanionic ligands. Importantly, AD-associated variations in TREM2 appear to alter the electrostatics or gross structure of this surface patch, but do not cause larger structural changes in published crystal structures. Because crystal structures for many rare variants involved in disease remain unpublished, the precise effects of these variants on binding site structure and dynamic motion remain unclear. Here we perform molecular dynamics using AMBER14 to study the effects of mutations associated with AD, NHD, and FTD on stability of TREM2. Preliminary results show increased conformational flexibility in FTD and NHD variants, which is unchanged in AD variants. Consistent with proposed losses of structural stability from previous reports, this increased flexibility is present near the putative ligand-binding region and could directly contribute to lost or weakened binding between TREM2 and putative ligands, such as the AD-associated proteins APOE and amyloid-β. Thus, further work toward thorough understanding of conformation and dynamical motion in this region of TREM2 remains critical to our understanding of the role of TREM2 in AD and other neurodegenerative diseases.

Erratum: Whole-exome sequencing in 20,197 persons for rare variants in Alzheimer's disease.

[This corrects the article DOI: 10.1002/acn3.582.].

Protective Variants in Alzheimer's Disease.

Over the last decade over 40 loci have been associated with risk of Alzheimer's disease (AD). However, most studies have either focused on identifying risk loci or performing unbiased screens without a focus on protective variation in AD. Here, we provide a review of known protective variants in AD and their putative mechanisms of action. Additionally, we recommend strategies for finding new protective variants. Recent Genome-Wide Association Studies have identified both common and rare protective variants associated with AD. These include variants in or near APP, APOE, PLCG2, MS4A, MAPT-KANSL1, RAB10, ABCA1, CCL11, SORL1, NOCT, SCL24A4-RIN3, CASS4, EPHA1, SPPL2A, and NFIC. There are very few protective variants with functional evidence and a derived allele with a frequency below 20%. Additional fine mapping and multi-omic studies are needed to further validate and characterize known variants as well as specialized genome-wide scans to identify novel variants.

Visual cognition in non-amnestic Alzheimer's disease: Relations to tau, amyloid, and cortical atrophy.

Heterogeneity within the Alzheimer's disease (AD) syndromic spectrum is typically classified in a domain-specific manner (e.g., language vs. visual cognitive function). The central aim of this study was to investigate whether impairment in visual cognitive tasks thought to be subserved by posterior cortical dysfunction in non-amnestic AD presentations is associated with tau, amyloid, or neurodegeneration in those regions using 18F-AV-1451 and 11C-PiB positron emission tomography (PET) and magnetic resonance imaging (MRI). Sixteen amyloid-positive patients who met criteria for either Posterior Cortical Atrophy (PCA; n = 10) or logopenic variant Primary Progressive Aphasia (lvPPA; n = 6) were studied. All participants underwent a structured clinical assessment, neuropsychological battery, structural MRI, amyloid PET, and tau PET. The neuropsychological battery included two visual cognitive tests: VOSP Number Location and Benton Facial Recognition. Surface-based whole-cortical general linear models were used to first explore the similarities and differences between these biomarkers in the two patient groups, and then to assess their regional associations with visual cognitive test performance. The results show that these two variants of AD have both dissociable and overlapping areas of tau and atrophy, but amyloid is distributed with a stereotyped localization in both variants. Performance on both visual cognitive tests were associated with tau and atrophy in the right lateral and medial occipital association cortex, superior parietal cortex, and posterior ventral occipitotemporal cortex. No cortical associations were observed with amyloid PET. We further demonstrate that cortical atrophy has a partially mediating effect on the association between tau pathology and visual cognitive task performance. Our findings show that non-amnestic variants of AD have partially dissociable spatial patterns of tau and atrophy that localize as expected based on symptoms, but similar patterns of amyloid. Further, we demonstrate that impairments of visual cognitive dysfunction are strongly associated with tau in visual cortical regions and mediated in part by atrophy.

Disease Knowledge Transfer across Neurodegenerative Diseases.

We introduce Disease Knowledge Transfer (DKT), a novel technique for transferring biomarker information between related neurodegenerative diseases. DKT infers robust multimodal biomarker trajectories in rare neurodegenerative diseases even when only limited, unimodal data is available, by transferring information from larger multimodal datasets from common neurodegenerative diseases. DKT is a joint-disease generative model of biomarker progressions, which exploits biomarker relationships that are shared across diseases. Our proposed method allows, for the first time, the estimation of plausible multimodal biomarker trajectories in Posterior Cortical Atrophy (PCA), a rare neurodegenerative disease where only unimodal MRI data is available. For this we train DKT on a combined dataset containing subjects with two distinct diseases and sizes of data available: 1) a larger, multimodal typical AD (tAD) dataset from the TADPOLE Challenge, and 2) a smaller unimodal Posterior Cortical Atrophy (PCA) dataset from the Dementia Research Centre (DRC), for which only a limited number of Magnetic Resonance Imaging (MRI) scans are available. Although validation is challenging due to lack of data in PCA, we validate DKT on synthetic data and two patient datasets (TADPOLE and PCA cohorts), showing it can estimate the ground truth parameters in the simulation and predict unseen biomarkers on the two patient datasets. While we demonstrated DKT on Alzheimer's variants, we note DKT is generalisable to other forms of related neurodegenerative diseases. Source code for DKT is available online: https://github.com/mrazvan22/dkt.

Independent associations of TOMM40 and APOE variants with body mass index.

The TOMM40‐APOE variants are known for their strong, antagonistic associations with Alzheimer's disease and body weight. While a stronger role of the APOE than TOMM40 variants in Alzheimer's disease was suggested, comparative contribution of the TOMM40‐APOE variants in the regulation of body weight remains elusive. We examined additive effects of rs2075650 and rs157580 TOMM40 variants and rs429358 and rs7412 APOE variants coding the ε2/ε3/ε4 polymorphism on body mass index (BMI) in age‐aggregated and age‐stratified cohort‐specific and cohort‐pooled analysis of 27,863 Caucasians aged 20–100 years from seven longitudinal studies. Minor alleles of rs2075650, rs429358, and rs7412 were individually associated with BMI (β = −1.29, p = 3.97 × 10−9; β = −1.38, p = 2.78 × 10−10; and β = 0.58, p = 3.04 × 10−2, respectively). Conditional analysis with rs2075650 and rs429358 identified independent BMI‐lowering associations for minor alleles (β = −0.63, p = 3.99 × 10−2 and β = −0.94, p = 2.17 × 10−3, respectively). Polygenic mega‐analysis identified additive effects of the rs2075650 and rs429358 heterozygotes (β = −1.68, p = 3.00 × 10−9), and the strongest BMI‐lowering association for the rs2075650 heterozygous and rs429358 minor allele homozygous carriers (β = −4.11, p = 2.78 × 10−3). Conditional analysis with four polymorphisms identified independent BMI‐lowering (rs2075650, rs157580, and rs429358) and BMI‐increasing (rs7412) associations of heterozygous genotypes with BMI. Age‐stratified conditional analysis revealed well‐powered support for a differential and independent association of the rs429358 heterozygote with BMI in younger and older individuals, β = 0.58, 95% confidence interval (CI) = −1.18, 2.35, p = 5.18 × 10−1 for 3,068 individuals aged ≤30 years and β = −4.28, CI = −5.65, −2.92, p = 7.71 × 10−10 for 6,052 individuals aged >80 years. TOMM40 and APOE variants are independently and additively associated with BMI. The APOE ε4‐coding rs429358 polymorphism is associated with BMI in older individuals but not in younger individuals.