Molecular mechanisms linking type 2 diabetes mellitus and late-onset Alzheimer's disease: A systematic review and qualitative meta-analysis.

Research evidence indicating common metabolic mechanisms through which type 2 diabetes mellitus (T2DM) increases risk of late-onset Alzheimer's dementia (LOAD) has accumulated over recent decades. The aim of this systematic review is to provide a comprehensive review of common mechanisms, which have hitherto been discussed in separate perspectives, and to assemble and evaluate candidate loci and epigenetic modifications contributing to polygenic risk linkages between T2DM and LOAD. For the systematic review on pathophysiological mechanisms, both human and animal studies up to December 2023 are included. For the qualitative meta-analysis of genomic bases, human association studies were examined; for epigenetic mechanisms, data from human studies and animal models were accepted. Papers describing pathophysiological studies were identified in databases, and further literature gathered from cited work. For genomic and epigenomic studies, literature mining was conducted by formalised search codes using Boolean operators in search engines, and augmented by GeneRif citations in Entrez Gene, and other sources (WikiGenes, etc.). For the systematic review of pathophysiological mechanisms, 923 publications were evaluated, and 138 gene loci extracted for testing candidate risk linkages. 3 57 publications were evaluated for genomic association and descriptions of epigenomic modifications. Overall accumulated results highlight insulin signalling, inflammation and inflammasome pathways, proteolysis, gluconeogenesis and glycolysis, glycosylation, lipoprotein metabolism and oxidation, cell cycle regulation or survival, autophagic-lysosomal pathways, and energy. Documented findings suggest interplay between brain insulin resistance, neuroinflammation, insult compensatory mechanisms, and peripheral metabolic dysregulation in T2DM and LOAD linkage. The results allow for more streamlined longitudinal studies of T2DM-LOAD risk linkages.

Effect of the ROCK inhibitor fasudil on the brain proteomic profile in the tau transgenic mouse model of Alzheimer's disease.

Introduction: The goal of this study is to explore the pharmacological potential of the amyloid-reducing vasodilator fasudil, a selective Ras homolog (Rho)-associated kinases (ROCK) inhibitor, in the P301S tau transgenic mouse model (Line PS19) of neurodegenerative tauopathy and Alzheimer's disease (AD). Methods: We used LC-MS/MS, ELISA and bioinformatic approaches to investigate the effect of treatment with fasudil on the brain proteomic profile in PS19 tau transgenic mice. We also explored the efficacy of fasudil in reducing tau phosphorylation, and the potential beneficial and/or toxic effects of its administration in mice. Results: Proteomic profiling of mice brains exposed to fasudil revealed the activation of the mitochondrial tricarboxylic acid (TCA) cycle and blood-brain barrier (BBB) gap junction metabolic pathways. We also observed a significant negative correlation between the brain levels of phosphorylated tau (pTau) at residue 396 and both fasudil and its metabolite hydroxyfasudil. Conclusions: Our results provide evidence on the activation of proteins and pathways related to mitochondria and BBB functions by fasudil treatment and support its further development and therapeutic potential for AD.

Reduction of Phosphorylated Tau in Alzheimer's Disease Induced Pluripotent Stem Cell-Derived Neuro-Spheroids by Rho-Associated Coiled-Coil Kinase Inhibitor Fasudil.

BACKGROUND: Alzheimer's disease (AD) is the most predominant form of dementia. Rho-associated coiled coil kinase (ROCK) inhibitor, fasudil, is one of the candidate drugs against the AD progression. OBJECTIVE: We aimed to investigate possible changes of AD associated markers in three-dimensional neuro-spheroids (3D neuro-spheroids) generated from induced pluripotent stem cells derived from AD patients or healthy control subjects (HC) and to determine the impact of pharmacological intervention with the ROCK inhibitor fasudil. METHODS: We treated 3D neuro-spheroids with fasudil and tested the possible effect on AD markers by ELISA, transcriptomic and proteomic analyses. RESULTS: Transcriptomic analysis revealed a reduction in the expression of AKT serine/threonine-protein kinase 1 (AKT1) in AD neuro-spheroids, compared to HC. This decrease was reverted in the presence of fasudil. Proteomic analysis showed up- and down-regulation of proteins related to AKT pathway in fasudil-treated neuro-spheroids. We found an evident increase of phosphorylated tau at four different residues (pTau181, 202, 231, and 396) in AD compared to HC-derived neuro-spheroids. This was accompanied by a decrease of secreted clusterin (clu) and an increase of intracellular clu levels in AD patient-derived neuro-spheroids. Increases of phosphorylated tau in AD patient-derived neuro-spheroids were suppressed in the presence of fasudil. CONCLUSIONS: Fasudil modulates clu protein levels and enhances AKT1 that results in the suppression of AD associated tau phosphorylation.

Masking the transmembrane region of the amyloid ß precursor protein as a safe means to lower amyloid ß production.

Introduction: Reducing brain levels of both soluble and insoluble forms of amyloid beta (Aß) remains the primary goal of most therapies that target Alzheimer's disease (AD). However, no treatment has so far resulted in patient benefit, and clinical trials of the most promising drug candidates have generally failed due to significant adverse effects. This highlights the need for safer and more selective ways to target and modulate Aß biogenesis. Methods: Peptide technology has advanced to allow reliable synthesis, purification, and delivery of once-challenging hydrophobic sequences. This is opening up new routes to target membrane processes associated with disease. Here we deploy a combination of atomic detail molecular dynamics (MD) simulations, living-cell Förster resonance energy transfer (FRET), and in vitro assays to elucidate the atomic-detail dynamics, molecular mechanisms, and cellular activity and selectivity of a membrane-active peptide that targets the Aß precursor protein (APP). Results: We demonstrate that Aß biogenesis can be downregulated selectively using an APP occlusion peptide (APPOP). APPOP inhibits Aß production in a dose-dependent manner, with a mean inhibitory concentration (IC50) of 450 nM toward exogenous APP and 50 nM toward endogenous APP in primary rat cortical neuronal cultures. APPOP does not impact the γ-secretase cleavage of Notch-1, or exhibit toxicity toward cultured primary rat neurons, suggesting that it selectively shields APP from proteolysis. Discussion: Drugs targeting AD need to be given early and for very long periods to prevent the onset of clinical symptoms. This necessitates being able to target Aß production precisely and without affecting the activity of key cellular enzymes such as γ-secretase for other substrates. Peptides offer a powerful way for targeting key pathways precisely, thereby reducing the risk of adverse effects. Here we show that protecting APP from proteolytic processing offers a promising route to safely and specifically lower Aß burden. In particular, we show that the amyloid pathway can be targeted directly and specificically. This reduces the risk of off-target effects and paves the way for a safe prophylactic treatment.

Neurodegenerative Disease Associated Pathways in the Brains of Triple Transgenic Alzheimer's Model Mice Are Reversed Following Two Weeks of Peripheral Administration of Fasudil.

The pan Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor fasudil acts as a vasodilator and has been used as a medication for post-cerebral stroke for the past 29 years in Japan and China. More recently, based on the involvement of ROCK inhibition in synaptic function, neuronal survival, and processes associated with neuroinflammation, it has been suggested that the drug may be repurposed for neurodegenerative diseases. Indeed, fasudil has demonstrated preclinical efficacy in many neurodegenerative disease models. To facilitate an understanding of the wider biological processes at play due to ROCK inhibition in the context of neurodegeneration, we performed a global gene expression analysis on the brains of Alzheimer's disease model mice treated with fasudil via peripheral IP injection. We then performed a comparative analysis of the fasudil-driven transcriptional profile with profiles generated from a meta-analysis of multiple neurodegenerative diseases. Our results show that fasudil tends to drive gene expression in a reverse sense to that seen in brains with post-mortem neurodegenerative disease. The results are most striking in terms of pathway enrichment analysis, where pathways perturbed in Alzheimer's and Parkinson's diseases are overwhelmingly driven in the opposite direction by fasudil treatment. Thus, our results bolster the repurposing potential of fasudil by demonstrating an anti-neurodegenerative phenotype in a disease context and highlight the potential of in vivo transcriptional profiling of drug activity.

NRF2: An emerging role in neural stem cell regulation and neurogenesis.

The birth of new neurons from neural stem cells (NSC)s during developmental and adult neurogenesis arises from a myriad of highly complex signalling cascades. Emerging as one of these is the nuclear factor erythroid 2-related factor (NRF2)-signaling pathway. Regulation by NRF2 is reported to span the neurogenic process from early neural lineage specification and NSC regulation to neuronal fate commitment and differentiation. Here, we review these reports selecting only those where NRF2 signaling was directly manipulated to provide a clearer case for a direct role of NRF2 in embryonic and adult neurogenesis. With few studies providing mechanistic insight into this relationship, we lastly discuss key pathways linking NRF2 and stem cell regulation outside the neural lineage to shed light on mechanisms that may also be relevant to NSCs and neurogenesis.

In vivo multi-parametric manganese-enhanced MRI for detecting amyloid plaques in rodent models of Alzheimer's disease.

Amyloid plaques are a hallmark of Alzheimer's disease (AD) that develop in its earliest stages. Thus, non-invasive detection of these plaques would be invaluable for diagnosis and the development and monitoring of treatments, but this remains a challenge due to their small size. Here, we investigated the utility of manganese-enhanced MRI (MEMRI) for visualizing plaques in transgenic rodent models of AD across two species: 5xFAD mice and TgF344-AD rats. Animals were given subcutaneous injections of MnCl2 and imaged in vivo using a 9.4 T Bruker scanner. MnCl2 improved signal-to-noise ratio but was not necessary to detect plaques in high-resolution images. Plaques were visible in all transgenic animals and no wild-types, and quantitative susceptibility mapping showed that they were more paramagnetic than the surrounding tissue. This, combined with beta-amyloid and iron staining, indicate that plaque MR visibility in both animal models was driven by plaque size and iron load. Longitudinal relaxation rate mapping revealed increased manganese uptake in brain regions of high plaque burden in transgenic animals compared to their wild-type littermates. This was limited to the rhinencephalon in the TgF344-AD rats, while it was most significantly increased in the cortex of the 5xFAD mice. Alizarin Red staining suggests that manganese bound to plaques in 5xFAD mice but not in TgF344-AD rats. Multi-parametric MEMRI is a simple, viable method for detecting amyloid plaques in rodent models of AD. Manganese-induced signal enhancement can enable higher-resolution imaging, which is key to visualizing these small amyloid deposits. We also present the first in vivo evidence of manganese as a potential targeted contrast agent for imaging plaques in the 5xFAD model of AD.

Transcription-based drug repurposing for COVID-19.

We have utilised the transcriptional response of lung epithelial cells following infection by the original Severe Acute Respiratory Syndrome coronavirus (SARS) to identify repurposable drugs for COVID-19. Drugs best able to recapitulate the infection profile are highly enriched for antiviral activity. Nine of these have been tested against SARS-2 and found to potently antagonise SARS-2 infection/replication, with a number now being considered for clinical trials. It is hoped that this approach may serve to broaden the spectrum of approved drugs that should be further assessed as potential anti-COVID-19 agents and may help elucidate how this seemingly disparate collection of drugs are able to inhibit SARS-2 infection/replication.

Dickkopf-1 Overexpression in vitro Nominates Candidate Blood Biomarkers Relating to Alzheimer's Disease Pathology.

BACKGROUND: Previous studies suggest that Dickkopf-1 (DKK1), an inhibitor of Wnt signaling, plays a role in amyloid-induced toxicity and hence Alzheimer's disease (AD). However, the effect of DKK1 expression on protein expression, and whether such proteins are altered in disease, is unknown. OBJECTIVE: We aim to test whether DKK1 induced protein signature obtained in vitro were associated with markers of AD pathology as used in the amyloid/tau/neurodegeneration (ATN) framework as well as with clinical outcomes. METHODS: We first overexpressed DKK1 in HEK293A cells and quantified 1,128 proteins in cell lysates using aptamer capture arrays (SomaScan) to obtain a protein signature induced by DKK1. We then used the same assay to measure the DKK1-signature proteins in human plasma in two large cohorts, EMIF (n = 785) and ANM (n = 677). RESULTS: We identified a 100-protein signature induced by DKK1 in vitro. Subsets of proteins, along with age and apolipoprotein E ɛ4 genotype distinguished amyloid pathology (A + T-N-, A+T+N-, A+T-N+, and A+T+N+) from no AD pathology (A-T-N-) with an area under the curve of 0.72, 0.81, 0.88, and 0.85, respectively. Furthermore, we found that some signature proteins (e.g., Complement C3 and albumin) were associated with cognitive score and AD diagnosis in both cohorts. CONCLUSIONS: Our results add further evidence for a role of DKK regulation of Wnt signaling in AD and suggest that DKK1 induced signature proteins obtained in vitro could reflect theATNframework as well as predict disease severity and progression in vivo.

Bridging Integrator-1 protein loss in Alzheimer's disease promotes synaptic tau accumulation and disrupts tau release.

Polymorphisms associated with BIN1 confer the second greatest risk for developing late onset Alzheimer's disease. The biological consequences of this genetic variation are not fully understood, however BIN1 is a binding partner for tau. Tau is normally a highly soluble cytoplasmic protein, but in Alzheimer's disease tau is abnormally phosphorylated and accumulates at synapses to exert synaptotoxicity. The purpose of this study was to determine if alterations to BIN1 and tau in Alzheimer's disease promote the damaging redistribution of tau to synapses, as a mechanism by which BIN1 polymorphisms may increase risk of developing Alzheimer's disease. We show that BIN1 is lost from the cytoplasmic fraction of Alzheimer's disease cortex, and this is accompanied by the progressive mislocalization of phosphorylated tau to synapses. We confirmed proline 216 in tau as critical for tau interaction with the BIN1-SH3 domain and show that phosphorylation of tau disrupts this binding, suggesting that tau phosphorylation in Alzheimer's disease disrupts tau-BIN1 associations. Moreover, we show that BIN1 knockdown in rat primary neurons to mimic BIN1 loss in Alzheimer's disease brain, causes the damaging accumulation of phosphorylated tau at synapses and alterations in dendritic spine morphology. We also observed reduced release of tau from neurons upon BIN1 silencing, suggesting that BIN1 loss disrupts the function of extracellular tau. Together, these data indicate that polymorphisms associated with BIN1 that reduce BIN1 protein levels in the brain likely act synergistically with increased tau phosphorylation to increase risk of Alzheimer's disease by disrupting cytoplasmic tau-BIN1 interactions, promoting the damaging mis-sorting of phosphorylated tau to synapses to alter synapse structure, and by reducing the release of physiological forms of tau to disrupt tau function.

Correction to: Wnt3a induces exosome secretion from primary cultured rat microglia.

Following the publication of this article [1], it has been noted by the authors that an image of the same cell nuclei has been used in error twice, in Fig. 8, parts A and B. These images are redundant in this figure as the images in parts D and E show Wnt3a treated and control cells stained with both Hoechst 33342 (as in parts A and B) and fluorescein diacetate. The data from multiple repetitions of the Hoechst 33342 stain experiment are presented in graph C. Thus, the duplicated images (in Fig. 8A and B) add no additional data and do not change the results or conclusions reached in the article. The authors apologize for any confusion this may have caused.

A role for APP in Wnt signalling links synapse loss with ß-amyloid production.

In Alzheimer's disease (AD), the canonical Wnt inhibitor Dickkopf-1 (Dkk1) is induced by ß-amyloid (Aß) and shifts the balance from canonical towards non-canonical Wnt signalling. Canonical (Wnt-ß-catenin) signalling promotes synapse stability, while non-canonical (Wnt-PCP) signalling favours synapse retraction; thus Aß-driven synapse loss is mediated by Dkk1. Here we show that the Amyloid Precursor Protein (APP) co-activates both arms of Wnt signalling through physical interactions with Wnt co-receptors LRP6 and Vangl2, to bi-directionally modulate synapse stability. Furthermore, activation of non-canonical Wnt signalling enhances Aß production, while activation of canonical signalling suppresses Aß production. Together, these findings identify a pathogenic-positive feedback loop in which Aß induces Dkk1 expression, thereby activating non-canonical Wnt signalling to promote synapse loss and drive further Aß production. The Swedish familial AD variant of APP (APPSwe) more readily co-activates non-canonical, at the expense of canonical Wnt activity, indicating that its pathogenicity likely involves direct effects on synapses, in addition to increased Aß production. Finally, we report that pharmacological inhibition of the Aß-Dkk1-Aß positive feedback loop with the drug fasudil can restore the balance between Wnt pathways, prevent dendritic spine withdrawal in vitro, and reduce Aß load in vivo in mice with advanced amyloid pathology. These results clarify a relationship between Aß accumulation and synapse loss and provide direction for the development of potential disease-modifying treatments.

Clusterin Is Required for ß-Amyloid Toxicity in Human iPSC-Derived Neurons.

Our understanding of the molecular processes underlying Alzheimer's disease (AD) is still limited, hindering the development of effective treatments, and highlighting the need for human-specific models. Advances in identifying components of the amyloid cascade are progressing, including the role of the protein clusterin in mediating ß-amyloid (Aß) toxicity. Mutations in the clusterin gene (CLU), a major genetic AD risk factor, are known to have important roles in Aß processing. Here we investigate how CLU mediates Aß-driven neurodegeneration in human induced pluripotent stem cell (iPSC)-derived neurons. We generated a novel CLU-knockout iPSC line by CRISPR/Cas9-mediated gene editing to investigate Aß-mediated neurodegeneration in cortical neurons differentiated from wild type and CLU knockout iPSCs. We measured response to Aß using an imaging assay and measured changes in gene expression using qPCR and RNA sequencing. In wild type neurons imaging indicated that neuronal processes degenerate following treatment with Aß25-35 peptides and Aß1-42 oligomers, in a dose dependent manner, and that intracellular levels of clusterin are increased following Aß treatment. However, in CLU knockout neurons Aß exposure did not affect neurite length, suggesting that clusterin is an important component of the amyloid cascade. Transcriptomic data were analyzed to elucidate the pathways responsible for the altered response to Aß in neurons with the CLU deletion. Four of the five genes previously identified as downstream to Aß and Dickkopf-1 (DKK1) proteins in an Aß-driven neurotoxic pathway in rodent cells were also dysregulated in human neurons with the CLU deletion. AD and lysosome pathways were the most significantly dysregulated pathways in the CLU knockout neurons, and pathways relating to cytoskeletal processes were most dysregulated in Aß treated neurons. The absence of neurodegeneration in the CLU knockout neurons in response to Aß compared to the wild type neurons supports the role of clusterin in Aß-mediated AD pathogenesis.

Amyloid ß synaptotoxicity is Wnt-PCP dependent and blocked by fasudil.

INTRODUCTION: Synapse loss is the structural correlate of the cognitive decline indicative of dementia. In the brains of Alzheimer's disease sufferers, amyloid ß (Aß) peptides aggregate to form senile plaques but as soluble peptides are toxic to synapses. We previously demonstrated that Aß induces Dickkopf-1 (Dkk1), which in turn activates the Wnt-planar cell polarity (Wnt-PCP) pathway to drive tau pathology and neuronal death. METHODS: We compared the effects of Aß and of Dkk1 on synapse morphology and memory impairment while inhibiting or silencing key elements of the Wnt-PCP pathway. RESULTS: We demonstrate that Aß synaptotoxicity is also Dkk1 and Wnt-PCP dependent, mediated by the arm of Wnt-PCP regulating actin cytoskeletal dynamics via Daam1, RhoA and ROCK, and can be blocked by the drug fasudil. DISCUSSION: Our data add to the importance of aberrant Wnt signaling in Alzheimer's disease neuropathology and indicate that fasudil could be repurposed as a treatment for the disease.

Clusterin expression is upregulated following acute head injury and localizes to astrocytes in old head injury.

There is mounting evidence linking traumatic brain injury (TBI) to neurodegeneration. Clusterin (apolipoprotein J or ApoJ) is a complement inhibitor that appears to have a neuroprotective effect in response to tissue damage and has been reported to be upregulated in Alzheimer's disease. Here we investigated the time course and cellular expression pattern of clusterin in human TBI. Tissue from 32 patients with TBI of varying survival times (from under 30 min to 10 months) was examined using immunohistochemistry for clusterin alongside other markers of neurodegeneration and neuroinflammation. TBI cases were compared to ischemic brain damage, Alzheimer's disease and controls. Double immunofluorescence was carried out in order to examine cellular expression. Clusterin was initially expressed in an axonal location less than 30 min following TBI and increased in intensity and the frequency of deposits with increasing survival time up to 24 h, after which it appeared to reduce in intensity but was still evident several weeks after injury. Clusterin was first evident in astrocytes after 45 min, being increasingly seen up to 48 h but remaining intense in TBI cases with long survival times. Our results suggest clusterin plays a role in modulating the inflammatory response of acute and chronic TBI and that it is a useful marker for TBI, particularly in cases with short survival times. Its prominent accumulation in astrocytes, alongside a mounting inflammatory response and activation of microglial cells supports a potential role in the neurodegenerative changes that occur as a result of TBI.

Knockdown of the schizophrenia susceptibility gene TCF4 alters gene expression and proliferation of progenitor cells from the developing human neocortex.

BACKGROUND: Common variants in the TCF4 gene are among the most robustly supported genetic risk factors for schizophrenia. Rare TCF4 deletions and loss-of-function point mutations cause Pitt-Hopkins syndrome, a developmental disorder associated with severe intellectual disability. METHODS: To explore molecular and cellular mechanisms by which TCF4 perturbation could interfere with human cortical development, we experimentally reduced the endogenous expression of TCF4 in a neural progenitor cell line derived from the developing human cerebral cortex using RNA interference. Effects on genome-wide gene expression were assessed by microarray, followed by Gene Ontology and pathway analysis of differentially expressed genes. We tested for genetic association between the set of differentially expressed genes and schizophrenia using genome-wide association study data from the Psychiatric Genomics Consortium and competitive gene set analysis (MAGMA). Effects on cell proliferation were assessed using high content imaging. RESULTS: Genes that were differentially expressed following TCF4 knockdown were highly enriched for involvement in the cell cycle. There was a nonsignificant trend for genetic association between the differentially expressed gene set and schizophrenia. Consistent with the gene expression data, TCF4 knockdown was associated with reduced proliferation of cortical progenitor cells in vitro. LIMITATIONS: A detailed mechanistic explanation of how TCF4 knockdown alters human neural progenitor cell proliferation is not provided by this study. CONCLUSION: Our data indicate effects of TCF4 perturbation on human cortical progenitor cell proliferation, a process that could contribute to cognitive deficits in individuals with Pitt-Hopkins syndrome and risk for schizophrenia.

How Does p73 Cause Neuronal Defects?

The p53-family member, p73, plays a key role in the development of the central nervous system (CNS), in senescence, and in tumor formation. The role of p73 in neuronal differentiation is complex and involves several downstream pathways. Indeed, in the last few years, we have learnt that TAp73 directly or indirectly regulates several genes involved in neural biology. In particular, TAp73 is involved in the maintenance of neural stem/progenitor cell self-renewal and differentiation throughout the regulation of SOX-2, Hey-2, TRIM32 and Notch. In addition, TAp73 is also implicated in the regulation of the differentiation and function of postmitotic neurons by regulating the expression of p75NTR and GLS2 (glutamine metabolism). Further still, the regulation of miR-34a by TAp73 indicates that microRNAs can also participate in this multifunctional role of p73 in adult brain physiology. However, contradictory results still exist in the relationship between p73 and brain disorders, and this remains an important area for further investigation.

The Notch intracellular domain represses CRE-dependent transcription.

Members of the cyclic-AMP response-element binding protein (CREB) transcription factor family regulate the expression of genes needed for long-term memory formation. Loss of Notch impairs long-term, but not short-term, memory in flies and mammals. We investigated if the Notch-1 (N1) exerts an effect on CREB-dependent gene transcription. We observed that N1 inhibits CREB mediated activation of cyclic-AMP response element (CRE) containing promoters in a γ-secretase-dependent manner. We went on to find that the γ-cleaved N1 intracellular domain (N1ICD) sequesters nuclear CREB1α, inhibits cAMP/PKA-mediated neurite outgrowth and represses the expression of specific CREB regulated genes associated with learning and memory in primary cortical neurons. Similar transcriptional effects were observed with the N2ICD, N3ICD and N4ICDs. Together, these observations indicate that the effects of Notch on learning and memory are, at least in part, via an effect on CREB-regulated gene expression.

Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.

The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias.