Alzheimer's Presenilin Research Articles

Abstract 6142: Interactions of processed meat and red meat intake with pathway-based polygenic risk scores for colorectal cancer: A novel approach for PRSs construction

Abstract Introduction: Colorectal cancer (CRC) is the third most common cancer, and second cause of cancer death worldwide. Established CRC risk factors (E) include high red meat and processed meat intake. Genome-wide association studies (GWAS) have reported over 200 genetic variants associated with CRC risk. We used functional annotation data to identify subsets of GWAS variants within known pathways and constructed corresponding pathway Polygenic Risk Scores (pPRS). We evaluated pPRS by E interactions to determine whether genes within specific pathways interacted with meat intake to impact CRC risk. Methods: A pooled sample of 54,531 CRC controls and 48,260 cases of European ancestry from 27 studies were analyzed. Study-specific quartiles for red and processed meat intake were generated through in-person interviews and structured self-administered questionnaires. Variants were imported to AnnoQ for annotation (n=203) and analyzed for overrepresentation in PANTHER-reported pathways with Fisher’s exact test. Standard approaches were used to compute polygenic risk score weights relating the 203 variants to CRC. The subset of weights corresponding to each of five pathways were then used to compute the corresponding pPRS. Covariate-adjusted logistic regression models evaluated pPRSxE interactions with red meat and processed meat intake. Results: A total of 34 unique variants were overrepresented in five pathways: Apoptosis signaling, Alzheimer disease-presenilin, Wnt-signaling, Gonadotropin-releasing hormone receptor, and TGF-beta signaling. We found a statistically significant interaction between TGF-beta-pPRS and red meat intake (p = 0.0012). Stratified analyses reported a dose-response trend in the red meat and CRC risk association, with decreasing estimates of red meat and CRC risk association, comparing first to fourth quartiles of meat intake, with increasing quartiles of TGF-beta-pPRS: 13% (Q1), 12% (Q2), 7% (Q3), and 6% (Q4). This association remained significant after adjustment for all other variants (p = 0.0013), and all other pPRS with variants that did not overlap with the TGF-beta-pPRS (p = 0.0012). Independent GxE interaction models for individual variants that were included in the TGF-beta pathway showed significant interactions with red meat for rs2337113 (intron SMAD7 gene, Chr18), and rs2208603 (intergenic region BMP5, Chr6) (p = 0.013 & 0.0108, respectively). We did not find significant pPRS x red meat interactions for the other four pathways or with any pPRS x processed meat. Conclusion: This pathway-based interaction analysis revealed a statistical interaction between SNPs in the TGF-beta pathway and red meat consumption that impacts CRC risk. These findings shed light into the possible mechanistic link between CRC risk and red meat consumption. Citation Format: Joel Sanchez Mendez, Mariana C. Stern, Yubo Fu, John Morrison, Juan P. Lewinger, Eric Kawaguchi, Bryan Queme, Huaiyu Mi, Flora Qu, Ulrike Peters, Li Hsu, Stephen B. Gruber, Li Li, Michelle Cotterchio, Loic Le Marchand, Andrew J. Pellat, Elizabeth A. Platz, W James Gauderman. Interactions of processed meat and red meat intake with pathway-based polygenic risk scores for colorectal cancer: A novel approach for PRSs construction [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6142.

Gene expression profiles underlying aggressive behavior in the prefrontal cortex of cattle

BackgroundAggressive behavior is an ancient and conserved trait, habitual for most animals in order to eat, protect themselves, compete for mating and defend their territories. Genetic factors have been shown to play an important role in the development of aggression both in animals and humans, displaying moderate to high heritability estimates. Although such types of behaviors have been studied in different animal models, the molecular architecture of aggressiveness remains poorly understood. This study compared gene expression profiles of 16 prefrontal cortex (PFC) samples from aggressive and non-aggressive cattle breeds: Lidia, selected for agonistic responses, and Wagyu, selected for tameness.ResultsA total of 918 up-regulated and 278 down-regulated differentially expressed genes (DEG) were identified, representing above-chance overlap with genes previously identified in studies of aggression across species, as well as those implicated in recent human evolution. The functional interpretation of the up-regulated genes in the aggressive cohort revealed enrichment of pathways such as Alzheimer disease-presenilin, integrins and the ERK/MAPK signaling cascade, all implicated in the development of abnormal aggressive behaviors and neurophysiological disorders. Moreover, gonadotropins, are up-regulated as natural mechanisms enhancing aggression. Concomitantly, heterotrimeric G-protein pathways, associated with low reactivity mental states, and the GAD2 gene, a repressor of agonistic reactions associated with PFC activity, are down-regulated, promoting the development of the aggressive responses selected for in Lidia cattle. We also identified six upstream regulators, whose functional activity fits with the etiology of abnormal behavioral responses associated with aggression.ConclusionsThese transcriptional correlates of aggression, resulting, at least in part, from controlled artificial selection, can provide valuable insights into the complex architecture that underlies naturally developed agonistic behaviors.This analysis constitutes a first important step towards the identification of the genes and metabolic pathways that promote aggression in cattle and, providing a novel model species to disentangle the mechanisms underlying variability in aggressive behavior.

Attenuated presenilin-1 endoproteolysis enhances store-operated calcium currents in neuronal cells.

Presenilins have been reported to regulate calcium homeostasis in the endoplasmic reticulum, and dysregulation of intracellular calcium has been implicated in the pathogenesis of Alzheimer's disease (AD). Reduced endoproteolysis levels of presenilin-1 (PS1) have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. This study deals with the effect of attenuated endoproteolysis of PS1 on store-operated calcium (SOC) entry in neuronal cells and mouse fibroblasts with double knockouts of PS1 and PS2. Significant enhancement of SOC channel activation has been detected by electrophysiological measurements in cells with reduced PS1 endoproteolysis. The increase in SOC entry was not accompanied by any changes in protein levels of channels subunits or stromal interaction molecule. These data are important for understanding the role of PS1 in AD, apart from its involvement in γ-secretase cleavage of amyloid precursor protein into Aβ. Taking into account that most of familial AD-connected mutations in PS1 are loss-of-function, the observed effects may well be general for familial AD. Reduced endoproteolysis levels of presenilin-1 (PS1) have been detected in postmortem brains of patients carrying familial Alzheimer's disease PS1 mutations. Significant enhancement of SOC channel activation has been detected by electrophysiological measurements in cells with reduced PS1 endoproteolysis. The data obtained shed light on Alzheimer's disease pathogenesis and implicates to the future drugs development.

Cortical atrophy in presymptomatic Alzheimer's disease presenilin 1 mutation carriers

BackgroundSporadic late-onset Alzheimer's disease (AD) dementia has been associated with a ‘signature’ of cortical atrophy in paralimbic and heteromodal association regions measured with MRI.ObjectiveTo investigate whether a similar pattern of...

Highly Pathogenic Alzheimer's Disease Presenilin 1 P117R Mutation Causes a specific Increase in p53 and p21 Protein Levels and Cell Cycle Dysregulation in Human Lymphocytes

Cell cycle (CC) reentry in neurons precedes the formation of amyloid-β (Aβ) plaques in Alzheimer's disease (AD). CC alterations were also detected in lymphocytes from sporadic AD patients. In the present study, we investigated the influence of nine presenilin 1 (PS1) mutations (P117R, M139V, L153V, H163R, S170F, F177L, I213F, L226F, E318G) on CC and Aβ production in immortalized B-lymphocytes from familial AD (FAD) patients and in stably transfected human embryonic kidney cells. In both cell types, only the P117R mutation increased levels of key G1/S phase regulatory proteins, p53, and its effector p21, causing G1 phase prolongation with simultaneous S phase shortening, and lowering basal apoptosis. The CC changes were rescued by inhibition of p53, but not of γ-secretase. Moreover, the investigated PS1 mutants showed differences in the increased levels of secreted Aβ40 and Aβ42 and in Aβ42/Aβ40 ratios, but these differences did not correlate with CC patterns. Altogether, we found that both CC regulation and Aβ production differentiate PS1 mutations, and that CC PS1 activity is mediated by p53/p21 signaling but not by γ-secretase activity. The identified CC dysregulation linked with increased p53 and p21 protein levels distinguishes the highly pathogenic PS1 P117R mutation and may contribute to the specific severity of the clinical progression of FAD associated with the mutation in the PS1 117 site. These findings suggest that impairment in lymphocyte CC might play a pathogenic function in AD and are relevant to the development of new diagnostic approaches and personalized therapeutic strategies.

Presenilins: Role in calcium homeostasis

Mutations in presenilins are responsible for the vast majority of early-onset familial Alzheimer's disease cases. Full-length presenilin structure is composed of nine transmembrane domains which are localized on the endoplasmic reticulum membrane. Upon endoproteolytic cleavage, presenilins assemble into the γ-secretase multiprotein complex and subsequently get transported to the cell surface. There is a wealth of knowledge around the role of presenilins as the catalytic component of γ-secretase, their involvement in amyloid precursor protein processing and generation of neurotoxic β-amyloid species. However recent findings have revealed a wide range of γ-secretase-independent presenilin functions, including involvement in calcium homeostasis. Particularly, familial Alzheimer's disease presenilin mutations have been shown to interfere with the function of several molecular elements involved in endoplasmic reticulum calcium homeostasis. Presenilins modulate the activity of IP3 and Ryanodine receptor channels, regulate SERCA pump function, affect capacitative calcium entry and function per se as endoplasmic reticulum calcium leak conductance pores.

Progressive age-related impairment of the late long-term potentiation in Alzheimer's disease presenilin-1 mutant knock-in mice

Progressive age-related impairment of the late long-term potentiation in Alzheimer's disease presenilin-1 mutant knock-in mice

Enhanced ROS Generation Mediated by Alzheimer's Disease Presenilin Regulation of InsP3R Ca2+ Signaling

Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein and presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca(2+)) homeostasis by proximal mechanisms independent of amyloid production by dramatically enhancing gating of the inositol trisphosphate receptor (InsP(3)R) intracellular Ca(2+) release channel by a gain-of-function effect that mirrors genetics of FAD and is independent of secretase activity. Electrophysiological recordings of InsP(3)R in FAD patient B cells, cortical neurons of asymptomatic PS1-AD mice, and other cells revealed they have higher occupancy in a high open probability burst mode, resulting in enhanced Ca(2+) signaling. Exaggerated Ca(2+) signaling through this mechanism results in enhanced generation of reactive oxygen species, believed to be an important component in AD pathogenesis. Exaggerated Ca(2+) signaling through InsP(3)R-PS interaction is a disease specific and robust proximal mechanism in AD that may contribute to the pathology of AD by enhanced generation of reactive oxygen species.

An Alzheimer disease presenilin mutation, syndrome diversity, and a shrinking world

In this issue of Neurology ®, Bruni et al.1 report that several geographically distinct Alzheimer disease (AD) kindreds with the PSEN1 Met146Leu mutation have a common founder. The authors used haplotype analysis to establish that these individually identified kindreds are in fact one extended kindred. The mutation arose in Italy at least several hundred years ago; branches of this family are now found on different continents. This represents an impressive piece of detective work and demonstrates the power of modern molecular genetics. In addition to using a shared chromosome 14 region to “lump” the different PSEN1 Met146Leu kindreds, a careful clinical analysis was performed and revealed that persons with PSEN1 Met146Leu mutations may have different clinical presentations: some had a more typical AD picture of bi-mesiotemporal-parietal dysfunction, while others developed early symptoms typical of frontal lobe dysfunction. In both cases the age at onset was the start of the fifth decade. All worsened regardless of …

Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice

Presenilin 1 (PS1) mutations are responsible for many early-onset familial Alzheimer's disease (FAD) cases. While increasing evidence points to impaired synaptic plasticity as an early event in AD, PS1 mutant mice exhibit a paradoxical increase in hippocampal long-term potentiation (LTP). Among PS1 mouse models, PS1 M146V mutant knock-in mice (PS1KI) are particularly interesting in that they exhibit memory impairment in spatial tasks. Here we investigated the effects of aging on two forms of LTP in PS1KI mice, the widely-studied early phase of LTP (E-LTP) and a particular form of LTP called late-LTP (L-LTP) which requires transcription and protein synthesis. L-LTP is thought to be critical for long-term memory. We found a lower L-LTP maintenance phase in PS1KI mice compared to wild type littermates at 3 months of age. As the mice age, they exhibit impairment of both the induction and maintenance phases of LTP. When E-LTP and NMDA receptor-mediated transmission were analyzed, PS1KI mice displayed an increase at 3 months compared to wild type littermates; this difference did not persist at older ages and finally decreased at 12 months. These results reveal an L-LTP decrease in PS1 mutant mice at an early stage, which occurs coincidently with a paradoxical enhancement of E-LTP. The observation of a decrease in both forms of LTP during aging supports the view that PS1KI mice are a valuable model for the study of age-dependent synaptic dysfunction and cognitive decline in AD.

Alzheimer's Presenilin Regulation of InsP3R Ca2+ Release Channel Gating

Familial Alzheimer's disease (FAD) is caused by mutations in amyloid precursor protein and presenilins (PS1, PS2). Many FAD-linked PS mutations affect intracellular calcium (Ca2+) homeostasis by proximal mechanisms independent of amyloid production, although the molecular details are controversial. Here, we demonstrate that several FAD-causing PS dramatically enhance gating of the inositol trisphosphate receptor (InsP3R) intracellular Ca2+ release channel measured in native endoplasmic reticulum membranes by nuclear patch clamp electrophysiology. In contrast, wild type or mutant PS that cause frontotemporal dementia have no such effect. FAD PS alter InsP3R channel gating by modal switching to a high open probability burst mode. Single channel recordings of endogenous InsP3R in FAD patient B cells as well as cortical neurons of asymptomatic PS1-AD mice revealed they have higher occupancy in the burst mode than controls, resulting in enhanced intracellular Ca2+ signals. These results indicate that exaggerated Ca2+ signaling through InsP3R-PS interaction is a disease specific and robust proximal mechanism in AD.

Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice.

Progressive Age-Related Impairment of the Late Long-Term Potentiation in Alzheimer's Disease Presenilin-1 Mutant Knock-in Mice.

A new and simple approach for genotyping Alzheimer's disease presenilin-1 mutant knock-in mice

The use of transgenic mice expressing point mutations demands that the detection of the different alleles is efficient and reliable. In addition, the multiplication of transgenes included in mouse models of human disease underlines the importance of correct controls and the fact that investigators need an accurate and rapid genotyping of the littermates generated. In this study, we demonstrate a powerful alternative for genotyping using presenilin-1 mutant knock-in (PS1M146KI) mice as an example.Mutations in the presenilin-1 (PS1) gene are causally linked to many cases of early-onset inherited Alzheimer's disease (AD). PS1M146VKI mice that express the PS1M146V targeted allele at normal physiological levels and triple-transgenic model (3×Tg-AD) derived from homozygous PS1M146VKI mice were generated to study the pathogenesis of AD. Genotyping PS1M146VKI line requires many steps and thus a large quantity of DNA. In PS1M146VKI mice, only three nucleotides are modified in the gene. Here we show that this small mutated DNA sequence can affect its secondary structure resulting in altered mobility that can be easily detected on a polyacrylamide gel, by the single-strand conformation polymorphism (SSCP) technique. Our results demonstrate that SSCP is a simple, accurate, repeatable and efficient method for the routine genotyping of this current AD model. This method could be easily applied to other transgenic mice.

Hyperphosphorylation and accumulation of neurofilament proteins in transgenic mice with Alzheimer presenilin 1 mutation.

Neurofilaments (NFs) are hyperphosphorylated and accumulate in Alzheimer's disease (AD) brains. In this study, employing the transgenic mouse model, we explored the effect of presenilin 1 (PS-1) mutation on the phosphorylation and distribution of NFs. Western blot analysis showed that there was a significant increase in the phosphorylation of NF-H and NF-M subunits with a concomitant increase in phosphorylated c-Jun N-terminal protein kinase 1/2 (JNK1/2) mitogen-activated protein kinase (MAPK) in hippocampus of PS-1 transgenic mice compared to that of wild-type littermates. Immunohistochemical analysis revealed that phosphorylated NFs accumulated throughout the hippocampal neurons of the transgenic mice. These findings suggest that PS-1 mutation may induce hyperphosphorylation and accumulation of NFs via a JNK1/2-involved mechanism.

Prominent Neuroleptic Sensitivity in a Case of Early-onset Alzheimer Disease due to Presenilin-1 G206A Mutation

We describe atypical motor and cognitive features in a case of familial Alzheimer disease (FAD) due to presenilin-1 (PS-1) mutation. Extrapyramidal signs (EPS) typically are a late-presenting feature of sporadic Alzheimer disease (AD), but relatively little data are available regarding EPS in FAD. A 59-year-old, right-handed man of Caribbean-Hispanic descent underwent brain imaging studies, laboratory tests for AD, and serial neurologic and neuropsychologic evaluations. The patient presented with recent-onset delusional ideation associated with cognitive decline. Prominent EPS developed soon after initiation of an atypical neuroleptic agent. Neuropsychologic evaluation revealed global cognitive deficits; he was found to be a carrier of a PS-1 point mutation at position G206A. EPS resolved completely after discontinuing the neuroleptic agent and coincided with improved motor speed, set initiation, and verbal fluency. Severe neuroleptic sensitivity and associated deficits of cognitive speed occurred in response to a dopaminergic antagonist agent; both responded readily to withdrawal of the offending agent. Patients with PS-1 AD may be at substantially increased risk of neuroleptic-induced EPS. That feature underscores the heterogeneity of the FAD clinical phenotype.

P2-158: Coenzyme Q10 attenuates hyperphosphorylation of tau with upregulation of Akt signaling in the aged transgenic mice with Alzheimer presenilin 1 mutation

P2-158: Coenzyme Q10 attenuates hyperphosphorylation of tau with upregulation of Akt signaling in the aged transgenic mice with Alzheimer presenilin 1 mutation

Loss of neuronal cell cycle control as a mechanism of neurodegeneration in the Presenilin-1 Alzheimer's disease brain

Presenilin-1 (PS1) is a component of the β-catenin degradation machinery, and PS1 mutations linked to familial Alzheimer’s disease (FAD) represent a loss of this function, leading, in non-neuronal cells, to accumulation of cyclin D1, aberrant cell cycle activation and hyperproliferation. In post-mitotic neurons, cell cycle activation is thought to be abortive and initiate apoptosis, thus contributing to AD pathogenesis. Consequently, we tested here the hypothesis that, in the PS1 FAD brain, cyclin D1 accumulation may occur and lead to neuronal apoptosis secondary to an abortive entry into the cell cycle.We show that cyclin D1 is indeed upregulated in cortical neurons of mice expressing the knock-in PS1 FAD mutation M146V, as well as in temporal cortex of FAD patients expressing different PS1 mutations. Cyclin D1 upregulation in mutant neurons leads to cell cycle-driven apoptosis, a phenotype reversed by blocking entry into the cell cycle by small interfering RNA (siRNA) cyclin D1 downregulation and by treatment with the cell cycle inhibitor quercetin, but not by γ-secretase inhibition. Furthermore, β-catenin accumulates in neurons and adult hippocampus of PS1 KIM146V mice, as well as in temporal cortex of PS1 FAD patients, strongly suggesting an initiating role for aberrant β-catenin signalling in cell cycle-driven neuronal apoptosis.The present work identifies a novel mechanism by which PS1 mutations may exacerbate neurodegeneration in the FAD brain beyond dysregulation of γ-secretase activity, and it lends support to the notion that Alzheimer’s disease may be, at least in part, a disease driven by loss of cell cycle control.

Effect of inhalational anesthetics on cytotoxicity and intracellular calcium differently in rat pheochromocytoma cells (PC12)

Isoflurane, a commonly used inhaled anesthetic, induces apoptosis in rat pheochromocytoma cells (PC12) in a concentration-and time-dependent manner with unknown mechanism. We hypothesized that isoflurane induced apoptosis by causing abnormal calcium release from the endoplasmic reticulum (ER) via activation of inositol 1,4,5-trisphosphate (IP3) receptors. Alzheimer's presenilin-1 (PS1) mutation increased activity of IP3 receptors and therefore rendered cells vulnerable to isoflurane-induced cytotoxicity. Sevoflurane and desflurane had less ability to disrupt intracellular calcium homeostasis and thus being less potent to cause cytotoxicity. This study examined and compared the cytotoxic effects of various inhaled anesthetics on PC12 cells transfected with the Alzheimer's mutated PS1 (L286V) and the disruption of intracellular calcium homeostasis. PC12 cells transfected with wild type (WT) and mutated PS1 (L286V) were treated with equivalent of 1 MAC of isoflurane, sevoflurane and desflurane for 12 h. MTT reduction and LDH release assays were performed to evaluate cell viability. Changes of calcium concentration in cytosolic space ([Ca2+]c) were determined after exposing different types of cells to various inhalational anesthetics. The effects of IP3 receptor antagonist xestospongin C on isoflurane-induced cytotoxicity and calcium release from the ER in L286V PC12 cells were also determined. The results showed that isoflurane at 1 MAC for 12 h induced cytoxicity in L286V but not WT PC12 cells, which was also associated with greater and faster elevation of peak [Ca2+]c in L286V than in the WT cells. Xestospongin C significantly ameliorated isoflurane cytotoxicity in L286V cells, as well as inhibited the calcium release from the ER in L286V cells. Sevoflurane and desflurane at equivalent exposure to isoflurane did not induce similar cytotoxicity or elevation of peak [Ca2+]c in L286V PC12 cells. These results suggested that isoflurane induced cytoxicity by partially causing abnormal calcium release from the ER via activation of IP3 receptors in L286V PC12 cells. Sevoflurane and desflurane at equivalent exposure to isoflurane did not induce similar elevation of [Ca2+]c or neurotoxicity in PC12 cells transfected with the Alzheimer's PS1 mutation.

Coenzyme Q10 Attenuates β-Amyloid Pathology in the Aged Transgenic Mice with Alzheimer Presenilin 1 Mutation

One of the neuropathological features of Alzheimer's disease (AD) is the deposition of senile plaques containing beta-amyloid (A beta). There is limited evidence for the treatment to arrest A beta pathology of AD. In our present study, we tested the effect of coenzyme Q10 (CoQ10), an endogenous antioxidant and a powerful free radical scavenger, on A beta in the aged transgenic mice overexpressing Alzheimer presenilin 1-L235P (leucine-to-proline mutation at codon 235, 16-17 months old). The treatment by feeding the transgenic mice with CoQ10 for 60 days (1,200 mg kg(-1) day(-1)) partially attenuated A beta overproduction and intracellular A beta deposit in the cortex of the transgenic mice compared with the age-matched untreated transgenic mice. Meanwhile, an increased oxidative stress reaction was detected as evidenced by elevated level of malondialdehyde (MDA) and decreased activity of superoxide dismutase (SOD) in the transgenic mice relative to the wild-type mice, and supplementation of CoQ10 partially decreased MDA level and upregulated the activity of SOD. The results indicate that oxidative stress is enhanced in the brain of the transgenic mice, that this enhancement may further promote A beta 42 overproduction in a vicious formation, and that CoQ10 would be beneficial for the therapy of AD.

Variable phenotype of Alzheimer’s disease with spastic paraparesis

Pedigrees with familial Alzheimer's disease (AD) show considerable phenotypic variability. Spastic paraparesis (SP), or progressive spasticity of the lower limbs is frequently hereditary and exists either as uncomplicated (paraparesis alone) or complicated (paraparesis and other neurological features) disease subtypes. In some AD families, with presenilin-1 (PSEN1) mutations, affected individuals also have SP. These PSEN1 AD pedigrees frequently have a distinctive and variant neuropathology, namely large, non-cored plaques without neuritic dystrophy called cotton wool plaques (CWP). The PSEN1 AD mutations giving rise to CWP produce unusually high levels of the amyloid beta peptide (Abeta) ending at position 42 or 43, and the main component of CWP is amino-terminally truncated forms of amyloid beta peptide starting after the alternative beta-secretase cleavage site at position 11. This suggests a molecular basis for the formation of CWP and an association with both SP and AD. The SP phenotype in some PSEN1 AD pedigrees also appears to be associated with a delayed onset of dementia compared with affected individuals who present with dementia only, suggesting the existence of a protective factor in some individuals with SP. Variations in neuropathology and neurological symptoms in PSEN1 AD raise the prospect that modifier genes may underlie this phenotypic heterogeneity.