Trial of Pimavanserin in Dementia-Related Psychosis.

BACKGROUND: Patients with dementia due to neurodegenerative disease can have dementia-related psychosis. The effects of the oral 5-HT2A inverse agonist and antagonist pimavanserin on psychosis related to various causes of dementia are not clear. METHODS: We conducted a phase 3, double-blind, randomized, placebo-controlled discontinuation trial involving patients with psychosis related to Alzheimer's disease, Parkinson's disease dementia, dementia with Lewy bodies, frontotemporal dementia, or vascular dementia. Patients received open-label pimavanserin for 12 weeks. Those who had a reduction from baseline of at least 30% in the score on the Scale for the Assessment of Positive Symptoms-Hallucinations and Delusions (SAPS-H+D, with higher scores indicating greater psychosis) and a Clinical Global Impression-Improvement (CGI-I) score of 1 (very much improved) or 2 (much improved) at weeks 8 and 12 were randomly assigned in a 1:1 ratio to continue receiving pimavanserin or to receive placebo for up to 26 weeks. The primary end point, assessed in a time-to-event analysis, was a relapse of psychosis as defined by any of the following: an increase of at least 30% in the SAPS-H+D score and a CGI-I score of 6 (much worse) or 7 (very much worse), hospitalization for dementia-related psychosis, stopping of the trial regimen or withdrawal from the trial for lack of efficacy, or use of antipsychotic agents for dementia-related psychosis. RESULTS: Of the 392 patients in the open-label phase, 41 were withdrawn for administrative reasons because the trial was stopped for efficacy; of the remaining 351 patients, 217 (61.8%) had a sustained response, of whom 105 were assigned to receive pimavanserin and 112 to receive placebo. A relapse occurred in 12 of 95 patients (13%) in the pimavanserin group and in 28 of 99 (28%) in the placebo group (hazard ratio, 0.35; 95% confidence interval, 0.17 to 0.73; P = 0.005). During the double-blind phase, adverse events occurred in 43 of 105 patients (41.0%) in the pimavanserin group and in 41 of 112 (36.6%) in the placebo group. Headache, constipation, urinary tract infection, and asymptomatic QT prolongation occurred with pimavanserin. CONCLUSIONS: In a trial that was stopped early for efficacy, patients with dementia-related psychosis who had a response to pimavanserin had a lower risk of relapse with continuation of the drug than with discontinuation. Longer and larger trials are required to determine the effects of pimavanserin in dementia-related psychosis. (Funded by Acadia Pharmaceuticals; HARMONY ClinicalTrials.gov number, NCT03325556.).

Pathologies Underlying Longitudinal Cognitive Decline in the Oldest Old.

BACKGROUND: Understanding contributions of different brain pathologies to domain-specific cognitive trajectories in the oldest old is crucial to guide future intervention studies. METHODS: Two-hundred-twenty Oregon Alzheimer's Disease Center research participants who were cognitively intact at entry were followed on average for 7.3 years with annual neuropsychological testing until death (mean age, 93.7 y) and autopsy. Mixed effects models examined the relationship between trajectories in memory, verbal fluency, and mini-mental state examination (MMSE) and pathology (neurofibrillary tangles, neuritic plaques, gross infarcts, hippocampal sclerosis, Lewy bodies, APOE genotype, age at death, and years of education). The association between the MMSE trajectory and pathologic variables were examined using a Poisson model with MMSE errors as outcomes given the nonlinear distribution of MMSE scores. RESULTS: Memory trajectory was associated with the APOε4 allele (P=0.006). Verbal fluency trajectory was associated with gross infarcts (P=0.008). MMSE trajectory was associated with high Braak scores (P=0.03), gross infarcts (P<0.0001), hippocampal sclerosis (P=0.003), moderate neuritic plaques (P=0.04), and the APOε4 allele (P=0.02). CONCLUSIONS: The association between trajectory of decline in global cognitive scores and multiple brain pathologies highlights the importance of accounting for comorbid pathologies in therapeutic trials aimed at one specific pathology in the oldest old. Only the APOε4 allele showed an association with memory decline, despite accounting for Alzheimer's disease pathology, suggesting that APOE may be involved in mechanisms beyond amyloid metabolism in its role in memory. Further studies are needed to examine the role of APOE in brain aging.

Review of selected databases of longitudinal aging studies.

One of the recommendations of the 2010 Leon Thal Symposium, organized to develop strategies to prevent Alzheimer's disease, was to build a global database of longitudinal aging studies. Although several databases of longitudinal aging studies exist, none of these are comprehensive or complete. In this article, we review selected databases of longitudinal aging studies. We also make recommendations on future steps to create a comprehensive database. Additionally, we discuss issues related to data harmonization.

Microcephaly genes and risk of late-onset Alzheimer disease.

Brain development in the early stages of life has been suggested to be one of the factors that may influence an individual's risk of Alzheimer disease (AD) later in life. Four microcephaly genes, which regulate brain development in utero and have been suggested to play a role in the evolution of the human brain, were selected as candidate genes that may modulate the risk of AD. We examined the association between single nucleotide polymorphisms tagging common sequence variations in these genes and risk of AD in two case-control samples. We found that the G allele of rs2442607 in microcephalin 1 was associated with an increased risk of AD (under an additive genetic model, P=0.01; odds ratio=3.41; confidence interval, 1.77-6.57). However, this association was not replicated using another case-control sample research participants from the Alzheimer Disease Neuroimaging Initiative. We conclude that the common variations we measured in the 4 microcephaly genes do not affect the risk of AD or that their effect size is small.

I Have to Pay to Use the Montreal Cognitive Assessment: What Should I Do?

BACKGROUND: For many years, the Montreal Cognitive Assessment (MoCA) has been one of the most commonly used cognitive screening instruments in ambulatory care settings. Because the MoCA will no longer be in the free public domain by the end of 2020, it is important to consider cognitive screening tests that are comparable and free. METHODS: We briefly review three cognitive screening instruments, the Saint Louis University Mental Status examination, the Short Test of Mental Status, and the Addenbrooke's cognitive examination, and compare these tests with the MoCA. CONCLUSION: The Addenbrooke's cognitive examination is a comprehensive cognitive examination that is too long for administration in primary care. The Short Test of Mental Status uses a 38-point scale, does not account for education, and is available only in English. The Saint Louis University Mental Status is an ideal candidate to replace the MoCA because similar to the MoCA, it is based on a 30-point scale and available in many languages. In addition to dementia, it has been validated for diagnosing mild cognitive impairment. While the MoCA has more tests suited for detecting dysexecutive dementias, it is possible to supplement the Saint Louis University Mental Status with comparable public domain executive function tests. In summary, we believe the Saint Louis University Mental Status to be a suitable free alternative to the MoCA.

The FAS gene, brain volume, and disease progression in Alzheimer's disease.

OBJECTIVE: We sought to identify single-nucleotide polymorphisms (SNPs) associated with Alzheimer's disease (AD) progression and brain volume. METHODS: Ninety-seven SNPs were genotyped in 243 subjects from a longitudinal study of healthy aging. Subjects who received a diagnosis of cognitive impairment (CI) at any study visit (before their most recent visit) and had DNA in the study's DNA bank were included. Progression of AD was defined as the duration from onset of CI to diagnosis of AD. Association of each of the 97 SNPs with AD progression was tested via Cox model. Those SNPs meeting a criterion of nominal significance (P < 0.05) for association with AD progression were reassessed to account for multiple testing by repeating the marker selection process in 10,000 random permutations. Next, the association between the one SNP that survived the multiple-testing adjustment and brain volume was determined by multiple regression analysis in a subgroup of subjects for whom magnetic-resonance imaging (MRI)-derived brain-volume data were available. Brain volumes were adjusted for age at MRI, gender, and time from MRI to onset of CI. RESULTS: The minor allele of rs1468063 in the FAS gene, which is member 6 of the tumor necrosis factor receptor superfamily, was significantly associated with faster AD progression after adjustment for multiple testing (P(permutation) = 0.049). The same allele in rs1468063 was associated with smaller brain volumes and larger ventricular volumes (P = 0.02 and 0.04, respectively). CONCLUSIONS: The FAS gene, which plays a role in apoptosis, may be associated with AD by modulating the apoptosis and neuronal loss secondary to AD neuropathology.

Validation of SATURN, a free, electronic, self-administered cognitive screening test.

BACKGROUND: Cognitive screening is limited by clinician time and variability in administration and scoring. We therefore developed Self-Administered Tasks Uncovering Risk of Neurodegeneration (SATURN), a free, public-domain, self-administered, and automatically scored cognitive screening test, and validated it on inexpensive (<$100) computer tablets. METHODS: SATURN is a 30-point test including orientation, word recall, and math items adapted from the Saint Louis University Mental Status test, modified versions of the Stroop and Trails tasks, and other assessments of visuospatial function and memory. English-speaking neurology clinic patients and their partners 50 to 89 years of age were given SATURN, the Montreal Cognitive Assessment (MoCA), and a brief survey about test preferences. For patients recruited from dementia clinics (n = 23), clinical status was quantified with the Clinical Dementia Rating (CDR) scale. Care partners (n = 37) were assigned CDR = 0. RESULTS: SATURN and MoCA scores were highly correlated (P < .00001; r = 0.90). CDR sum-of-boxes scores were well-correlated with both tests (P < .00001) (r = -0.83 and -0.86, respectively). Statistically, neither test was superior. Most participants (83%) reported that SATURN was easy to use, and most either preferred SATURN over the MoCA (47%) or had no preference (32%). DISCUSSION: Performance on SATURN-a fully self-administered and freely available (https://doi.org/10.5061/dryad.02v6wwpzr) cognitive screening test-is well-correlated with MoCA and CDR scores.

Telemedicine in neurology: Telemedicine Work Group of the American Academy of Neurology update.

PURPOSE: While there is strong evidence supporting the importance of telemedicine in stroke, its role in other areas of neurology is not as clear. The goal of this review is to provide an overview of evidence-based data on the role of teleneurology in the care of patients with neurologic disorders other than stroke. RECENT FINDINGS: Studies across multiple specialties report noninferiority of evaluations by telemedicine compared with traditional, in-person evaluations in terms of patient and caregiver satisfaction. Evidence reports benefits in expediting care, increasing access, reducing cost, and improving diagnostic accuracy and health outcomes. However, many studies are limited, and gaps in knowledge remain. SUMMARY: Telemedicine use is expanding across the vast array of neurologic disorders. More studies are needed to validate and support its use.

Chronic meningoencephalitis with mixed pathology mimics progressive supranuclear palsy.

We report a case of a progressive supranuclear palsy-like phenotype with rapidly progressive dementia and prominent language and executive dysfunction. Pathological examination revealed no midbrain or white matter tauopathy, but rather chronic meningoencephalitis and other mixed pathology. The cerebrospinal fluid (CSF) in this case showed a novel antibody against central nervous system and renal tissue.

Dementia Care Comes Home: Patient and Caregiver Assessment via Telemedicine.

Purpose of the Study: We evaluated the feasibility and reliability of commonly used clinical dementia assessments when administered via direct-to-home telemedicine videoconferencing. To date, few studies assessed the suitability of these measures when used in this setting. Design and Methods: Sixty-six participants (33 patients with Alzheimer's disease (AD) and their 33 caregivers) consented to assessment with a battery of tests in both the clinic setting and via telemedicine. We administered cognitive, behavior, and mood assessments to persons with mild, moderate, and severe AD both in the clinic setting and via direct-to-home telemedicine videoconferencing; test-retest reliability was assessed. We also explored how three caregiver measures performed when administered via telemedicine. Assessments were administered 2 weeks apart. Participant feedback about their experience was solicited. Results: Twenty-eight dyads completed the assessments. Reliability was found to be good to excellent in all measures when used with direct-to-home telemedicine. For the most part, participants and clinicians found telemedicine to be a feasible option for assessing cognitive function and caregiver coping. Implications: Findings indicate that these measures can be used to assess persons with AD, as well as their caregivers, across the telemedicine platform, directly to their homes. Use of this technology can expand access to care to the millions across the United States with AD and their caregivers.

The effects of noncoding aquaporin-4 single-nucleotide polymorphisms on cognition and functional progression of Alzheimer's disease.

INTRODUCTION: The glymphatic system is a brain-wide perivascular network that facilitates clearance of proteins, including amyloid ß, from the brain interstitium through the perivascular exchange of cerebrospinal fluid and interstitial fluid. The astrocytic water channel aquaporin-4 (AQP4) is required for glymphatic system function, and impairment of glymphatic function in the aging brain is associated with altered AQP4 expression and localization. In human cortical tissue, alterations in AQP4 expression and localization are associated with Alzheimer's disease (AD) status and pathology. Although this suggests a potential role for AQP4 in the development or progression of AD, the relationship between of naturally occurring variants in the human AQP4 gene and cognitive function has not yet been evaluated. METHODS: Using data from several longitudinal aging cohorts, we investigated the association between five AQP4 single-nucleotide polymorphisms (SNPs) and the rate of cognitive decline in participants with a diagnosis of AD. RESULTS: None of the five SNPs were associated with different rates of AD diagnosis, age of dementia onset in trial subjects. No association between AQP4 SNPs with histological measures of AD pathology, including Braak stage or neuritic plaque density was observed. However, AQP4 SNPs were associated with altered rates of cognitive decline after AD diagnosis, with two SNPS (rs9951307 and rs3875089) associated with slower cognitive decline and two (rs3763040 and rs3763043) associated with more rapid cognitive decline after AD diagnosis. DISCUSSION: These results provide the first evidence that variations in the AQP4 gene, whose gene product AQP4 is vital for glymphatic pathway function, may modulate the progression of cognitive decline in AD.

Less Daily Computer Use is Related to Smaller Hippocampal Volumes in Cognitively Intact Elderly.

BACKGROUND: Computer use is becoming a common activity in the daily life of older individuals and declines over time in those with mild cognitive impairment (MCI). The relationship between daily computer use (DCU) and imaging markers of neurodegeneration is unknown. OBJECTIVE: The objective of this study was to examine the relationship between average DCU and volumetric markers of neurodegeneration on brain MRI. METHODS: Cognitively intact volunteers enrolled in the Intelligent Systems for Assessing Aging Change study underwent MRI. Total in-home computer use per day was calculated using mouse movement detection and averaged over a one-month period surrounding the MRI. Spearman's rank order correlation (univariate analysis) and linear regression models (multivariate analysis) examined hippocampal, gray matter (GM), white matter hyperintensity (WMH), and ventricular cerebral spinal fluid (vCSF) volumes in relation to DCU. A voxel-based morphometry analysis identified relationships between regional GM density and DCU. RESULTS: Twenty-seven cognitively intact participants used their computer for 51.3 minutes per day on average. Less DCU was associated with smaller hippocampal volumes (r = 0.48, p = 0.01), but not total GM, WMH, or vCSF volumes. After adjusting for age, education, and gender, less DCU remained associated with smaller hippocampal volume (p = 0.01). Voxel-wise analysis demonstrated that less daily computer use was associated with decreased GM density in the bilateral hippocampi and temporal lobes. CONCLUSIONS: Less daily computer use is associated with smaller brain volume in regions that are integral to memory function and known to be involved early with Alzheimer's pathology and conversion to dementia. Continuous monitoring of daily computer use may detect signs of preclinical neurodegeneration in older individuals at risk for dementia.

Rural-Urban Differences in Chronic Disease and Drug Utilization in Older Oregonians.

PURPOSE: To characterize disease burden and medication usage in rural and urban adults aged ≥85 years. METHODS: This is a secondary analysis of 5 years of longitudinal data starting in the year 2000 from 3 brain-aging studies. Cohorts consisted of community-dwelling adults: 1 rural cohort, the Klamath Exceptional Aging Project (KEAP), was compared to 2 urban cohorts, the Oregon Brain Aging Study (OBAS) and the Dementia Prevention study (DPS). In this analysis, 121 participants were included from OBAS/DPS and 175 participants were included from KEAP. Eligibility was determined based on age ≥85 years and having at least 2 follow-up visits after the year 2000. Disease burden was measured by the Modified Cumulative Illness Rating Scale (MCIRS), with higher values representing more disease. Medication usage was measured by the estimated mean number of medications used by each cohort. FINDINGS: Rural participants had significantly higher disease burden as measured by MCIRS, 23.0 (95% CI: 22.3-23.6), than urban participants, 21.0 (95% CI: 20.2-21.7), at baseline. The rate of disease accumulation was a 0.2 increase in MCIRS per year (95% CI: 0.05-0.34) in the rural population. Rural participants used a higher mean number of medications, 5.5 (95% CI: 4.8-6.1), than urban participants, 3.7 (95% CI: 3.1-4.2), at baseline (P < .0001). CONCLUSIONS: These data suggest that rural and urban Oregonians aged ≥85 years may differ by disease burden and medication usage. Future research should identify opportunities to improve health care for older adults.

Comparison of cerebral blood flow and structural penumbras in relation to white matter hyperintensities: A multi-modal magnetic resonance imaging study.

Normal-appearing white matter (NAWM) surrounding WMHs is associated with decreased structural integrity and perfusion, increased risk of WMH growth, and is referred to as the WMH penumbra. Studies comparing structural and cerebral blood flow (CBF) penumbras within the same individuals are lacking, however, and would facilitate our understanding of mechanisms resulting in WM damage. This study aimed to compare both CBF and structural WMH penumbras in non-demented aging. Eighty-two elderly volunteers underwent 3T-MRI including fluid attenuated inversion recovery (FLAIR), pulsed arterial spin labeling and diffusion tensor imaging (DTI). A NAWM layer mask was generated for periventricular and deep WMHs. Mean CBF, DTI-fractional anisotropy (DTI-FA), DTI-mean diffusivity (DTI-MD) and FLAIR intensity for WMHs and its corresponding NAWM layer masks were computed and compared against its mean within total brain NAWM using mixed effects models. For both periventricular and deep WMHs, DTI-FA, DTI-MD and FLAIR intensity changes extended 2-9 mm surrounding WMHs (p ≤ 0.05), while CBF changes extended 13-14 mm (p ≤ 0.05). The CBF penumbra is more extensive than structural penumbras in relation to WMHs and includes WM tissue both with and without microstructural changes. Findings implicate CBF as a potential target for the prevention of both micro and macro structural WM damage.

Memory Complaints in Older Adults: Prognostic Value and Stability in Reporting over Time.

OBJECTIVE: The purpose of this longitudinal study was to examine the prognostic value of subjective memory complaints in 156 cognitively intact community-dwelling older adults with a mean age of 83 years. METHODS: Participants were assessed for subjective memory complaints, cognitive performance, functional status, and mood at annual evaluations with a mean follow-up of 4.5 years. RESULTS: Subjective memory complaint at entry (n=24) was not associated with impaired memory performance and did not predict memory decline or progression to incipient dementia. Memory complaints were inconsistent across examinations for 62% of participants who reported memory problems. CONCLUSIONS: Memory complaints by older adults are inconsistent over time. Memory complaint's value as a research criterion for selecting people at risk for dementia is weak among community dwelling older adults. Age, length of follow-up, and other population characteristics may affect the implication of self-reported memory problems.

Neuropathologic basis of age-associated brain atrophy.

IMPORTANCE: While brain volume changes are used as surrogate markers for Alzheimer disease neuropathology in clinical studies, the extent to which these changes are due to pathologic features of Alzheimer disease in the aging brain is not well established. This study aims to clarify the neuropathologic correlates of longitudinal brain atrophy. OBJECTIVE: To examine the association between brain atrophy during life and neuropathology in an elderly population. DESIGN: Autopsy study of a cohort of elderly individuals. SETTING: Community-based population. PARTICIPANTS: Seventy-one healthy elderly individuals were selected from participants of the Oregon Brain Aging Study for having an autopsy, more than 1 magnetic resonance imaging scan, and the last magnetic resonance imaging scan within 36 months of death. MAIN OUTCOMES AND MEASURES: The associations between brain volume trajectories (ventricular, total brain, and hippocampal) and time interaction terms for neurofibrillary tangles, neuritic plaques, gross infarcts, microinfarcts, amyloid angiopathy, Lewy bodies, APOE ε4 presence, and clinical diagnosis (no cognitive impairment, mild cognitive impairment, or dementia as time-varying covariates) were examined in mixed-effects models, adjusting for duration of follow-up and age at death. RESULTS: Ventricular volume trajectory was significantly associated with age, presence of infarcts, neurofibrillary tangle and neuritic plaque scores, APOE ε4 allele presence, and dementia diagnosis. Total brain volume trajectory was significantly associated with age and mild cognitive impairment diagnosis. Hippocampal volume trajectory was significantly associated with amyloid angiopathy. CONCLUSIONS AND RELEVANCE: Ventricular volume trajectory is more sensitive than total brain and hippocampal volume trajectories as a marker of accruing Alzheimer disease and vascular pathology in elderly individuals. The association between brain volume trajectories and cognitive impairment (mild cognitive impairment and dementia) remained after controlling for the degree of neuropathology and other covariates. This suggests that there may be other factors not measured in this study that could be contributing to brain atrophy in those with cognitive impairment.

Neuropathologic basis of white matter hyperintensity accumulation with advanced age.

OBJECTIVE: To determine which vascular pathology measure most strongly correlates with white matter hyperintensity (WMH) accumulation over time, and whether Alzheimer disease (AD) neuropathology correlates with WMH accumulation. METHODS: Sixty-six older persons longitudinally followed as part of an aging study were included for having an autopsy and >1 MRI scan, with last MRI scan within 36 months of death. Mixed-effects models were used to examine the associations between longitudinal WMH accumulation and the following neuropathologic measures: myelin pallor, arteriolosclerosis, microvascular disease, microinfarcts, lacunar infarcts, large-vessel infarcts, atherosclerosis, neurofibrillary tangle rating, and neuritic plaque score. Each measure was included one at a time in the model, adjusted for duration of follow-up and age at death. A final model included measures showing an association with p < 0.1. RESULTS: Mean age at death was 94.5 years (5.5 SD). In the final mixed-effects models, arteriolosclerosis, myelin pallor, and Braak score remained significantly associated with increased WMH accumulation over time. In post hoc analysis, we found that those with Braak score 5 or 6 were more likely to also have high atherosclerosis present compared with those with Braak score 1 or 2 (p = 0.003). CONCLUSION: Accumulating white matter changes in advanced age are likely driven by small-vessel ischemic disease. Additionally, these results suggest a link between AD pathology and white matter integrity disruption. This may be due to wallerian degeneration secondary to neurodegenerative changes. Alternatively, a shared mechanism, for example ischemia, may lead to both vascular brain injury and neurodegenerative changes of AD. The observed correlation between atherosclerosis and AD pathology supports the latter.

Trajectory of white matter hyperintensity burden preceding mild cognitive impairment.

OBJECTIVE: To determine the time of acceleration in white matter hyperintensity (WMH) burden, a common indicator of cerebrovascular pathology, in relation to conversion to mild cognitive impairment (MCI) in the elderly. METHODS: A total of 181 cognitively intact elderly volunteers from the longitudinal, prospective, Oregon Brain Aging Study underwent yearly evaluations, including brain MRI, and cognitive testing. MRIs were analyzed for imaging markers of neurodegeneration: WMH and ventricular CSF (vCSF) volumes. The time before MCI, when the changes in WMH and vCSF burden accelerate, was assessed using a mixed-effects model with a change point for subjects who developed MCI during follow-up. RESULTS: During a follow-up duration of up to 19.6 years, 134 subjects converted to MCI. Acceleration in %WMH volume increase occurred 10.6 years before MCI onset. On average, the annual rate of change in %WMH increased an additional 3.3% after the change point. Acceleration in %vCSF volume increase occurred 3.7 years before the onset of MCI. Out of 63 subjects who converted to MCI and had autopsy, only 28.5% had Alzheimer disease (AD) as the sole etiology of their dementia, while almost just as many (24%) had both AD and significant ischemic cerebrovascular disease present. CONCLUSIONS: Acceleration in WMH burden, a common indicator of cerebrovascular disease in the elderly, is a pathologic change that emerges early in the presymptomatic phase leading to MCI. Longitudinal changes in WMH may thus be useful in determining those at risk for cognitive impairment and for planning strategies for introducing disease-modifying therapies prior to dementia onset.

Alzheimer disease pathology in cognitively healthy elderly: a genome-wide study.

Many elderly individuals remain dementia-free throughout their life. However, some of these individuals exhibit Alzheimer disease neuropathology on autopsy, evidenced by neurofibrillary tangles (NFTs) in AD-specific brain regions. We conducted a genome-wide association study to identify genetic mechanisms that distinguish non-demented elderly with a heavy NFT burden from those with a low NFT burden. The study included 299 non-demented subjects with autopsy (185 subjects with low and 114 with high NFT levels). Both a genotype test, using logistic regression, and an allele test provided consistent evidence that variants in the RELN gene are associated with neuropathology in the context of cognitive health. Immunohistochemical data for reelin expression in AD-related brain regions added support for these findings. Reelin signaling pathways modulate phosphorylation of tau, the major component of NFTs, either directly or through ß-amyloid pathways that influence tau phosphorylation. Our findings suggest that up-regulation of reelin may be a compensatory response to tau-related or beta-amyloid stress associated with AD even prior to the onset of dementia.