The effect of age on cerebral vasospasm and delayed cerebral ischemia in patients with aneurysmal subarachnoid hemorrhage.

BACKGROUND: The association between patient age and cerebral arterial vasospasm (CVS) and delayed cerebral ischemia (DCI) risk following aneurysmal subarachnoid hemorrhage (aSAH) remains unclear. This study aims to assess the role of age on aSAH-related complications. METHODS: Single-center retrospective study comprising aSAH patients treated between January 2009 and March 2023. Age was analyzed as continuous and categorical variables (<60yrs vs. ≥60yrs and by decade). Outcomes of interest included radiographic CVS, DCI, cerebral infarction, in-hospital mortality, length-of-stay, ventriculoperitoneal shunt placement, and modified Rankin Scale (mRS) scores at discharge and 3-month follow-up. RESULTS: 925 aSAH patients were included. Most (n=598; 64.6%) were <60yrs old (46±9.1yrs). CVS likelihood was lower in the older cohort (aOR=0.56 [0.38-0.82]). Patients ≥60yrs had higher mortality rates (aOR=2.24 [1.12-4.47]) and worse mRS scores at discharge (aOR=2.66 [1.91-3.72]) and 3-month follow-up (aOR=2.19 [1.44-3.32]). Advanced age did not have a significant effect on DCI or cerebral infarction risk. Higher in-hospital mortality was documented with increasing age (p<0.001). A significant interaction between CVS and age for the outcome of DCI was documented, with a stronger positive effect on poor outcomes (i.e., higher odds of DCI) among patients aged <60 years compared to those aged ≥60. CONCLUSION: There is an inverse relationship between patient age and CVS incidence following aSAH. Nonetheless, patients ≥60yrs had comparable DCI rates, higher in-hospital mortality, and worse functional outcomes than their younger counterparts. Routine screening and reliance on radiographic CVS as primary marker for aSAH-related complications should be reconsidered, particularly in older patients.

Racial and Ethnic Differences in Mortality and Functional Outcomes Following Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Ischemic and hemorrhagic stroke incidence tends to be higher among minority racial and ethnic groups. The effect of race and ethnicity following an aneurysmal subarachnoid hemorrhage (aSAH) remains poorly understood. Thus, we aimed to explore the association between race and ethnicity and aSAH outcomes. METHODS: Single-center retrospective review of patients with aSAH from January 2009 to March 2023. Primary outcome was in-hospital mortality. Secondary outcomes included delayed cerebral ischemia, cerebral infarction, radiographic and symptomatic vasospasm, pulmonary complications, epileptic seizures, external ventricular drain placement, and modified Rankin Scale score at discharge and 3-month follow-up. Associations between race and ethnicity and outcomes were assessed using binary and ordinal regression models, with multivariable models adjusted for significant covariates. RESULTS: A total of 1325 patients with subarachnoid hemorrhage presented to our center. Among them, 443 cases were excluded, and data from 882 patients with radiographically confirmed aSAH were analyzed. Distribution by race and ethnicity was 40.8% (n=360) White, 31.4% (n=277) Hispanic, 22.1% (n=195) Black, and 5.7% (n=50) Asian. Based on Hunt-Hess and modified Fisher grade, aSAH severity was similar among groups (P=0.269 and P=0.469, respectively). In-hospital mortality rates were highest for Asian (14.0%) and Hispanic (11.2%) patients; however, after adjusting for patient sex, age, health insurance, smoking history, alcohol and substance abuse, and aneurysm treatment, the overall likelihood was comparable to White patients. Hispanic patients had higher risks of developing cerebral infarction (adjusted odds ratio, 2.17 [1.20-3.91]) and symptomatic vasospasm (adjusted odds ratio, 1.64 [1.05-2.56]) than White patients and significantly worse discharge modified Rankin Scale scores (adjusted odds ratio, 1.44 [1.05-1.99]). Non-White patients also demonstrated a lower likelihood of 0 to 2 discharge modified Rankin Scale scores (adjusted odds ratio, 0.71 [0.50-0.98]). No significant interactions between race and ethnicity and age or sex were found for in-hospital mortality and functional outcomes. CONCLUSIONS: Our study identified significant differences in cerebral infarction and symptomatic vasospasm risk between Hispanic and White patients following aSAH. A higher likelihood of worse functional outcomes at discharge was found among non-White patients. These findings emphasize the need to better understand predisposing risk factors that may influence aSAH outcomes. Efforts toward risk stratification and patient-centered management should be pursued.

Asian Cohort for Alzheimer's Disease (ACAD) pilot study on genetic and non-genetic risk factors for Alzheimer's disease among Asian Americans and Canadians.

INTRODUCTION: Clinical research in Alzheimer's disease (AD) lacks cohort diversity despite being a global health crisis. The Asian Cohort for Alzheimer's Disease (ACAD) was formed to address underrepresentation of Asians in research, and limited understanding of how genetics and non-genetic/lifestyle factors impact this multi-ethnic population. METHODS: The ACAD started fully recruiting in October 2021 with one central coordination site, eight recruitment sites, and two analysis sites. We developed a comprehensive study protocol for outreach and recruitment, an extensive data collection packet, and a centralized data management system, in English, Chinese, Korean, and Vietnamese. RESULTS: ACAD has recruited 606 participants with an additional 900 expressing interest in enrollment since program inception. DISCUSSION: ACAD's traction indicates the feasibility of recruiting Asians for clinical research to enhance understanding of AD risk factors. ACAD will recruit > 5000 participants to identify genetic and non-genetic/lifestyle AD risk factors, establish blood biomarker levels for AD diagnosis, and facilitate clinical trial readiness. HIGHLIGHTS: The Asian Cohort for Alzheimer's Disease (ACAD) promotes awareness of under-investment in clinical research for Asians. We are recruiting Asian Americans and Canadians for novel insights into Alzheimer's disease. We describe culturally appropriate recruitment strategies and data collection protocol. ACAD addresses challenges of recruitment from heterogeneous Asian subcommunities. We aim to implement a successful recruitment program that enrolls across three Asian subcommunities.

The complete anterior petrosectomy: an expanded extended-middle fossa approach with removal of the infratrigeminal petrous apex and drilling of the lateral clivus.

Intradural exposure in the extended middle fossa anterior transpetrosal approach is traditionally limited to the inferior petrosal sinus inferomedially. Expanding bone removal of the petrous apex around the petrous internal carotid artery (ICA), underneath the trigeminal ganglion/mandibular nerve, and into the lateral component of the clivus can significantly expand the limits of this approach beyond the inferior petrosal sinus and allows for exposure of the midline structures, aspects of the contralateral inferior clival region, and, when high riding, the vertebrobasilar junction. To date, no descriptive techniques for drilling into the lateral clivus in this approach have been published. The authors provide a detailed stepwise description of their complete anterior petrosectomy, in use at their institution, that involves skeletonization of the posteromedial petrous ICA, gentle elevation of the trigeminal ganglion/mandibular nerve, removal of the infratrigeminal petrous apex, and two techniques for drilling into the lateral clivus along the petroclival fissure. These techniques provide a direct and unobstructed corridor to the midpetroclival region and ventral brainstem with greater maneuverability and enhanced control of the midline structures, which is especially useful for resection of petroclival meningiomas, chondrosarcomas, and giant vascular lesions of the mid- and upper basilar artery and its proximal branches.

Expansion of the Foramen Ovale in Patients With Cerebrospinal Fluid Leak or Encephalocele.

OBJECTIVE: Spontaneous cerebrospinal fluid (CSF) leaks are associated with elevated intracranial pressure and idiopathic intracranial hypertension (IIH). Skull base erosion and widening of the foramen ovale have been reported in patients with IIH. This study sought to investigate changes in the size of the foramen ovale and foramen spinosum in patients with IIH, spontaneous CSF leak, and encephalocele. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary care academic medical center. PATIENTS: Adult patients treated from 2014 to 2018 with computed tomographic imaging of the head and who were diagnosed with IIH, encephalocele, or CSF leak. INTERVENTION: Two blinded observers measured the long and short axes of the foramen ovale and foramen spinosum on axial computed tomographic images. Measurements were used to calculate the approximate elliptical cross-sectional area of the foramina. MAIN OUTCOME MEASURES: Length, width, and area of the foramen ovale and foramen spinosum. RESULTS: A total of 264 patients were identified meeting the inclusion criteria and were placed into three groups. There were 170 patients with IIH, 48 with spontaneous CSF leak or encephalocele (CSF/E group), and 46 with traumatic or iatrogenic CSF leak (control group). Mean foramen ovale short axis (4.85 ± 1.00 mm) and cross-sectional area (30.17 ± 9.25 mm2) in the CSF/E group were significantly increased compared with measurements in patients with IIH or the control groups. Foramen ovale size was positively correlated with age in the CSF/E group. No significant difference in foramen spinosum size was found. CONCLUSION: Skull base defect resulting in spontaneous CSF leak or encephalocele is associated with enlargement of the foramen ovale on axial computed tomography.

Enlarging Ventriculus Terminalis in a Patient With Polyarteritis Nodosa.

Ventriculus terminalis (VT) is a cystic embryological remnant within the conus medullaris that normally regresses after birth. In rare cases, it may persist into adulthood and give rise to neurologic symptoms. The pathogenesis remains unclear but is thought to be related to failed embryonic regression with other proposed possible etiologies including vascular disturbances. We present an intriguing case of a slow-growing VT in a woman with progressive neurologic symptoms who experiences symptomatic relief following thoracic laminectomy and fenestration. Our case is the first to present a unique association with polyarteritis nodosa and only the third to report a case of documented enlargement of the VT over time successfully treated with surgical fenestration.

Regional association of pCASL-MRI with FDG-PET and PiB-PET in people at risk for autosomal dominant Alzheimer's disease.

Autosomal dominant Alzheimer's disease (ADAD) is a small subset of Alzheimer's disease that is genetically determined with 100% penetrance. It provides a valuable window into studying the course of pathologic processes that leads to dementia. Arterial spin labeling (ASL) MRI is a potential AD imaging marker that non-invasively measures cerebral perfusion. In this study, we investigated the relationship of cerebral blood flow measured by pseudo-continuous ASL (pCASL) MRI with measures of cerebral metabolism (FDG PET) and amyloid deposition (Pittsburgh Compound B (PiB) PET). Thirty-one participants at risk for ADAD (age 39 ± 13 years, 19 females) were recruited into this study, and 21 of them received both MRI and FDG and PiB PET scans. Considerable variability was observed in regional correlations between ASL-CBF and FDG across subjects. Both regional hypo-perfusion and hypo-metabolism were associated with amyloid deposition. Cross-sectional analyses of each biomarker as a function of the estimated years to expected dementia diagnosis indicated an inverse relationship of both perfusion and glucose metabolism with amyloid deposition during AD development. These findings indicate that neurovascular dysfunction is associated with amyloid pathology, and also indicate that ASL CBF may serve as a sensitive early biomarker for AD. The direct comparison among the three biomarkers provides complementary information for understanding the pathophysiological process of AD.

Two Novel Mutations in the First Transmembrane Domain of Presenilin1 Cause Young-Onset Alzheimer's Disease.

BACKGROUND: The presenilin-1 protein (PS1) is the catalytic unit of γ-secretase implicated in the production of abnormally long forms of amyloid-ß (Aß), including Aß42, proteins thought critical in the pathogenesis of Alzheimer's disease (AD). In AD of autosomal dominant inheritance, the majority of pathogenic mutations have been found in the PSEN1 gene within which the location of the mutation can provide clues as to the mechanism of pathogenesis. OBJECTIVE: To describe clinical features of two novel mutations in the transmembrane portion 1 (TMD-1) of PSEN1 as well as biochemical features in one and neuropathological findings in the other. METHODS: Two index patients with young onset AD with an autosomal dominant pattern of inheritance underwent clinical and imaging assessments, as well as PSEN1 sequencing. Postmortem examination was completed in one patient. An artificial construct in which the P88L mutation was introduced was created to examine its effects on γ-secretase cleavage. RESULTS: Two novel variants in TMD-1 (P88L and V89L) were identified in affected probands. The neuropathological findings of AD were confirmed in the V89L mutation. Both patients presented around age 40 with early short-term memory deficits followed by seizures and corticospinal tract signs. The P88L mutation additionally featured early myoclonus followed by Parkinsonism. The causal role of the P88L mutation is supported by demonstration that this mutation dramatically increased Aß42 and decreased APP and Notch intracellular domain production in vitro. CONCLUSION: Changes in a single amino acid in codons 88 and 89 of TMD-1 can result in young-onset AD. The TMD-1 of PS1 is a region important for the γ-secretase cleavage of Aß.

The Role of Neuroimaging in the Assessment of the Cognitively Impaired Elderly.

This article reviews the current diagnostic tools that are available for structural, functional, and molecular imaging of the brain, summarizing some of the key findings that have been reported in individuals diagnosed with Alzheimer disease, mild cognitive impairment, prodromal AD, or other prevalent dementias. Given recent advances in the development of amyloid PET tracers, current guidelines for the use of amyloid PET imaging in patients with cognitive complaints are reviewed. In addition, data addressing the potential value of amyloid PET imaging in the clinical setting are highlighted.

The sulci of the inferior surface of the temporal lobe: An anatomical study.

Understanding the anatomy of temporal lobe sulci and their variations can allow for safer neurosurgical approaches. Although the inferior temporal sulci and their relations to each other has been described by several authors, the nomenclature used has not been universal. The aim of this study was to investigate the anatomic features of the three main sulci of the inferior temporal lobe and provide a simple description of complex patterns among these sulci. Sulcal variations and their relations were examined in seventy formalin-fixed, adult cadaveric cerebral hemispheres. We recommend a simple but modified classification specifically for anatomic variations of the rhinal and collateral sulci. Furthermore, we describe the frequency of occipitotemporal sulci that contain 5 and 6 segments, not previously mentioned. The length and depth of all sulci were measured in all samples. Additionally, more detailed results regarding the patterns, courses, connections, relationships and measurements were given. Understanding of the complex anatomy of this clinically important region is of benefit to neurosurgeons, providing necessary guidance for neurosurgical approaches to the inferior surface of the temporal lobe. Clin. Anat. 29:932-942, 2016. © 2016 Wiley Periodicals, Inc.

A Multidisciplinary Model of Dementia Care in an Underserved Retirement Community, Made Possible by Telemedicine.

The need for memory specialists is increasing as the incidence of dementia rapidly rises across the globe. In rural areas, demand for these specialists far outstrips supply. It is increasingly difficulty for patients to receive care in a timely manner. In this paper, we document our experience using videoconference telemedicine to bring a multidisciplinary model of care to a rural retirement community in Southern California. To our knowledge, we are one of the first to integrate telemedicine into dementia care on this large a scale. Given the relatively remote location, patients and neurologists have previously had to travel great distances and bear with long wait times. With neurological consultation by telemedicine and a local team consisting of a geriatrician, a neuropsychologist, and a case manager, we have been able to provide comprehensive dementia care in this underserved area, comparable to university-affiliated California Alzheimer's Disease Centers, typically found only in major metropolitan areas. We have shown that telemedicine can be very effective in improving access and quality of dementia care.

Assessing intracranial vascular compliance using dynamic arterial spin labeling.

Vascular compliance (VC) is an important marker for a number of cardiovascular diseases and dementia, which is typically assessed in the central and peripheral arteries indirectly by quantifying pulse wave velocity (PWV), and/or pulse pressure waveform. To date, very few methods are available for the quantification of intracranial VC. In the present study, a novel MRI technique for in-vivo assessment of intracranial VC was introduced, where dynamic arterial spin labeling (ASL) scans were synchronized with the systolic and diastolic phases of the cardiac cycle. VC is defined as the ratio of change in arterial cerebral blood volume (ΔCBV) and change in arterial pressure (ΔBP). Intracranial VC was assessed in different vascular components using the proposed dynamic ASL method. Our results show that VC mainly occurs in large arteries, and gradually decreases in small arteries and arterioles. The comparison of intracranial VC between young and elderly subjects shows that aging is accompanied by a reduction of intracranial VC, in good agreement with the literature. Furthermore, a positive association between intracranial VC and cerebral perfusion measured using pseudo-continuous ASL with 3D GRASE MRI was observed independent of aging effects, suggesting loss of VC is associated with a decline in perfusion. Finally, a significant positive correlation between intracranial and central (aortic arch) VC was observed using an ungated phase-contrast 1D projection PWV technique. The proposed dynamic ASL method offers a promising approach for assessing intracranial VC in a range of cardiovascular diseases and dementia.

Blood-brain barrier breakdown in the aging human hippocampus.

The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment.

Reliability of two-dimensional and three-dimensional pseudo-continuous arterial spin labeling perfusion MRI in elderly populations: comparison with 15O-water positron emission tomography.

PURPOSE: To investigate the reliability and accuracy of two pseudo-continuous arterial spin labeling (pCASL) sequences, using two-dimensional (2D) gradient-echo echo planar imaging (EPI) and 3D gradient and spin echo (GRASE) as the readout, respectively. MATERIALS AND METHODS: Each sequence was performed twice 4 weeks apart on six normal control subjects, six elderly subjects with mild cognitive impairment (MCI), and one participant with Alzheimer's disease (AD). Eight of these subjects also underwent H2 (15) O positron emission tomography (PET) scans on the same day or proximal to their second MRI scan. The longitudinal repeatability of EPI and GRASE pCASL were evaluated with the intraclass correlation coefficient (ICC) and within-subject coefficient of variation (wsCV). RESULTS: The ICCs of global perfusion measurements were 0.697 and 0.413 for GRASE and EPI based pCASL respectively. GRASE pCASL also demonstrated a higher longitudinal repeatability for regional perfusion measurements across 24 regions-of-interests (ICC = 0.707; wsCV = 10.9%) compared with EPI pCASL (ICC = 0.362; wsCV = 15.3%). When compared with PET, EPI pCASL showed a higher degree of spatial correlation with PET than GRASE pCASL, although the difference was not statistically significant. CONCLUSION: The 3D GRASE pCASL offers better repeatability than 2D EPI pCASL, thereby may provide a reliable imaging marker for the evaluation of disease progression and treatment effects in MCI and early AD subjects.

Complexity and synchronicity of resting state blood oxygenation level-dependent (BOLD) functional MRI in normal aging and cognitive decline.

PURPOSE: To explore the use of approximate entropy (ApEn) as an index of the complexity and the synchronicity of resting state blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) in normal aging and cognitive decline associated with familial Alzheimer's disease (fAD). MATERIALS AND METHODS: Resting state BOLD fMRI data were acquired at 3T from two independent cohorts of subjects consisting of healthy young (age 23 ± 2 years, n = 8) and aged volunteers (age 66 ± 3 years, n = 8), as well as 22 fAD associated subjects (14 mutation carriers, age 41.2 ± 15.8 years; and eight nonmutation carrying family members, age 28.8 ± 5.9 years). Mean ApEn values were compared between the two age groups and correlated with cognitive performance in the fAD group. Cross-ApEn (C-ApEn) was further calculated to assess the asynchrony between precuneus and the rest of the brain. RESULTS: Complexity of brain activity measured by mean ApEn in gray and white matter decreased with normal aging. In the fAD group, cognitive impairment was associated with decreased mean ApEn in gray matter as well as decreased regional ApEn in right precuneus, right lateral parietal regions, left precentral gyrus, and right paracentral gyrus. A pattern of asynchrony between BOLD fMRI series emerged from C-ApEn analysis, with significant regional anti-correlation with cross-correlation coefficient of functional connectivity analysis. CONCLUSION: ApEn and C-ApEn may be useful for assessing the complexity and synchronicity of brain activity in normal aging and cognitive decline associated with neurodegenerative diseases.

Neuropsychological and neuroimaging markers in early versus late-onset Alzheimer's disease.

BACKGROUND: Early-onset Alzheimer's disease (EOAD) has been overshadowed by the more common late-onset AD (LOAD). Yet, the literature indicates EOAD may have less hippocampal-memory presentations and more focal neocortical localization early in the disease. OBJECTIVE: To evaluate these proposed differences between these 2 forms of AD and to explore what they inform about differences in AD pathophysiology. METHODS: In all, 21 patients with EOAD and 24 patients with LOAD matched for disease progression and severity were compared on neurocognitive measures and resting state fluorodeoxy-glucose positron-emission tomography (FDG-PET). RESULTS: Patients with EOAD had worse executive functions with greater hypometabolism in the parietal regions; whereas patients with LOAD had worse confrontation naming and verbal recognition memory with greater hypometabolism in inferior frontotemporal regions. CONCLUSIONS: In addition to highlighting significant differences between EOAD and LOAD, these results reveal dissociation between executive deficits in AD and frontal hypometabolism, suggesting early disturbances of the parietal-frontal network in EOAD.

Posterior cortical atrophy: evidence for discrete syndromes of early-onset Alzheimer's disease.

BACKGROUND: Posterior cortical atrophy (PCA) may represent a discrete syndrome of Alzheimer's disease (AD) rather than amnestic AD with visual deficits. METHODS: We separated 30 patients with PCA based on ventral and dorsal visual symptoms using cluster analysis and analyzed the demographic, cognitive, and functional imaging features. RESULTS: This analysis revealed subgroups of 26 dorsal and 4 ventral patients. The ventral subgroup had greater confrontational naming impairment, and the dorsal subgroup had greater hypofunction in the parietal regions. The PCA cohort had memory retrieval rather than encoding deficits, and clinical follow-up showed relative isolation of dorsal and ventral visual manifestations. CONCLUSION: These results support 2, mostly nonoverlapping syndromes in patients with PCA, with the commonest affecting the dorsal visual pathway; moreover, the memory retrieval difficulty in the patients with PCA was dissimilar to the amnestic pattern in typical AD. These results suggest that, in most cases, PCA syndromes are discrete clinical variants of AD.

Relationships between Cerebral Blood Flow and IQ in Typically Developing Children and Adolescents.

The objective of this study was to explore the relationships between IQ and cerebral blood flow (CBF) measured by arterial spin labeling (ASL) in children and adolescents. ASL was used to collect perfusion MRI data on 39 healthy participants aged 7 to 17. The Wechsler Abbreviated Intelligence Scale was administered to determine IQ scores. Multivariate regression was applied to reveal correlations between CBF and IQ scores, accounting for age, sex and global mean CBF. Voxel Based Morphometry (VBM) analysis, which measures regional cortical volume, was performed as a control. Regression analyses were further performed on CBF data with adjustment of regional gray matter density (GMD). A positive correlation between CBF and IQ scores was primarily seen in the subgenual/anterior cingulate, right orbitofrontal, superior temporal and right inferior parietal regions. An inverse relationship between CBF and IQ was mainly observed in bilateral posterior temporal regions. After adjusting for regional GMD, the correlations between CBF and IQ in the subgenual/anterior cingulate cortex, right orbitofrontal, superior temporal regions and left insula remained significant. These findings support the Parieto-Frontal Integration Theory of intelligence, especially the role of the subgenual/anterior cingulate cortex in the neural networks associated with intelligence. The present study also demonstrates the unique value of CBF in assessing brain-behavior relationships, in addition to structural morphometric measures.

APOE4 allele disrupts resting state fMRI connectivity in the absence of amyloid plaques or decreased CSF Aß42.

Identifying high-risk populations is an important component of disease prevention strategies. One approach for identifying at-risk populations for Alzheimer's disease (AD) is examining neuroimaging parameters that differ between patients, including functional connections known to be disrupted within the default-mode network. We have previously shown these same disruptions in cognitively normal elderly who have amyloid-ß (Aß) plaques [detected using Pittsburgh Compound B (PIB) PET imaging], suggesting neuronal toxicity of plaques. Here we sought to determine if pathological effects of apolipoprotein E ε4 (APOE4) genotype could be seen independent of Aß plaque toxicity by examining resting state fMRI functional connectivity (fcMRI) in participants without preclinical fibrillar amyloid deposition (PIB-). Cognitively normal participants enrolled in longitudinal studies (n = 100, mean age = 62) who were PIB- were categorized into those with and without an APOE4 allele and studied using fcMRI. APOE4 allele carriers (E4+) differed significantly from E4- in functional connectivity of the precuneus to several regions previously defined as having abnormal connectivity in a group of AD participants. These effects were observed before any manifestations of cognitive changes and in the absence of brain fibrillar Aß plaque deposition, suggesting that early manifestations of a genetic effect can be detected using fcMRI and that these changes may antedate the pathological effects of fibrillar amyloid plaque toxicity.