Gene specific effects on brain volume and cognition of TMEM106B in frontotemporal lobar degeneration.

Background and Objectives: TMEM106B has been proposed as a modifier of disease risk in FTLD-TDP, particularly in GRN mutation carriers. Furthermore, TMEM106B has been investigated as a disease modifier in the context of healthy aging and across multiple neurodegenerative diseases. The objective of this study is to evaluate and compare the effect of TMEM106B on gray matter volume and cognition in each of the common genetic FTD groups and in sporadic FTD patients. Methods: Participants were enrolled through the ARTFL/LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study, which includes symptomatic and presymptomatic individuals with a pathogenic mutation in C9orf72, GRN, MAPT, VCP, TBK1, TARDBP, symptomatic non-mutation carriers, and non-carrier family controls. All participants were genotyped for the TMEM106B rs1990622 SNP. Cross-sectionally, linear mixed-effects models were fitted to assess an association between TMEM106B and genetic group interaction with each outcome measure (gray matter volume and UDS3-EF for cognition), adjusting for education, age, sex and CDR®+NACC-FTLD sum of boxes. Subsequently, associations between TMEM106B and each outcome measure were investigated within the genetic group. For longitudinal modeling, linear mixed-effects models with time by TMEM106B predictor interactions were fitted. Results: The minor allele of TMEM106B rs1990622, linked to a decreased risk of FTD, associated with greater gray matter volume in GRN mutation carriers under the recessive dosage model. This was most pronounced in the thalamus in the left hemisphere, with a retained association when considering presymptomatic GRN mutation carriers only. The minor allele of TMEM106B rs1990622 also associated with greater cognitive scores among all C9orf72 mutation carriers and in presymptomatic C9orf72 mutation carriers, under the recessive dosage model. Discussion: We identified associations of TMEM106B with gray matter volume and cognition in the presence of GRN and C9orf72 mutations. This further supports TMEM106B as modifier of TDP-43 pathology. The association of TMEM106B with outcomes of interest in presymptomatic GRN and C9orf72 mutation carriers could additionally reflect TMEM106B's impact on divergent pathophysiological changes before the appearance of clinical symptoms.

Reliability and Validity of Smartphone Cognitive Testing for Frontotemporal Lobar Degeneration.

Importance: Frontotemporal lobar degeneration (FTLD) is relatively rare, behavioral and motor symptoms increase travel burden, and standard neuropsychological tests are not sensitive to early-stage disease. Remote smartphone-based cognitive assessments could mitigate these barriers to trial recruitment and success, but no such tools are validated for FTLD. Objective: To evaluate the reliability and validity of smartphone-based cognitive measures for remote FTLD evaluations. Design, Setting, and Participants: In this cohort study conducted from January 10, 2019, to July 31, 2023, controls and participants with FTLD performed smartphone application (app)-based executive functioning tasks and an associative memory task 3 times over 2 weeks. Observational research participants were enrolled through 18 centers of a North American FTLD research consortium (ALLFTD) and were asked to complete the tests remotely using their own smartphones. Of 1163 eligible individuals (enrolled in parent studies), 360 were enrolled in the present study; 364 refused and 439 were excluded. Participants were divided into discovery (n = 258) and validation (n = 102) cohorts. Among 329 participants with data available on disease stage, 195 were asymptomatic or had preclinical FTLD (59.3%), 66 had prodromal FTLD (20.1%), and 68 had symptomatic FTLD (20.7%) with a range of clinical syndromes. Exposure: Participants completed standard in-clinic measures and remotely administered ALLFTD mobile app (app) smartphone tests. Main Outcomes and Measures: Internal consistency, test-retest reliability, association of smartphone tests with criterion standard clinical measures, and diagnostic accuracy. Results: In the 360 participants (mean [SD] age, 54.0 [15.4] years; 209 [58.1%] women), smartphone tests showed moderate-to-excellent reliability (intraclass correlation coefficients, 0.77-0.95). Validity was supported by association of smartphones tests with disease severity (r range, 0.38-0.59), criterion-standard neuropsychological tests (r range, 0.40-0.66), and brain volume (standardized ß range, 0.34-0.50). Smartphone tests accurately differentiated individuals with dementia from controls (area under the curve [AUC], 0.93 [95% CI, 0.90-0.96]) and were more sensitive to early symptoms (AUC, 0.82 [95% CI, 0.76-0.88]) than the Montreal Cognitive Assessment (AUC, 0.68 [95% CI, 0.59-0.78]) (z of comparison, -2.49 [95% CI, -0.19 to -0.02]; P = .01). Reliability and validity findings were highly similar in the discovery and validation cohorts. Preclinical participants who carried pathogenic variants performed significantly worse than noncarrier family controls on 3 app tasks (eg, 2-back ß = -0.49 [95% CI, -0.72 to -0.25]; P < .001) but not a composite of traditional neuropsychological measures (ß = -0.14 [95% CI, -0.42 to 0.14]; P = .32). Conclusions and Relevance: The findings of this cohort study suggest that smartphones could offer a feasible, reliable, valid, and scalable solution for remote evaluations of FTLD and may improve early detection. Smartphone assessments should be considered as a complementary approach to traditional in-person trial designs. Future research should validate these results in diverse populations and evaluate the utility of these tests for longitudinal monitoring.

Latitudinal patterns in stabilizing density dependence of forest communities.

Numerous studies have shown reduced performance in plants that are surrounded by neighbours of the same species1,2, a phenomenon known as conspecific negative density dependence (CNDD)3. A long-held ecological hypothesis posits that CNDD is more pronounced in tropical than in temperate forests4,5, which increases community stabilization, species coexistence and the diversity of local tree species6,7. Previous analyses supporting such a latitudinal gradient in CNDD8,9 have suffered from methodological limitations related to the use of static data10-12. Here we present a comprehensive assessment of latitudinal CNDD patterns using dynamic mortality data to estimate species-site-specific CNDD across 23 sites. Averaged across species, we found that stabilizing CNDD was present at all except one site, but that average stabilizing CNDD was not stronger toward the tropics. However, in tropical tree communities, rare and intermediate abundant species experienced stronger stabilizing CNDD than did common species. This pattern was absent in temperate forests, which suggests that CNDD influences species abundances more strongly in tropical forests than it does in temperate ones13. We also found that interspecific variation in CNDD, which might attenuate its stabilizing effect on species diversity14,15, was high but not significantly different across latitudes. Although the consequences of these patterns for latitudinal diversity gradients are difficult to evaluate, we speculate that a more effective regulation of population abundances could translate into greater stabilization of tropical tree communities and thus contribute to the high local diversity of tropical forests.

Plasma phosphorylated tau-217 exhibits sex-specific prognostication of cognitive decline and brain atrophy in cognitively unimpaired adults.

INTRODUCTION: Accumulating evidence indicates disproportionate tau burden and tau-related clinical progression in females. However, sex differences in plasma phosphorylated tau (p-tau)217 prediction of subclinical cognitive and brain changes are unknown. METHODS: We measured baseline plasma p-tau217, glial fibrillary acidic protein (GFAP), and neurofilament light (NfL) in 163 participants (85 cognitively unimpaired [CU], 78 mild cognitive impairment [MCI]). In CU, linear mixed effects models examined sex differences in plasma biomarker prediction of longitudinal domain-specific cognitive decline and brain atrophy. Cognitive models were repeated in MCI. RESULTS: In CU females, baseline plasma p-tau217 predicted verbal memory and medial temporal lobe trajectories such that trajectories significantly declined once p-tau217 concentrations surpassed 0.053 pg/ml, a threshold that corresponded to early levels of cortical amyloid aggregation in secondary amyloid positron emission tomography analyses. CU males exhibited similar rates of cognitive decline and brain atrophy, but these trajectories were not dependent on plasma p-tau217. Plasma GFAP and NfL exhibited similar female-specific prediction of medial temporal lobe atrophy in CU. Plasma p-tau217 exhibited comparable prediction of cognitive decline across sex in MCI. DISCUSSION: Plasma p-tau217 may capture earlier Alzheimer's disease (AD)-related cognitive and brain atrophy hallmarks in females compared to males, possibly reflective of increased susceptibility to AD pathophysiology.

Biogeographic context is related to local scale tree demography, co-occurrence and functional differentiation.

Identifying the drivers of community structure and dynamics is a major pursuit in ecology. Emphasis is typically placed on the importance of local scale interactions when attempting to explain these fundamental ecological patterns. However, regional scale phenomena are also important predictors. The importance of regional scale context should be more evident in assemblages where multiple species are close to their range margins. Here, we test the importance of regional scale context using data from a temperate forest plot that contains two species groups - one near its northern range limit and one near its southern range limit. We show the proximity of species to their southern or northern range margins is linked to local scale co-occurrence, similarity in gene expression responses to a key environmental driver, demographic performance and inter-specific variation in conspecific negative density dependence. In sum, many of the key local scale patterns and processes of interest to community ecologists are linked to biogeographic context that is frequently ignored.

Temporal order of clinical and biomarker changes in familial frontotemporal dementia.

Unlike familial Alzheimer's disease, we have been unable to accurately predict symptom onset in presymptomatic familial frontotemporal dementia (f-FTD) mutation carriers, which is a major hurdle to designing disease prevention trials. We developed multimodal models for f-FTD disease progression and estimated clinical trial sample sizes in C9orf72, GRN and MAPT mutation carriers. Models included longitudinal clinical and neuropsychological scores, regional brain volumes and plasma neurofilament light chain (NfL) in 796 carriers and 412 noncarrier controls. We found that the temporal ordering of clinical and biomarker progression differed by genotype. In prevention-trial simulations using model-based patient selection, atrophy and NfL were the best endpoints, whereas clinical measures were potential endpoints in early symptomatic trials. f-FTD prevention trials are feasible but will likely require global recruitment efforts. These disease progression models will facilitate the planning of f-FTD clinical trials, including the selection of optimal endpoints and enrollment criteria to maximize power to detect treatment effects.

Detection of emerging neurodegeneration using Bayesian linear mixed-effect modeling.

Early detection of neurodegeneration, and prediction of when neurodegenerative diseases will lead to symptoms, are critical for developing and initiating disease modifying treatments for these disorders. While each neurodegenerative disease has a typical pattern of early changes in the brain, these disorders are heterogeneous, and early manifestations can vary greatly across people. Methods for detecting emerging neurodegeneration in any part of the brain are therefore needed. Prior publications have described the use of Bayesian linear mixed-effects (BLME) modeling for characterizing the trajectory of change across the brain in healthy controls and patients with neurodegenerative disease. Here, we use an extension of such a model to detect emerging neurodegeneration in cognitively healthy individuals at risk for dementia. We use BLME to quantify individualized rates of volume loss across the cerebral cortex from the first two MRIs in each person and then extend the BLME model to predict future values for each voxel. We then compare observed values at subsequent time points with the values that were expected from the initial rates of change and identify voxels that are lower than the expected values, indicating accelerated volume loss and neurodegeneration. We apply the model to longitudinal imaging data from cognitively normal participants in the Alzheimer's Disease Neuroimaging Initiative (ADNI), some of whom subsequently developed dementia, and two cognitively normal cases who developed pathology-proven frontotemporal lobar degeneration (FTLD). These analyses identified regions of accelerated volume loss prior to or accompanying the earliest symptoms, and expanding across the brain over time, in all cases. The changes were detected in regions that are typical for the likely diseases affecting each patient, including medial temporal regions in patients at risk for Alzheimer's disease, and insular, frontal, and/or anterior/inferior temporal regions in patients with likely or proven FTLD. In the cases where detailed histories were available, the first regions identified were consistent with early symptoms. Furthermore, survival analysis in the ADNI cases demonstrated that the rate of spread of accelerated volume loss across the brain was a statistically significant predictor of time to conversion to dementia. This method for detection of neurodegeneration is a potentially promising approach for identifying early changes due to a variety of diseases, without prior assumptions about what regions are most likely to be affected first in an individual.

Wisdom and fluid intelligence are dissociable in healthy older adults.

OBJECTIVES: The relationship between wisdom and fluid intelligence (Gf) is poorly understood, particularly in older adults. We empirically tested the magnitude of the correlation between wisdom and Gf to help determine the extent of overlap between these two constructs. DESIGN: Cross-sectional study with preregistered hypotheses and well-powered analytic plan (https://osf.io/h3pjx). SETTING: Memory and Aging Center at the University of California San Francisco, located in the USA. PARTICIPANTS: 141 healthy older adults (mean age = 76 years; 56% female). MEASUREMENTS: Wisdom was quantified using a well-validated self-report-based scale (San Diego Wisdom Scale or SD-WISE). Gf was assessed via composite measures of processing speed (Gf-PS) and executive functioning (Gf-EF). The relationships of SD-WISE scores to Gf-PS and Gf-EF were tested in bivariate correlational analyses and multiple regression models adjusted for demographics (age, sex, and education). Exploratory analyses evaluated the relationships between SD-WISE and age, episodic memory performance, and dorsolateral and ventromedial prefrontal cortical volumes on magnetic resonance imaging. RESULTS: Wisdom showed a small, positive association with Gf-EF (r = 0.181 [95% CI 0.016, 0.336], p = .031), which was reduced to nonsignificance upon controlling for demographics, and no association with Gf-PS (r = 0.019 [95% CI -0.179, 0.216], p = .854). Wisdom demonstrated a small, negative correlation with age (r = -0.197 [95% CI -0.351, -0.033], p = .019), but was not significantly related to episodic memory or prefrontal volumes. CONCLUSIONS: Our findings indicate that most of the variance in wisdom (>95%) is unaccounted for by Gf. The independence of wisdom from cognitive functions that reliably show age-associated declines suggests that it may hold unique potential to bolster decision-making, interpersonal functioning, and other everyday activities in older adults.

Plasma phosphorylated tau 217 and phosphorylated tau 181 as biomarkers in Alzheimer's disease and frontotemporal lobar degeneration: a retrospective diagnostic performance study.

BACKGROUND: Plasma tau phosphorylated at threonine 217 (p-tau217) and plasma tau phosphorylated at threonine 181 (p-tau181) are associated with Alzheimer's disease tau pathology. We compared the diagnostic value of both biomarkers in cognitively unimpaired participants and patients with a clinical diagnosis of mild cognitive impairment, Alzheimer's disease syndromes, or frontotemporal lobar degeneration (FTLD) syndromes. METHODS: In this retrospective multicohort diagnostic performance study, we analysed plasma samples, obtained from patients aged 18-99 years old who had been diagnosed with Alzheimer's disease syndromes (Alzheimer's disease dementia, logopenic variant primary progressive aphasia, or posterior cortical atrophy), FTLD syndromes (corticobasal syndrome, progressive supranuclear palsy, behavioural variant frontotemporal dementia, non-fluent variant primary progressive aphasia, or semantic variant primary progressive aphasia), or mild cognitive impairment; the participants were from the University of California San Francisco (UCSF) Memory and Aging Center, San Francisco, CA, USA, and the Advancing Research and Treatment for Frontotemporal Lobar Degeneration Consortium (ARTFL; 17 sites in the USA and two in Canada). Participants from both cohorts were carefully characterised, including assessments of CSF p-tau181, amyloid-PET or tau-PET (or both), and clinical and cognitive evaluations. Plasma p-tau181 and p-tau217 were measured using electrochemiluminescence-based assays, which differed only in the biotinylated antibody epitope specificity. Receiver operating characteristic analyses were used to determine diagnostic accuracy of both plasma markers using clinical diagnosis, neuropathological findings, and amyloid-PET and tau-PET measures as gold standards. Difference between two area under the curve (AUC) analyses were tested with the Delong test. FINDINGS: Data were collected from 593 participants (443 from UCSF and 150 from ARTFL, mean age 64 years [SD 13], 294 [50%] women) between July 1 and Nov 30, 2020. Plasma p-tau217 and p-tau181 were correlated (r=0·90, p<0·0001). Both p-tau217 and p-tau181 concentrations were increased in people with Alzheimer's disease syndromes (n=75, mean age 65 years [SD 10]) relative to cognitively unimpaired controls (n=118, mean age 61 years [SD 18]; AUC=0·98 [95% CI 0·95-1·00] for p-tau217, AUC=0·97 [0·94-0·99] for p-tau181; pdiff=0·31) and in pathology-confirmed Alzheimer's disease (n=15, mean age 73 years [SD 12]) versus pathologically confirmed FTLD (n=68, mean age 67 years [SD 8]; AUC=0·96 [0·92-1·00] for p-tau217, AUC=0·91 [0·82-1·00] for p-tau181; pdiff=0·22). P-tau217 outperformed p-tau181 in differentiating patients with Alzheimer's disease syndromes (n=75) from those with FTLD syndromes (n=274, mean age 67 years [SD 9]; AUC=0·93 [0·91-0·96] for p-tau217, AUC=0·91 [0·88-0·94] for p-tau181; pdiff=0·01). P-tau217 was a stronger indicator of amyloid-PET positivity (n=146, AUC=0·91 [0·88-0·94]) than was p-tau181 (n=214, AUC=0·89 [0·86-0·93]; pdiff=0·049). Tau-PET binding in the temporal cortex was more strongly associated with p-tau217 than p-tau181 (r=0·80 vs r=0·72; pdiff<0·0001, n=230). INTERPRETATION: Both p-tau217 and p-tau181 had excellent diagnostic performance for differentiating patients with Alzheimer's disease syndromes from other neurodegenerative disorders. There was some evidence in favour of p-tau217 compared with p-tau181 for differential diagnosis of Alzheimer's disease syndromes versus FTLD syndromes, as an indication of amyloid-PET-positivity, and for stronger correlations with tau-PET signal. Pending replication in independent, diverse, and older cohorts, plasma p-tau217 and p-tau181 could be useful screening tools to identify individuals with underlying amyloid and Alzheimer's disease tau pathology. FUNDING: US National Institutes of Health, State of California Department of Health Services, Rainwater Charitable Foundation, Michael J Fox foundation, Association for Frontotemporal Degeneration, Alzheimer's Association.

Pattern and degree of individual brain atrophy predicts dementia onset in dominantly inherited Alzheimer's disease.

INTRODUCTION: Asymptomatic and mildly symptomatic dominantly inherited Alzheimer's disease mutation carriers (DIAD-MC) are ideal candidates for preventative treatment trials aimed at delaying or preventing dementia onset. Brain atrophy is an early feature of DIAD-MC and could help predict risk for dementia during trial enrollment. METHODS: We created a dementia risk score by entering standardized gray-matter volumes from 231 DIAD-MC into a logistic regression to classify participants with and without dementia. The score's predictive utility was assessed using Cox models and receiver operating curves on a separate group of 65 DIAD-MC followed longitudinally. RESULTS: Our risk score separated asymptomatic versus demented DIAD-MC with 96.4% (standard error = 0.02) and predicted conversion to dementia at next visit (hazard ratio = 1.32, 95% confidence interval [CI: 1.15, 1.49]) and within 2 years (area under the curve = 90.3%, 95% CI [82.3%-98.2%]) and improved prediction beyond established methods based on familial age of onset. DISCUSSION: Individualized risk scores based on brain atrophy could be useful for establishing enrollment criteria and stratifying DIAD-MC participants for prevention trials.

Retinal imaging demonstrates reduced capillary density in clinically unimpaired APOE ε4 gene carriers.

INTRODUCTION: Apolipoprotein E (APOE) ε4, the strongest non-Mendelian genetic risk factor for Alzheimer's disease (AD), has been shown to affect brain capillaries in mice, with potential implications for AD-related neurodegenerative disease. However, human brain capillaries cannot be directly visualized in vivo. We therefore used retinal imaging to test APOE ε4 effects on human central nervous system capillaries. METHODS: We collected retinal optical coherence tomography angiography, cognitive testing, and brain imaging in research participants and built statistical models to test genotype-phenotype associations. RESULTS: Our analyses demonstrate lower retinal capillary densities in early disease, in cognitively normal APOE ε4 gene carriers. Furthermore, through regression modeling with a measure of brain perfusion (arterial spin labeling), we provide support for the relevance of these findings to cerebral vasculature. DISCUSSION: These results suggest that APOE ε4 affects capillary health in humans and that retinal capillary measures could serve as surrogates for brain capillaries, providing an opportunity to study microangiopathic contributions to neurodegenerative disorders directly in humans.

Multimodal neuroimaging of sex differences in cognitively impaired patients on the Alzheimer's continuum: greater tau-PET retention in females.

We assessed sex differences in amyloid- and tau-PET retention in 119 amyloid positive patients with mild cognitive impairment or Alzheimer's disease (AD) dementia. Patients underwent 3T-MRI, 11C-PIB amyloid-PET and 18F-Flortaucipir tau-PET. Linear ordinary least squares regression models tested sex differences in Flortaucipir-PET SUVR in a summary temporal region of interest as well as global PIB-PET. No sex differences were observed in demographics, Clinical Dementia Rating Sum of Boxes (CDR-SoB), Mini-Mental State Exam (MMSE), raw episodic memory scores, or cortical thickness. Females had higher global PIB SUVR (ηp²=.043, p=.025) and temporal Flortaucipir SUVR (ηp²=.070, p=.004), adjusting for age and CDR-SoB. Sex differences in temporal Flortaucipir-PET remained significant when controlling additionally for PIB SUVR and APOE4 status (ηp²=.055, p=.013), or when using partial volume-corrected data. No sex differences were present in areas of known Flortaucipir off-target binding. Overall, females demonstrated greater AD regional tau-PET burden than males despite clinical comparability. Further characterization of sex differences will provide insight into AD pathogenesis and support development of personalized therapeutic strategies.

Selective vulnerability to atrophy in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Identification of brain regions susceptible to quantifiable atrophy in sporadic Creutzfeldt-Jakob disease (sCJD) should allow for improved understanding of disease pathophysiology and development of structural biomarkers that might be useful in future treatment trials. Although brain atrophy is not usually present by visual assessment of MRIs in sCJD, we assessed whether using voxel-based morphometry (VBM) can detect group-wise brain atrophy in sCJD. METHODS: 3T brain MRI data were analyzed with VBM in 22 sCJD participants and 26 age-matched controls. Analyses included relationships of regional brain volumes with major clinical variables and dichotomization of the cohort according to expected disease duration based on prion molecular classification (i.e., short-duration/Fast-progressors (MM1, MV1, and VV2) vs. long-duration/Slow-progressors (MV2, VV1, and MM2)). Structural equation modeling (SEM) was used to assess network-level interactions of atrophy between specific brain regions. RESULTS: sCJD showed selective atrophy in cortical and subcortical regions overlapping with all but one region of the default mode network (DMN) and the insulae, thalami, and right occipital lobe. SEM showed that the effective connectivity model fit in sCJD but not controls. The presence of visual hallucinations correlated with right fusiform, bilateral thalami, and medial orbitofrontal atrophy. Interestingly, brain atrophy was present in both Fast- and Slow-progressors. Worse cognition was associated with bilateral mesial frontal, insular, temporal pole, thalamus, and cerebellum atrophy. INTERPRETATION: Brain atrophy in sCJD preferentially affects specific cortical and subcortical regions, with an effective connectivity model showing strength and directionality between regions. Brain atrophy is present in Fast- and Slow-progressors, correlates with clinical findings, and is a potential biomarker in sCJD.

Consequences of spatial patterns for coexistence in species-rich plant communities.

Ecology cannot yet fully explain why so many tree species coexist in natural communities such as tropical forests. A major difficulty is linking individual-level processes to community dynamics. We propose a combination of tree spatial data, spatial statistics and dynamical theory to reveal the relationship between spatial patterns and population-level interaction coefficients and their consequences for multispecies dynamics and coexistence. Here we show that the emerging population-level interaction coefficients have, for a broad range of circumstances, a simpler structure than their individual-level counterparts, which allows for an analytical treatment of equilibrium and stability conditions. Mechanisms such as animal seed dispersal, which result in clustering of recruits that is decoupled from parent locations, lead to a rare-species advantage and coexistence of otherwise neutral competitors. Linking spatial statistics with theories of community dynamics offers new avenues for explaining species coexistence and calls for rethinking community ecology through a spatial lens.

APOE moderates the effect of hippocampal blood flow on memory pattern separation in clinically normal older adults.

Pattern separation, the ability to differentiate new information from previously experienced similar information, is highly sensitive to hippocampal structure and function and declines with age. Functional MRI studies have demonstrated hippocampal hyperactivation in older adults compared to young, with greater task-related activation associated with worse pattern separation performance. The current study was designed to determine whether pattern separation was sensitive to differences in task-free hippocampal cerebral blood flow (CBF) in 130 functionally intact older adults. Given prior evidence that apolipoprotein E e4 (APOE e4) status moderates the relationship between CBF and episodic memory, we predicted a stronger negative relationship between hippocampal CBF and pattern separation in APOE e4 carriers. An interaction between APOE group and right hippocampal CBF was present, such that greater right hippocampal CBF was related to better lure discrimination in noncarriers, whereas the effect reversed directionality in e4 carriers. These findings suggest that neurovascular changes in the medial temporal lobe may underlie memory deficits in cognitively normal older adults who are APOE e4 carriers.