Cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Cerebrospinal fluid (CSF) contains a tightly regulated immune system. However, knowledge is lacking about how CSF immunity is altered with aging or neurodegenerative disease. Here, we performed single-cell RNA sequencing on CSF from 45 cognitively normal subjects ranging from 54 to 82 years old. We uncovered an upregulation of lipid transport genes in monocytes with age. We then compared this cohort with 14 cognitively impaired subjects. In cognitively impaired subjects, downregulation of lipid transport genes in monocytes occurred concomitantly with altered cytokine signaling to CD8 T cells. Clonal CD8 T effector memory cells upregulated C-X-C motif chemokine receptor 6 (CXCR6) in cognitively impaired subjects. The CXCR6 ligand, C-X-C motif chemokine ligand 16 (CXCL16), was elevated in the CSF of cognitively impaired subjects, suggesting CXCL16-CXCR6 signaling as a mechanism for antigen-specific T cell entry into the brain. Cumulatively, these results reveal cerebrospinal fluid immune dysregulation during healthy brain aging and cognitive impairment.

Plasma pTau181 Reveals a Pathological Signature that Predicts Cognitive Outcomes in Lewy Body Disease.

OBJECTIVE: To determine whether plasma phosphorylated-Tau181 (pTau181) could be used as a diagnostic biomarker of concurrent Alzheimer's disease neuropathologic change (ADNC) or amyloidosis alone, as well as a prognostic, monitoring, and susceptibility/risk biomarker for clinical outcomes in Lewy body disease (LBD). METHODS: We studied 565 participants: 94 LBD with normal cognition, 83 LBD with abnormal cognition, 114 with Alzheimer's disease, and 274 cognitively normal. Plasma pTau181 levels were measured with the Lumipulse G platform. Diagnostic accuracy for concurrent ADNC and amyloidosis was assessed with Receiver Operating Characteristic curves in a subset of participants with CSF pTau181/Aß42, and CSF Aß42/Aß40 or amyloid-ß PET, respectively. Linear mixed effects models were used to examine the associations between baseline and longitudinal plasma pTau181 levels and clinical outcomes. RESULTS: Plasma pTau181 predicted concurrent ADNC and amyloidosis in LBD with abnormal cognition with 87% and 72% accuracy, respectively. In LBD patients with abnormal cognition, higher baseline plasma pTau181 was associated with worse baseline MoCA and CDR-SB, as well as accelerated decline in CDR-SB. Additionally, in this group, rapid increases in plasma pTau181 over 3 years predicted a faster decline in CDR-SB and memory. In LBD patients with normal cognition, there was no association between baseline or longitudinal plasma pTau181 levels and clinical outcomes; however, elevated pTau181 at baseline increased the risk of conversion to cognitive impairment. INTERPRETATION: Our findings suggest that plasma pTau181 is a promising biomarker for concurrent ADNC and amyloidosis in LBD. Furthermore, plasma pTau181 holds potential as a prognostic, monitoring, and susceptibility/risk biomarker, predicting disease progression in LBD. ANN NEUROL 2024.

Genome-wide analysis of common and rare variants via multiple knockoffs at biobank scale, with an application to Alzheimer disease genetics.

Knockoff-based methods have become increasingly popular due to their enhanced power for locus discovery and their ability to prioritize putative causal variants in a genome-wide analysis. However, because of the substantial computational cost for generating knockoffs, existing knockoff approaches cannot analyze millions of rare genetic variants in biobank-scale whole-genome sequencing and whole-genome imputed datasets. We propose a scalable knockoff-based method for the analysis of common and rare variants across the genome, KnockoffScreen-AL, that is applicable to biobank-scale studies with hundreds of thousands of samples and millions of genetic variants. The application of KnockoffScreen-AL to the analysis of Alzheimer disease (AD) in 388,051 WG-imputed samples from the UK Biobank resulted in 31 significant loci, including 14 loci that are missed by conventional association tests on these data. We perform replication studies in an independent meta-analysis of clinically diagnosed AD with 94,437 samples, and additionally leverage single-cell RNA-sequencing data with 143,793 single-nucleus transcriptomes from 17 control subjects and AD-affected individuals, and proteomics data from 735 control subjects and affected indviduals with AD and related disorders to validate the genes at these significant loci. These multi-omics analyses show that 79.1% of the proximal genes at these loci and 76.2% of the genes at loci identified only by KnockoffScreen-AL exhibit at least suggestive signal (p < 0.05) in the scRNA-seq or proteomics analyses. We highlight a potentially causal gene in AD progression, EGFR, that shows significant differences in expression and protein levels between AD-affected individuals and healthy control subjects.

Temporal tau asymmetry spectrum influences divergent behavior and language patterns in Alzheimer's disease.

Understanding the psychiatric symptoms of Alzheimer s disease (AD) is crucial for advancing precision medicine and therapeutic strategies. The relationship between AD behavioral symptoms and asymmetry in spatial tau PET patterns is not well-known. Braak tau progression implicates the temporal lobes early. However, the clinical and pathological implications of temporal tau laterality remain unexplored. This cross-sectional study investigated the correlation between temporal tau PET asymmetry and behavior assessed using the neuropsychiatric inventory and composite scores for memory, executive function, and language, using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) dataset. In the entire cohort, continuous right and left temporal tau contributions to behavior and cognition were evaluated, controlling for age, sex, education, and tau burden on the contralateral side. Additionally, a temporal tau laterality index was calculated to define "asymmetry-extreme" groups (individuals with laterality indices greater than two standard deviations from the mean). 695 individuals (age = 73.9 ± 7.6 years, 372 (53.5 %) females) were included, comprising 281 (40%) cognitively unimpaired (CU) amyloid negative, 185 (27%) CU amyloid positive, and 229 (33%) impaired (CI) amyloid positive participants. In the full cohort analysis, right temporal tau was associated with worse behavior (B = 8.14, p-value = 0.007), and left temporal tau was associated with worse language (B = 1.4, p-value < 0.001). Categorization into asymmetry-extreme groups revealed 20 right- and 27 left-asymmetric participants. Within these extreme groups, there was additional heterogeneity along the anterior-posterior dimension. Asymmetrical tau burden is associated with distinct behavioral and cognitive profiles. Wide multi-cultural implementation of social cognition measures is needed to understand right-sided asymmetry in AD.

Tau positron emission tomography in preclinical Alzheimer's disease.

Rates of tau accumulation in cognitively unimpaired older adults are subtle, with magnitude and spatial patterns varying in recent reports. Regional accumulation also likely varies in the degree to which accumulation is amyloid-ß-dependent. Thus, there is a need to evaluate the pattern and consistency of tau accumulation across multiple cognitively unimpaired cohorts and how these patterns relate to amyloid burden, in order to design optimal tau end points for clinical trials. Using three large cohorts of cognitively unimpaired older adults, the Anti-Amyloid Treatment in Asymptomatic Alzheimer's and companion study, Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (n = 447), the Alzheimer's Disease Neuroimaging Initiative (n = 420) and the Harvard Aging Brain Study (n = 190), we attempted to identify regions with high rates of tau accumulation and estimate how these rates evolve over a continuous spectrum of baseline amyloid deposition. Optimal combinations of regions, tailored to multiple ranges of baseline amyloid burden as hypothetical clinical trial inclusion criteria, were tested and validated. The inferior temporal cortex, fusiform gyrus and middle temporal cortex had the largest effect sizes of accumulation in both longitudinal cohorts when considered individually. When tau regions of interest were combined to find composite weights to maximize the effect size of tau change over time, both longitudinal studies exhibited a similar pattern-inferior temporal cortex, almost exclusively, was optimal for participants with mildly elevated amyloid ß levels. For participants with highly elevated baseline amyloid ß levels, combined optimal composite weights were 53% inferior temporal cortex, 31% amygdala and 16% fusiform. At mildly elevated levels of baseline amyloid ß, a sample size of 200/group required a treatment effect of 0.40-0.45 (40-45% slowing of tau accumulation) to power an 18-month trial using the optimized composite. Neither a temporal lobe composite nor a global composite reached 80% power with 200/group with an effect size under 0.5. The focus of early tau accumulation on the medial temporal lobe has resulted from the observation that the entorhinal cortex is the initial site to show abnormal levels of tau with age. However, these abnormal levels do not appear to be the result of a high rate of accumulation in the short term, but possibly a more moderate rate occurring early with respect to age. While the entorhinal cortex plays a central role in the early appearance of tau, it may be the inferior temporal cortex that is the critical region for rapid tau accumulation in preclinical Alzheimer's disease.

Speech patterns during memory recall relates to early tau burden across adulthood.

INTRODUCTION: Early cognitive decline may manifest in subtle differences in speech. METHODS: We examined 238 cognitively unimpaired adults from the Framingham Heart Study (32-75 years) who completed amyloid and tau PET imaging. Speech patterns during delayed recall of a story memory task were quantified via five speech markers, and their associations with global amyloid status and regional tau signal were examined. RESULTS: Total utterance time, number of between-utterance pauses, speech rate, and percentage of unique words significantly correlated with delayed recall score although the shared variance was low (2%-15%). Delayed recall score was not significantly different between ß-amyoid-positive (Aß+) and -negative (Aß-) groups and was not associated with regional tau signal. However, longer and more between-utterance pauses, and slower speech rate were associated with increased tau signal across medial temporal and early neocortical regions. DISCUSSION: Subtle speech changes during memory recall may reflect cognitive impairment associated with early Alzheimer's disease pathology. HIGHLIGHTS: Speech during delayed memory recall relates to tau PET signal across adulthood. Delayed memory recall score was not associated with tau PET signal. Speech shows greater sensitivity to detecting subtle cognitive changes associated with early tau accumulation. Our cohort spans adulthood, while most PET imaging studies focus on older adults.

Florbetaben amyloid PET acquisition time: Influence on Centiloids and interpretation.

INTRODUCTION: Amyloid positron emission tomography (PET) acquisition timing impacts quantification. METHODS: In florbetaben (FBB) PET scans of 245 adults with and without cognitive impairment, we investigated the impact of post-injection acquisition time on Centiloids (CLs) across five reference regions. CL equations for FBB were derived using standard methods, using FBB data collected between 90 and 110 min with paired Pittsburgh compound B data. Linear mixed models and t-tests evaluated the impact of acquisition time on CL increases. RESULTS: CL values increased significantly over the scan using the whole cerebellum, cerebellar gray matter, and brainstem as reference regions, particularly in amyloid-positive individuals. In contrast, CLs based on white matter-containing reference regions decreased across the scan. DISCUSSION: The quantification of CLs in FBB PET imaging is influenced by both the overall scan acquisition time and the choice of reference region. Standardized acquisition protocols or the application of acquisition time-specific CL equations should be implemented in clinical protocols. HIGHLIGHTS: Acquisition timing affects florbetaben positron emission tomography (PET) scan quantification, especially in amyloid-positive participants. The impact of acquisition timing on quantification varies across common reference regions. Consistent acquisitions and/or appropriate post-injection adjustments are needed to ensure comparability of PET data.

Post-translational modifications linked to preclinical Alzheimer's disease-related pathological and cognitive changes.

INTRODUCTION: In this study, we leverage proteomic techniques to identify communities of proteins underlying Alzheimer's disease (AD) risk among clinically unimpaired (CU) older adults. METHODS: We constructed a protein co-expression network using 3869 cerebrospinal fluid (CSF) proteins quantified by SomaLogic, Inc., in a cohort of participants along the AD clinical spectrum. We then replicated this network in an independent cohort of CU older adults and related these modules to clinically-relevant outcomes. RESULTS: We discovered modules enriched for phosphorylation and ubiquitination that were associated with abnormal amyloid status, as well as p-tau181 (M4: ß = 2.44, p < 0.001, M7: ß = 2.57, p < 0.001) and executive function performance (M4: ß = -2.00, p = 0.005, M7: ß = -2.39, p < 0.001). DISCUSSION: In leveraging CSF proteomic data from individuals spanning the clinical spectrum of AD, we highlight the importance of post-translational modifications for early cognitive and pathological changes.

Sex differences in the genetic architecture of cognitive resilience to Alzheimer's disease.

Approximately 30% of elderly adults are cognitively unimpaired at time of death despite the presence of Alzheimer's disease neuropathology at autopsy. Studying individuals who are resilient to the cognitive consequences of Alzheimer's disease neuropathology may uncover novel therapeutic targets to treat Alzheimer's disease. It is well established that there are sex differences in response to Alzheimer's disease pathology, and growing evidence suggests that genetic factors may contribute to these differences. Taken together, we sought to elucidate sex-specific genetic drivers of resilience. We extended our recent large scale genomic analysis of resilience in which we harmonized cognitive data across four cohorts of cognitive ageing, in vivo amyloid PET across two cohorts, and autopsy measures of amyloid neuritic plaque burden across two cohorts. These data were leveraged to build robust, continuous resilience phenotypes. With these phenotypes, we performed sex-stratified [n (males) = 2093, n (females) = 2931] and sex-interaction [n (both sexes) = 5024] genome-wide association studies (GWAS), gene and pathway-based tests, and genetic correlation analyses to clarify the variants, genes and molecular pathways that relate to resilience in a sex-specific manner. Estimated among cognitively normal individuals of both sexes, resilience was 20-25% heritable, and when estimated in either sex among cognitively normal individuals, resilience was 15-44% heritable. In our GWAS, we identified a female-specific locus on chromosome 10 [rs827389, ß (females) = 0.08, P (females) = 5.76 × 10-09, ß (males) = -0.01, P(males) = 0.70, ß (interaction) = 0.09, P (interaction) = 1.01 × 10-04] in which the minor allele was associated with higher resilience scores among females. This locus is located within chromatin loops that interact with promoters of genes involved in RNA processing, including GATA3. Finally, our genetic correlation analyses revealed shared genetic architecture between resilience phenotypes and other complex traits, including a female-specific association with frontotemporal dementia and male-specific associations with heart rate variability traits. We also observed opposing associations between sexes for multiple sclerosis, such that more resilient females had a lower genetic susceptibility to multiple sclerosis, and more resilient males had a higher genetic susceptibility to multiple sclerosis. Overall, we identified sex differences in the genetic architecture of resilience, identified a female-specific resilience locus and highlighted numerous sex-specific molecular pathways that may underly resilience to Alzheimer's disease pathology. This study illustrates the need to conduct sex-aware genomic analyses to identify novel targets that are unidentified in sex-agnostic models. Our findings support the theory that the most successful treatment for an individual with Alzheimer's disease may be personalized based on their biological sex and genetic context.

Influence of common reference regions on regional tau patterns in cross-sectional and longitudinal [18F]-AV-1451 PET data.

Tau PET has allowed for critical insights into in vivo patterns of tau accumulation and change in individuals early in the Alzheimer's disease (AD) continuum. A key methodological step in tau PET analyses is the selection of a reference region, but there is not yet consensus on the optimal region especially for longitudinal tau PET analyses. This study examines how reference region selection influences results related to disease stage at baseline and over time. Longitudinal flortaucipir ([18F]-AV1451) PET scans were examined using several common reference regions (e.g., eroded subcortical white matter, inferior cerebellar gray matter) in 62 clinically unimpaired amyloid negative (CU A-) individuals, 73 CU amyloid positive (CU A+) individuals, and 64 amyloid positive individuals with mild cognitive impairment (MCI A+) from the Alzheimer's Disease Neuroimaging Initiative (ADNI). Cross-sectionally, both reference regions resulted in robust group differences between CU A-, CU A+, and MCI A+ groups, along with significant associations with CSF phosphorylated tau (pTau-181). However, these results were more focally specific and akin to Braak Staging when using eroded white matter, whereas effects with inferior cerebellum were globally distributed across most cortical regions. Longitudinally, utilization of eroded white matter revealed significant accumulation greater than zero across more regions whereas change over time was diminished using inferior cerebellum. Interestingly, the inferior temporal target region seemed most robust to reference region selection with expected cross-sectional and longitudinal signal across both reference regions. With few exceptions, baseline tau did not significantly predict longitudinal change in tau in the same region regardless of reference region. In summary, reference region selection deserves further evaluation as this methodological step may lead to disparate findings. Inferior cerebellar gray matter may be more sensitive to cross-sectional flortaucipir differences, whereas eroded subcortical white matter may be more sensitive for longitudinal analyses examining regional patterns of change.

Sex Mediates Relationships Between Regional Tau Pathology and Cognitive Decline.

OBJECTIVE: The goal of this study was to examine sex differences in tau distribution across the brain of older adults, using positron emission tomography (PET), and investigate how these differences might associate with cognitive trajectories. METHODS: Participants were 343 clinically normal individuals (women, 58%; 73.8 [8.5] years) and 55 individuals with mild cognitive impairment (MCI; women, 38%; 76.9 [7.3] years) from the Harvard Aging Brain Study and the Alzheimer's Disease Neuroimaging Initiative. We examined 18 F-Flortaucipir (FTP)-positron emission tomography (PET) signal across 41 cortical and subcortical regions of interest (ROIs). Linear regression models estimated the effect of sex on FTP-signal for each ROI after adjusting for age and cohort. We also examined interactions between sex*Aß-PET positive / negative (+ / -) and sex*apolipoprotein ε4 (APOEε4) status. Linear mixed models estimated the moderating effect of sex on the relationship between a composite of sex-differentiated tau ROIs and cognitive decline. RESULTS: Women showed significantly higher FTP-signals than men across multiple regions of the cortical mantle (p < 0.007). ß-amyloid (Aß)-moderated sex differences in tau signal were localized to medial and inferio-lateral temporal regions (p < 0.007); Aß + women exhibited greater FTP-signal than other groups. APOEε4-moderated sex differences in FTP-signal were only found in the lateral occipital lobe. Women with higher FTP-signals in composite ROI exhibited faster cognitive decline than men (p = 0.04). INTERPRETATION: Tau vulnerability in women is not just limited to the medial temporal lobe and significantly contributed to greater risk of faster cognitive decline. Interactive effects of sex and Aß were predominantly localized in the temporal lobe, however, sex differences in extra-temporal tau highlights the possibility of accelerated tau proliferation in women with the onset of clinical symptomatology. ANN NEUROL 2020;88:921-932.

Tau PET imaging with 18F-PI-2620 in aging and neurodegenerative diseases.

PURPOSE: In vivo measurement of the spatial distribution of neurofibrillary tangle pathology is critical for early diagnosis and disease monitoring of Alzheimer's disease (AD). METHODS: Forty-nine participants were scanned with 18F-PI-2620 PET to examine the distribution of this novel PET ligand throughout the course of AD: 36 older healthy controls (HC) (age range 61 to 86), 11 beta-amyloid+ (Aß+) participants with cognitive impairment (CI; clinical diagnosis of either mild cognitive impairment or AD dementia, age range 57 to 86), and 2 participants with semantic variant primary progressive aphasia (svPPA, age 66 and 78). Group differences in brain regions relevant in AD (medial temporal lobe, posterior cingulate cortex, and lateral parietal cortex) were examined using standardized uptake value ratios (SUVRs) normalized to the inferior gray matter of the cerebellum. RESULTS: SUVRs in target regions were relatively stable 60 to 90 min post-injection, with the exception of very high binders who continued to show increases over time. Robust elevations in 18F-PI-2620 were observed between HC and Aß+ CI across all AD regions. Within the HC group, older age was associated with subtle elevations in target regions. Mildly elevated focal uptake was observed in the anterior temporal pole in one svPPA patient. CONCLUSION: Preliminary results suggest strong differences in the medial temporal lobe and cortical regions known to be impacted in AD using 18F-PI-2620 in patients along the AD trajectory. This work confirms that 18F-PI-2620 holds promise as a tool to visualize tau aggregations in AD.

TOMM40-APOE haplotypes are associated with cognitive decline in non-demented Blacks.

INTRODUCTION: The goal was to investigate effects of APOE-TOMM40-'523 haplotypes on cognitive decline in non-demented non-Hispanic Blacks (NHB), and determine whether effects differ from non-Hispanic Whites (NHW). METHODS: The impact of zero to two copies of the '523-Short variant (S; poly-T alleles < 20) within apolipoprotein E (APOE) genotype on a composite measure of global cognition and five domains was examined. RESULTS: In NHB with ε3/ε3 (N = 294), '523-S/S was associated with faster decline in global cognition (ß = -0.048, P = 0.017), episodic memory (ß = -0.05, P = 0.031), and visuospatial ability (ß = -0.037, P = 0.034) relative to those without '523-S. For NHB ε4+ (N = 182), '523-S/S had slower decline in global cognition (ß = 0.047, P = 0.042) and visuospatial ability (ß = 0.07, P = 0.0005) relative to '523-S non-carriers. NHB ε4+ with '523-S also had a slower rate of decline than NHWs ε4+ with '523-S. DISCUSSION: '523-S/S has a different effect on cognitive decline among NHB dependent on APOE allele. Differences in the effect of ε4-'523-S in NHB may explain prior mixed findings on ε4 and decline in this population.

The impact of amyloid-beta and tau on prospective cognitive decline in older individuals.

OBJECTIVES: Amyloid-beta (Aß) and tau pathologies are commonly observed among clinically normal older individuals at postmortem and can now be detected with in vivo neuroimaging. The association and interaction of these proteinopathies with prospective cognitive decline in normal aging and preclinical Alzheimer's disease (AD) remains to be fully elucidated. METHODS: One hundred thirty-seven older individuals (age = 76.3 ± 6.22 years) participating in the Harvard Aging Brain Study underwent Aß (11 C-Pittsburgh compound B) and tau (18 F-flortaucipir) positron emission tomography (PET) with prospective neuropsychological assessments following PET imaging (mean number of cognitive visits = 2.8 ± 1.1). Tau and Aß PET measures were assessed in regions of interest (ROIs) as well as vertex-wise map analyses. Cognitive change was evaluated with Memory and Executive Function composites. RESULTS: Higher levels of Aß and tau were both associated with greater memory decline, but not with change in executive function. Higher cortical Aß was associated with higher tau levels in all ROIs, independent of age, and very elevated levels of tau were observed primarily in clinically normal with elevated Aß. A significant interaction between tau and Aß was observed in both ROI and map-level analyses, such that rapid prospective memory decline was observed in participants who had high levels of both pathologies. INTERPRETATION: Our results are consistent with the supposition that both Aß and tau are necessary for memory decline in the preclinical stages of AD. These findings may be relevant for disambiguating aging and early cognitive manifestations of AD, and to inform secondary prevention trials in preclinical AD. Ann Neurol 2019;00:1-3 ANN NEUROL 2019;85:181-193.

Polygenic hazard score, amyloid deposition and Alzheimer's neurodegeneration.

Mounting evidence indicates that the polygenic basis of late-onset Alzheimer's disease can be harnessed to identify individuals at greatest risk for cognitive decline. We have previously developed and validated a polygenic hazard score comprising of 31 single nucleotide polymorphisms for predicting Alzheimer's disease dementia age of onset. In this study, we examined whether polygenic hazard scores are associated with: (i) regional tracer uptake using amyloid PET; (ii) regional volume loss using longitudinal MRI; (iii) post-mortem regional amyloid-ß protein and tau associated neurofibrillary tangles; and (iv) four common non-Alzheimer's pathologies. Even after accounting for APOE, we found a strong association between polygenic hazard scores and amyloid PET standard uptake volume ratio with the largest effects within frontal cortical regions in 980 older individuals across the disease spectrum, and longitudinal MRI volume loss within the entorhinal cortex in 607 older individuals across the disease spectrum. We also found that higher polygenic hazard scores were associated with greater rates of cognitive and clinical decline in 632 non-demented older individuals, even after controlling for APOE status, frontal amyloid PET and entorhinal cortex volume. In addition, the combined model that included polygenic hazard scores, frontal amyloid PET and entorhinal cortex volume resulted in a better fit compared to a model with only imaging markers. Neuropathologically, we found that polygenic hazard scores were associated with regional post-mortem amyloid load and neuronal neurofibrillary tangles, even after accounting for APOE, validating our imaging findings. Lastly, polygenic hazard scores were associated with Lewy body and cerebrovascular pathology. Beyond APOE, we show that in living subjects, polygenic hazard scores were associated with amyloid deposition and neurodegeneration in susceptible brain regions. Polygenic hazard scores may also be useful for the identification of individuals at the highest risk for developing multi-aetiological dementia.

Multi-modal latent factor exploration of atrophy, cognitive and tau heterogeneity in Alzheimer's disease.

Individuals with Alzheimer's disease (AD) dementia exhibit significant heterogeneity across clinical symptoms, atrophy patterns, and spatial distribution of Tau deposition. Most previous studies of AD heterogeneity have focused on atypical clinical subtypes, defined subtypes with a single modality, or restricted their analyses to a priori brain regions and cognitive tests. Here, we considered a data-driven hierarchical Bayesian model to identify latent factors from atrophy patterns and cognitive deficits simultaneously, thus exploiting the rich dimensionality within each modality. Unlike most previous studies, our model allows each factor to be expressed to varying degrees within an individual, in order to reflect potential multiple co-existing pathologies. By applying our model to ADNI-GO/2 AD dementia participants, we found three atrophy-cognitive factors. The first factor was associated with medial temporal lobe atrophy, episodic memory deficits and disorientation to time/place ("MTL-Memory"). The second factor was associated with lateral temporal atrophy and language deficits ("Lateral Temporal-Language"). The third factor was associated with atrophy in posterior bilateral cortex, and visuospatial executive function deficits ("Posterior Cortical-Executive"). While the MTL-Memory and Posterior Cortical-Executive factors were discussed in previous literature, the Lateral Temporal-Language factor is novel and emerged only by considering atrophy and cognition jointly. Several analyses were performed to ensure generalizability, replicability and stability of the estimated factors. First, the factors generalized to new participants within a 10-fold cross-validation of ADNI-GO/2 AD dementia participants. Second, the factors were replicated in an independent ADNI-1 AD dementia cohort. Third, factor loadings of ADNI-GO/2 AD dementia participants were longitudinally stable, suggesting that these factors capture heterogeneity across patients, rather than longitudinal disease progression. Fourth, the model outperformed canonical correlation analysis at capturing associations between atrophy patterns and cognitive deficits. To explore the influence of the factors early in the disease process, factor loadings were estimated in ADNI-GO/2 mild cognitively impaired (MCI) participants. Although the associations between the atrophy patterns and cognitive profiles were weak in MCI compared to AD, we found that factor loadings were associated with inter-individual regional variation in Tau uptake. Taken together, these results suggest that distinct atrophy-cognitive patterns exist in typical Alzheimer's disease, and are associated with distinct patterns of Tau depositions before clinical dementia emerges.

Nonlinear Distributional Mapping (NoDiM) for harmonization across amyloid-PET radiotracers.

INTRODUCTION: There is a growing need in clinical research domains for direct comparability between amyloid-beta (Aß) Positron Emission Tomography (PET) measures obtained via different radiotracers and processing methodologies. Previous efforts to provide a common measurement scale fail to account for non-linearities between measurement scales that can arise from these differences. We introduce a new application of distribution mapping, based on well established statistical orthodoxy, that we call Nonlinear Distribution Mapping (NoDiM). NoDiM uses cumulative distribution functions to derive mappings between Aß-PET measurements from different tracers and processing streams that align data based on their location in their respective distributions. METHODS: Utilizing large datasets of Florbetapir (FBP) from the Alzheimer's Disease Neuroimaging Initiative (n = 349 female (%) = 53) and Pittsburgh Compound B (PiB) from the Harvard Aging Brain Study (n = 305 female (%) = 59.3) and the Australian Imaging, Biomarker & Lifestyle Flagship Study of Ageing (n = 184 female (%) = 53.3), we fit explicit mathematical models of a mixture of two normal distributions, with parameter estimates from Gaussian Mixture Models, to each tracer's empirical data. We demonstrate the accuracy of these fits, and then show the ability of NoDiM to transform FBP measurements into PiB-like units. RESULTS: A mixture of two normal distributions fit both the FBP and PiB empirical data and provides a strong basis for derivation of a transfer function. Transforming Aß-PET data with NoDiM results in FBP and PiB distributions that are closely aligned throughout their entire range, while a linear transformation does not. Additionally the NoDiM transform better matches true positive and false positive profiles across tracers. DISCUSSION: The NoDiM transformation provides a useful alternative to the linear mapping advocated in the Centiloid project, and provides improved correspondence between measurements from different tracers across the range of observed values. This improved alignment enables disparate measures to be merged on to continuous scale, and better enables the use of uniform thresholds across tracers.

Dissecting the genetic relationship between cardiovascular risk factors and Alzheimer's disease.

Cardiovascular (CV)- and lifestyle-associated risk factors (RFs) are increasingly recognized as important for Alzheimer's disease (AD) pathogenesis. Beyond the ε4 allele of apolipoprotein E (APOE), comparatively little is known about whether CV-associated genes also increase risk for AD. Using large genome-wide association studies and validated tools to quantify genetic overlap, we systematically identified single nucleotide polymorphisms (SNPs) jointly associated with AD and one or more CV-associated RFs, namely body mass index (BMI), type 2 diabetes (T2D), coronary artery disease (CAD), waist hip ratio (WHR), total cholesterol (TC), triglycerides (TG), low-density (LDL) and high-density lipoprotein (HDL). In fold enrichment plots, we observed robust genetic enrichment in AD as a function of plasma lipids (TG, TC, LDL, and HDL); we found minimal AD genetic enrichment conditional on BMI, T2D, CAD, and WHR. Beyond APOE, at conjunction FDR < 0.05 we identified 90 SNPs on 19 different chromosomes that were jointly associated with AD and CV-associated outcomes. In meta-analyses across three independent cohorts, we found four novel loci within MBLAC1 (chromosome 7, meta-p = 1.44 × 10-9), MINK1 (chromosome 17, meta-p = 1.98 × 10-7) and two chromosome 11 SNPs within the MTCH2/SPI1 region (closest gene = DDB2, meta-p = 7.01 × 10-7 and closest gene = MYBPC3, meta-p = 5.62 × 10-8). In a large 'AD-by-proxy' cohort from the UK Biobank, we replicated three of the four novel AD/CV pleiotropic SNPs, namely variants within MINK1, MBLAC1, and DDB2. Expression of MBLAC1, SPI1, MINK1 and DDB2 was differentially altered within postmortem AD brains. Beyond APOE, we show that the polygenic component of AD is enriched for lipid-associated RFs. We pinpoint a subset of cardiovascular-associated genes that strongly increase the risk for AD. Our collective findings support a disease model in which cardiovascular biology is integral to the development of clinical AD in a subset of individuals.

Bayesian model reveals latent atrophy factors with dissociable cognitive trajectories in Alzheimer's disease.

We used a data-driven Bayesian model to automatically identify distinct latent factors of overlapping atrophy patterns from voxelwise structural MRIs of late-onset Alzheimer's disease (AD) dementia patients. Our approach estimated the extent to which multiple distinct atrophy patterns were expressed within each participant rather than assuming that each participant expressed a single atrophy factor. The model revealed a temporal atrophy factor (medial temporal cortex, hippocampus, and amygdala), a subcortical atrophy factor (striatum, thalamus, and cerebellum), and a cortical atrophy factor (frontal, parietal, lateral temporal, and lateral occipital cortices). To explore the influence of each factor in early AD, atrophy factor compositions were inferred in beta-amyloid-positive (Aß+) mild cognitively impaired (MCI) and cognitively normal (CN) participants. All three factors were associated with memory decline across the entire clinical spectrum, whereas the cortical factor was associated with executive function decline in Aß+ MCI participants and AD dementia patients. Direct comparison between factors revealed that the temporal factor showed the strongest association with memory, whereas the cortical factor showed the strongest association with executive function. The subcortical factor was associated with the slowest decline for both memory and executive function compared with temporal and cortical factors. These results suggest that distinct patterns of atrophy influence decline across different cognitive domains. Quantification of this heterogeneity may enable the computation of individual-level predictions relevant for disease monitoring and customized therapies. Factor compositions of participants and code used in this article are publicly available for future research.