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IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

IntroductionThe National Institute on Aging - Alzheimer's Association (NIA-AA) ATN research framework proposes to use biomarkers for amyloid (A), tau (T), and neurodegeneration (N) to stage individuals with AD pathological features and track changes longitudinally. The overall aim was to utilize this framework to characterize pre-mortem ATN status longitudinally in a clinically diagnosed cohort of dementia with Lewy bodies (DLB) and to correlate it with the post mortem diagnosis.MethodsThe cohort was subtyped by cerebrospinal fluid (CSF) ATN category. A subcohort had longitudinal data, and a subgroup was neuropathologically evaluated.ResultsWe observed a significant difference in Aβ42/40 after 12 months in the A+T- group. Post mortem neuropathologic analyses indicated that most of the p-Tau 181 positive (T+) cases also had a high Braak stage.DiscussionThis suggests that DLB patients who are A+ but T- may need to be monitored to determine whether they remain A+ or ever progress to T positivity.HighlightsSome A+T- DLB subjects transition from A+ to negative after 12-months. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Clinically diagnosed DLB with LBP-AD (A+T+) maintain their positivity. Monitoring of the A+T- sub-type of DLB may be necessary.

Limbic-predominant age-related TDP-43 encephalopathy (LATE) affects approximately one-third of older individuals and is associated with cognitive impairment. However, there is a highly incomplete understanding of the genetic determinants of LATE neuropathologic changes (LATE-NC) in diverse populations. The defining neuropathologic feature of LATE-NC is TDP-43 proteinopathy, often with comorbid hippocampal sclerosis (HS). In terms of genetic risk factors, LATE-NC and/or HS are associated with single nucleotide variants (SNVs) in 3 genes-TMEM106B (rs1990622), GRN (rs5848), and ABCC9 (rs1914361 and rs701478). We evaluated these 3 genes in convenience samples of individuals of African ancestry. The allele frequencies of the LATE-associated alleles were significantly different between persons of primarily African (versus European) ancestry: In persons of African ancestry, the risk-associated alleles for TMEM106B and ABCC9 were less frequent, whereas the risk allele in GRN was more frequent. We performed an exploratory analysis of data from African-American subjects processed by the Alzheimer's Disease Genomics Consortium, with a subset of African-American participants (n = 166) having corroborating neuropathologic data through the National Alzheimer's Coordinating Center (NACC). In this limited-size sample, the ABCC9/rs1914361 SNV was associated with HS pathology. More work is required concerning the genetic factors influencing non-Alzheimer disease pathology such as LATE-NC in diverse cohorts.

While amyloid-β (Aβ) plaques are considered a hallmark of Alzheimer's disease, clinical trials focused on targeting gamma secretase, an enzyme involved in aberrant Aβ peptide production, have not led to amelioration of AD symptoms or synaptic dysregulation. Screening strategies based on mechanistic, multi-omics approaches that go beyond pathological readouts can aid in the evaluation of therapeutics. Using early-onset Alzheimer's (EOFAD) disease patient lineage PSEN1A246E iPSC-derived neurons, we performed RNA-seq to characterize AD-associated endotypes, which are in turn used as a screening evaluation metric for two gamma secretase drugs, the inhibitor Semagacestat and the modulator BPN-15606. We demonstrate that drug treatment partially restores the neuronal state while concomitantly inhibiting cell cycle re-entry and dedifferentiation endotypes to different degrees depending on the mechanism of gamma secretase engagement. Our endotype-centric screening approach offers a new paradigm by which candidate AD therapeutics can be evaluated for their overall ability to reverse disease endotypes.

At present, no research criteria exist for the diagnosis of prodromal behavioural variant frontotemporal dementia (bvFTD), though early detection is of high research importance. Thus, we sought to develop and validate a proposed set of research criteria for prodromal bvFTD, termed 'mild behavioural and/or cognitive impairment in bvFTD' (MBCI-FTD). Participants included 72 participants deemed to have prodromal bvFTD; this comprised 55 carriers of a pathogenic mutation known to cause frontotemporal lobar degeneration, and 17 individuals with autopsy-confirmed frontotemporal lobar degeneration. All had mild behavioural and/or cognitive changes, as judged by an evaluating clinician. Based on extensive clinical workup, the prodromal bvFTD group was divided into a Development Group (n = 22) and a Validation Group (n = 50). The Development Group was selected to be the subset of the prodromal bvFTD group for whom we had the strongest longitudinal evidence of conversion to bvFTD, and was used to develop the MBCI-FTD criteria. The Validation Group was the remainder of the prodromal bvFTD group and was used as a separate sample on which to validate the criteria. Familial non-carriers were included as healthy controls (n = 165). The frequencies of behavioural and neuropsychiatric features, neuropsychological deficits, and social cognitive dysfunction in the prodromal bvFTD Development Group and healthy controls were assessed. Based on sensitivity and specificity analyses, seven core features were identified: apathy without moderate-severe dysphoria, behavioural disinhibition, irritability/agitation, reduced empathy/sympathy, repetitive behaviours (simple and/or complex), joviality/gregariousness, and appetite changes/hyperorality. Supportive features include a neuropsychological profile of impaired executive function or naming with intact orientation and visuospatial skills, reduced insight for cognitive or behavioural changes, and poor social cognition. Three core features or two core features plus one supportive feature are required for the diagnosis of possible MBCI-FTD; probable MBCI-FTD requires imaging or biomarker evidence, or a pathogenic genetic mutation. The proposed MBCI-FTD criteria correctly classified 95% of the prodromal bvFTD Development Group, and 74% of the prodromal bvFTD Validation Group, with a false positive rate of

Frontotemporal dementia (FTD) therapy development is hamstrung by a lack of susceptibility, diagnostic, and prognostic biomarkers. Blood neurofilament light (NfL) shows promise as a biomarker, but studies have largely focused only on core FTD syndromes, often grouping patients with different diagnoses. To expedite the clinical translation of NfL, we avail ARTFL LEFFTDS Longitudinal Frontotemporal Lobar Degeneration (ALLFTD) study resources and conduct a comprehensive investigation of plasma NfL across FTD syndromes and in presymptomatic FTD mutation carriers. We find plasma NfL is elevated in all studied syndromes, including mild cases; increases in presymptomatic mutation carriers prior to phenoconversion; and associates with indicators of disease severity. By facilitating the identification of individuals at risk of phenoconversion, and the early diagnosis of FTD, plasma NfL can aid in participant selection for prevention or early treatment trials. Moreover, its prognostic utility would improve patient care, clinical trial efficiency, and treatment outcome estimations.

IntroductionDespite women showing greater Alzheimer's disease (AD) prevalence, tau burden, and immune/neuroinflammatory response, whether neuroinflammation impacts cognition differently in women versus men and the biological basis of this impact remain unknown. We examined sex differences in how cerebrospinal fluid (CSF) neuroinflammation relates to cognition across the aging-mild cognitive impairment (MCI)-AD continuum and the mediating role of phosphorylated tau (p-tau) versus other AD biomarkers.MethodsParticipants included 284 individuals from the Alzheimer's Disease Neuroimaging Initiative study. CSF neuroinflammatory markers included interleukin-6, tumor necrosis factor α, soluble tumor necrosis factor receptor 2 (sTNFR2), and chitinase-3-like protein 1. AD biomarkers were CSF p-tau181 and amyloid beta1-42 levels and magnetic resonance imaging measures of hippocampal and white matter hyperintensity volumes.ResultsWe found a sex-by-sTNFR2 interaction on Mini-Mental State Examination and Clinical Dementia Rating-Sum of Boxes. Higher levels of sTNFR2 related to poorer cognition in women only. Among biomarkers, only p-tau181 eliminated the female-specific relationships between neuroinflammation and cognition.DiscussionWomen may be more susceptible than men to the adverse effects of sTNFR2 on cognition with a potential etiological link with tau to these effects.

The Lewy Body Dementia Association (LBDA) held a virtual event, the LBDA Biofluid/Tissue Biomarker Symposium, on January 25, 2021, to present advances in biomarkers for Lewy body dementia (LBD), which includes dementia with Lewy bodies (DLBs) and Parkinson's disease dementia (PDD). The meeting featured eight internationally known scientists from Europe and the United States and attracted over 200 scientists and physicians from academic centers, the National Institutes of Health, and the pharmaceutical industry. Methods for confirming and quantifying the presence of Lewy body and Alzheimer's pathology and novel biomarkers were discussed.

IntroductionNeurofilament light (NFL) reflects neuroaxonal damage and is implicated in mild cognitive impairment (MCI) and Alzheimer's disease (AD). Little is known about NFL in pre-MCI stages, such as in individuals with objectively-defined subtle cognitive decline (Obj-SCD).MethodsTwo hundred ninety-four participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) underwent baseline blood draw and serial neuropsychological testing over 5 years of follow-up.ResultsIndividuals with Obj-SCD and MCI showed elevated baseline plasma NFL relative to the cognitively normal (CN) group. Across the sample, elevated NFL predicted faster rate of cognitive and functional decline. Within the Obj-SCD and MCI groups, higher NFL levels predicted faster rate of decline in memory and preclinical AD composite score compared to the CN group.DiscussionFindings demonstrate the utility of plasma NFL as a biomarker of early AD-related changes, and provide support for the use of Obj-SCD criteria in clinical research to better capture subtle cognitive changes.

Background and objectivesGiven prior work demonstrating that mild cognitive impairment (MCI) can be empirically differentiated into meaningful cognitive subtypes, we applied actuarial methods to comprehensive neuropsychological data from the University of California San Diego Alzheimer's Disease Research Center (ADRC) in order to identify cognitive subgroups within ADRC participants without dementia and to examine cognitive, biomarker, and neuropathologic trajectories.MethodsCluster analysis was performed on baseline neuropsychological data (n = 738; mean age 71.8). Survival analysis examined progression to dementia (mean follow-up 5.9 years). CSF Alzheimer disease (AD) biomarker status and neuropathologic findings at follow-up were examined in a subset with available data.ResultsFive clusters were identified: optimal cognitively normal (CN; n = 130) with above-average cognition, typical CN (n = 204) with average cognition, nonamnestic MCI (naMCI; n = 104), amnestic MCI (aMCI; n = 216), and mixed MCI (mMCI; n = 84). Progression to dementia differed across MCI subtypes (mMCI > aMCI > naMCI), with the mMCI group demonstrating the highest rate of CSF biomarker positivity and AD pathology at autopsy. Actuarial methods classified 29.5% more of the sample with MCI and outperformed consensus diagnoses in capturing those who had abnormal biomarkers, progressed to dementia, or had AD pathology at autopsy.DiscussionWe identified subtypes of MCI and CN with differing cognitive profiles, clinical outcomes, CSF AD biomarkers, and neuropathologic findings over more than 10 years of follow-up. Results demonstrate that actuarial methods produce reliable cognitive phenotypes, with data from a subset suggesting unique biological and neuropathologic signatures. Findings indicate that data-driven algorithms enhance diagnostic sensitivity relative to consensus diagnosis for identifying older adults at risk for cognitive decline.

Although executive dysfunction is the characteristic cognitive marker of behavioral variant frontotemporal dementia (bvFTD), episodic memory deficits are relatively common, and may be present even during the prodromal disease phase. In a cohort of mutation carriers with mild behavioral and/or cognitive symptoms consistent with prodromal bvFTD, we aimed to investigate patterns of performance on an abbreviated list learning task, with a particular focus on recognition memory. We further aimed to characterize the cognitive prodromes associated with the three major genetic causes of frontotemporal dementia, as emerging evidence suggests there may be subtle differences in cognitive profiles among carriers of different genetic mutations. Participants included 57 carriers of a pathogenic mutation in microtubule-associated protein tau (MAPT, N = 23), or progranulin (GRN, N = 15), or a or a hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72, N = 19), with mild cognitive and/or behavioral symptoms consistent with prodromal bvFTD. Familial non-carriers were included as controls (N = 143). All participants completed a comprehensive neuropsychological examination, including an abbreviated list learning test assessing episodic memory recall and recognition. MAPT mutation carriers performed worse than non-carriers in terms of list recall, and had difficulty discriminating targets from distractors on the recognition memory task, primarily due to the endorsement of distractors as targets. MAPT mutation carriers also showed nonverbal episodic memory and semantic memory dysfunction (object naming). GRN mutation carriers were variable in performance and overall the most dysexecutive. Slowed psychomotor speed was evident in C9orf72 repeat expansion carriers. Identifying the earliest cognitive indicators of bvFTD is of critical clinical and research importance. List learning may be a sensitive cognitive marker for incipient dementia in MAPT and potentially a subset of GRN carriers. Our results highlight that distinct cognitive profiles may be evident in carriers of the three disease-causing genes during the prodromal disease stage.

Identifying the systems-level mechanisms that lead to Alzheimer's disease, an unmet need, is an essential step toward the development of therapeutics. In this work, we report that the key disease-causative mechanisms, including dedifferentiation and repression of neuronal identity, are triggered by changes in chromatin topology. Here, we generated human induced pluripotent stem cell (hiPSC)-derived neurons from donor patients with early-onset familial Alzheimer's disease (EOFAD) and used a multiomics approach to mechanistically characterize the modulation of disease-associated gene regulatory programs. We demonstrate that EOFAD neurons dedifferentiate to a precursor-like state with signatures of ectoderm and nonectoderm lineages. RNA-seq, ATAC-seq, and ChIP-seq analysis reveals that transcriptional alterations in the cellular state are orchestrated by changes in histone methylation and chromatin topology. Furthermore, we demonstrate that these mechanisms are observed in EOFAD-patient brains, validating our hiPSC-derived neuron models. The mechanistic endotypes of Alzheimer's disease uncovered here offer key insights for therapeutic interventions.

ObjectiveTo determine the cognitive consequences of anticholinergic medications (aCH) in cognitively normal older adults as well as interactive effects of genetic and CSF Alzheimer disease (AD) risk factors.MethodsA total of 688 cognitively normal participants from the Alzheimer's Disease Neuroimaging Initiative were evaluated (mean age 73.5 years, 49.6% female). Cox regression examined risk of progression to mild cognitive impairment (MCI) over a 10-year period and linear mixed effects models examined 3-year rates of decline in memory, executive function, and language as a function of aCH. Interactions with APOE ε4 genotype and CSF biomarker evidence of AD pathology were also assessed.ResultsaCH+ participants had increased risk of progression to MCI (hazard ratio [HR] 1.47, p = 0.02), and there was a significant aCH × AD risk interaction such that aCH+/ε4+ individuals showed greater than 2-fold increased risk (HR 2.69, p < 0.001) for incident MCI relative to aCH-/ε4-), while aCH+/CSF+) individuals demonstrated greater than 4-fold (HR 4.89, p < 0.001) increased risk relative to aCH-/CSF-. Linear mixed effects models revealed that aCH predicted a steeper slope of decline in memory (t = -2.35, p = 0.02) and language (t = -2.35, p = 0.02), with effects exacerbated in individuals with AD risk factors.ConclusionsaCH increased risk of incident MCI and cognitive decline, and effects were significantly enhanced among individuals with genetic risk factors and CSF-based AD pathophysiologic markers. Findings underscore the adverse impact of aCH medications on cognition and the need for deprescribing trials, particularly among individuals with elevated risk for AD.

ObjectiveWe analyzed the longitudinal profile of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers in early Parkinson's disease (PD) compared with healthy controls (HCs) and tested baseline CSF biomarkers for prediction of clinical decline in PD.MethodsAmyloid-β 1 to 42 (Aβ42 ), total tau (t-tau) and phosphorylated tau (p-tau) at the threonine 181 position were measured using the high-precision Roche Elecsys electrochemiluminescence immunoassay in all available CSF samples from longitudinally studied patients with PD (n = 416) and HCs (n = 192) followed for up to 3 years in the Parkinson's Progression Markers Initiative (PPMI). Longitudinal CSF and clinical data were analyzed with linear-mixed effects models.ResultsWe found patients with PD had lower CSF t-tau (median = 157.7 pg/mL; range = 80.9-467.0); p-tau (median = 13.4 pg/mL; range = 8.0-40.1), and Aβ42 (median = 846.2 pg/mL; range = 238.8-3,707.0) than HCs at baseline (CSF t-tau median = 173.5 pg/mL; range = 82.0-580.8; p-tau median = 15.4 pg/mL; range = 8.1-73.6; and Aβ42 median = 926.5 pg/mL; range = 239.1-3,297.0; p

Alzheimer's disease is an incurable neurodegenerative disorder in which neuroinflammation has a critical function1. However, little is known about the contribution of the adaptive immune response in Alzheimer's disease2. Here, using integrated analyses of multiple cohorts, we identify peripheral and central adaptive immune changes in Alzheimer's disease. First, we performed mass cytometry of peripheral blood mononuclear cells and discovered an immune signature of Alzheimer's disease that consists of increased numbers of CD8+ T effector memory CD45RA+ (TEMRA) cells. In a second cohort, we found that CD8+ TEMRA cells were negatively associated with cognition. Furthermore, single-cell RNA sequencing revealed that T cell receptor (TCR) signalling was enhanced in these cells. Notably, by using several strategies of single-cell TCR sequencing in a third cohort, we discovered clonally expanded CD8+ TEMRA cells in the cerebrospinal fluid of patients with Alzheimer's disease. Finally, we used machine learning, cloning and peptide screens to demonstrate the specificity of clonally expanded TCRs in the cerebrospinal fluid of patients with Alzheimer's disease to two separate Epstein-Barr virus antigens. These results reveal an adaptive immune response in the blood and cerebrospinal fluid in Alzheimer's disease and provide evidence of clonal, antigen-experienced T cells patrolling the intrathecal space of brains affected by age-related neurodegeneration.

IntroductionThe low mild cognitive impairment (MCI) to cognitively normal (CN) reversion rate in the Alzheimer's Disease Neuroimaging Initiative (2-3%) suggests the need to examine reversion by other means. We applied comprehensive neuropsychological criteria (NP criteria) to determine the resulting MCI to CN reversion rate.MethodsParticipants with CN (n = 641) or MCI (n = 569) were classified at baseline and year 1 using NP criteria. Demographic, neuropsychological, and Alzheimer's disease biomarker variables as well as progression to dementia were examined across stable CN, reversion, and stable MCI groups.ResultsNP criteria produced a one-year reversion rate of 15.8%. Reverters had demographics, Alzheimer's disease biomarkers, and risk-of-progression most similar to the stable CN group and showed the most improvement on neuropsychological measures from baseline to year 1.DiscussionNP criteria produced a reversion rate that is consistent with, albeit modestly improved from, reversion rates in meta-analyses. Reverters' biomarker profiles and progression rates suggest that NP criteria accurately tracked with underlying pathophysiologic status.

IntroductionThe Alzheimer's Disease Neuroimaging Initiative (ADNI) separates "early" and "late" mild cognitive impairment (MCI) based on a single memory test. We compared ADNI's MCI classifications to our neuropsychological approach, which more broadly assesses cognitive abilities.MethodsThree hundred thirty-six ADNI-2 participants were classified as "early" or "late" MCI. Cluster analysis was performed on neuropsychological test data, and participants were reclassified based on cluster results. These two staging approaches were compared on progression rates, cerebrospinal fluid biomarkers, and cortical thickness profiles.ResultsThere was little correspondence between the two staging methods. ADNI's early MCI group included a large proportion of false-positive diagnostic errors. The reclassified neuropsychological MCI groups showed steeper survival curves and more abnormal biomarkers.ConclusionsOur novel neuropsychological approach improved the staging of MCI by (1) capturing individuals at an early symptomatic stage, (2) minimizing false-positive cases, and (3) identifying a late MCI group further along the disease trajectory.

IntroductionWe examined reasons for low mild cognitive impairment (MCI)-to-cognitively normal (CN) reversion rates in the Alzheimer's Disease Neuroimaging Initiative (ADNI).MethodsCN and MCI participants were identified as remaining stable, progressing, or reverting at 1-year of follow-up (Year 1). Application of ADNI's MCI criteria at Year 1 in addition to Alzheimer's disease biomarkers by group were examined.ResultsThe MCI-to-CN reversion rate was 3.0%. When specific components were examined, 22.5% of stable MCI participants had normal memory performance at Year 1 and their Alzheimer's disease biomarkers were consistent with the stable CN group. At Year 1, when all MCI criteria were not met, the more subjective Clinical Dementia Rating rather than objective memory measure appeared to drive continuation of the MCI diagnosis.DiscussionResults demonstrate an artificially low 1-year MCI-to-CN reversion rate in ADNI-diagnosed participants. If the Logical Memory cutoffs had been consistently applied, the reversion rate would have been at least 21.8%.

INTRODUCTION: Cardiovascular health is important for brain aging, yet its role in the clinical manifestation of autosomal dominant or atypical forms of dementia has not been fully elucidated. We examined relationships between Life's Simple 7 (LS7) and clinical trajectories in individuals with autosomal dominant frontotemporal lobar degeneration (FTLD). METHODS: Two hundred forty‐seven adults carrying FTLD pathogenic genetic variants (53% asymptomatic) and 189 non‐carrier controls completed baseline LS7, and longitudinal neuroimaging and neuropsychological testing. RESULTS: Among variant carriers, higher baseline LS7 is associated with slower accumulation of frontal white matter hyperintensities (WMHs), as well as slower memory and language declines. Higher baseline LS7 associated with larger baseline frontotemporal volume, but not frontotemporal volume trajectories. DISCUSSION: Better baseline cardiovascular health related to slower cognitive decline and accumulation of frontal WMHs in autosomal dominant FTLD. Optimizing cardiovascular health may be an important modifiable approach to bolster cognitive health and brain integrity in FTLD. Highlights: Better cardiovascular health associates with slower cognitive decline in frontotemporal lobar degeneration (FTLD).Lifestyle relates to the accumulation of frontal white matter hyperintensities in FTLD.More optimal cardiovascular health associates with greater baseline frontotemporal lobe volume.Optimized cardiovascular health relates to more favorable outcomes in genetic dementia. [ABSTRACT FROM AUTHOR]

ObjectivesAlthough subjective cognitive complaints (SCC) are an integral component of the diagnostic criteria for mild cognitive impairment (MCI), previous findings indicate they may not accurately reflect cognitive ability. Within the Alzheimer's Disease Neuroimaging Initiative, we investigated longitudinal change in the discrepancy between self- and informant-reported SCC across empirically derived subtypes of MCI and normal control (NC) participants.MethodsData were obtained for 353 MCI participants and 122 "robust" NC participants. Participants were classified into three subtypes at baseline via cluster analysis: amnestic MCI, mixed MCI, and cluster-derived normal (CDN), a presumptive false-positive group who performed within normal limits on neuropsychological testing. SCC at baseline and two annual follow-up visits were assessed via the Everyday Cognition Questionnaire (ECog), and discrepancy scores between self- and informant-report were calculated. Analysis of change was conducted using analysis of covariance.ResultsThe amnestic and mixed MCI subtypes demonstrated increasing ECog discrepancy scores over time. This was driven by an increase in informant-reported SCC, which corresponded to participants' objective cognitive decline, despite stable self-reported SCC. Increasing unawareness was associated with cerebrospinal fluid Alzheimer's disease biomarker positivity and progression to Alzheimer's disease. In contrast, CDN and NC groups over-reported cognitive difficulty and demonstrated normal cognition at all time points.ConclusionsMCI participants' discrepancy scores indicate progressive underappreciation of their evolving cognitive deficits. Consistent over-reporting in the CDN and NC groups despite normal objective cognition suggests that self-reported SCC do not predict impending cognitive decline. Results demonstrate that self-reported SCC become increasingly misleading as objective cognitive impairment becomes more pronounced. (JINS, 2018, 24, 842-853).

IntroductionCriteria for mild cognitive impairment (MCI) used in many clinical trials are susceptible to "false-positive (FP)" errors that can be avoided by an actuarial psychometric approach.MethodsCluster analysis was applied to baseline neuropsychological test data from 756 MCI participants in the Alzheimer's Disease Cooperative Study donepezil trial. Treatment groups were compared after FP MCI cases were removed.ResultsCluster analyses revealed three groups: "single-domain amnestic MCI" (31%), "multi-domain amnestic MCI" (39%), and "FP MCI" (30%). After removing FP MCI cases, the donepezil treatment group had a lower rate of progression to Alzheimer's disease and better performance on cognitive tests than the placebo/vitamin E group.DiscussionRemoval of FP MCI diagnoses unmasked beneficial effects of donepezil, despite a 30% reduction in sample size. MCI subject selection based on actuarial methods with comprehensive neuropsychological test data can result in more efficient clinical trials and improved ability to detect treatment effects.

IntroductionPractice effects (PEs) present a potential confound in clinical trials with cognitive outcomes. A single-blind placebo run-in design, with repeated cognitive outcome assessments before randomization to treatment, can minimize effects of practice on trial outcome.MethodsWe investigated the potential implications of PEs in Alzheimer's disease prevention trials using placebo arm data from the Alzheimer's Disease Cooperative Study donepezil/vitamin E trial in mild cognitive impairment. Frequent ADAS-Cog measurements early in the trial allowed us to compare two competing trial designs: a 19-month trial with randomization after initial assessment, versus a 15-month trial with a 4-month single-blind placebo run-in and randomization after the second administration of the ADAS-Cog. Standard power calculations assuming a mixed-model repeated-measure analysis plan were used to calculate sample size requirements for a hypothetical future trial designed to detect a 50% slowing of cognitive decline.ResultsOn average, ADAS-Cog 13 scores improved at first follow-up, consistent with a PE and progressively worsened thereafter. The observed change for a 19-month trial (1.18 points) was substantively smaller than that for a 15-month trial with 4-month run-in (1.79 points). To detect a 50% slowing in progression under the standard design (i.e., a 0.59 point slowing), a future trial would require 3.4 times more subjects than would be required to detect the comparable percent slowing (i.e., 0.90 points) with the run-in design.DiscussionAssuming the improvement at first follow-up observed in this trial represents PEs, the rate of change from the second assessment forward is a more accurate representation of symptom progression in this population and is the appropriate reference point for describing treatment effects characterized as percent slowing of symptom progression; failure to accommodate this leads to an oversized clinical trial. We conclude that PEs are an important potential consideration when planning future trials.

To develop a cerebrospinal fluid (CSF) miRNA diagnostic biomarker for glioblastoma.Glioblastoma tissue and matched CSF from the same patient (obtained prior to tumor manipulation) were profiled by TaqMan OpenArray® Human MicroRNA Panel. CSF miRNA profiles from glioblastoma patients and controls were created from three discovery cohorts and confirmed in two validation cohorts.miRNA profiles from clinical CSF correlated with those found in glioblastoma tissues. Comparison of CSF miRNA profiles between glioblastoma patients and non-brain tumor patients yielded a tumor "signature" consisting of nine miRNAs. The "signature" correlated with glioblastoma tumor volume (p=0.008). When prospectively applied to cisternal CSF, the sensitivity and specificity of the 'signature' for glioblastoma detection were 67% and 80%, respectively. For lumbar CSF, the sensitivity and specificity of the signature were 28% and 95%, respectively. Comparable results were obtained from analyses of CSF extracellular vesicles (EVs) and crude CSF.We report a CSF miRNA signature as a "liquid biopsy" diagnostic platform for glioblastoma.

IntroductionGenetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.MethodsWe conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.ResultsGenome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)-based tests (P

Despite considerable research to uncover them, the anatomic and neuropathologic correlates of memory impairment in dementia with Lewy bodies (DLB) remain unclear. While some studies have implicated Lewy bodies in the neocortex, others have pointed to α-synuclein pathology in the hippocampus. We systematically examined hippocampal Lewy pathology and its distribution in hippocampal subfields in 95 clinically and neuropathologically characterized human cases of DLB, finding that α-synuclein pathology was highest in two hippocampal-related subregions: the CA2 subfield and the entorhinal cortex (EC). While the EC had numerous classic somatic Lewy bodies, CA2 contained mainly Lewy neurites in presumed axon terminals, suggesting the involvement of the EC → CA2 circuitry in the pathogenesis of DLB symptoms. Clinicopathological correlations with measures of verbal and visual memory supported a role for EC Lewy pathology, but not CA2, in causing these memory deficits. Lewy pathology in CA1-the main output region for CA2-correlated best with results from memory testing despite a milder pathology. This result indicates that CA1 may be more functionally relevant than CA2 in the context of memory impairment in DLB. These correlations remained significant after controlling for several factors, including concurrent Alzheimer's pathology (neuritic plaques and neurofibrillary tangles) and the interval between time of testing and time of death. Our data suggest that although hippocampal Lewy pathology in DLB is predominant in CA2 and EC, memory performance correlates most strongly with CA1 burden.SIGNIFICANCE STATEMENT This study provides a detailed neuropathologic analysis of hippocampal Lewy pathology in human patients with autopsy-confirmed dementia with Lewy bodies. The approach-informed by regional molecular markers, concurrent Alzheimer's pathology analysis, and relevant clinical data-helps tease out the relative contribution of Lewy pathology to memory dysfunction in the disease. Levels of Lewy pathology were found to be highest in the hippocampal CA2 subregion and entorhinal cortex, implicating a potentially overlooked circuit in disease pathogenesis. However, correlation with memory performance was strongest with CA1. This unexpected finding suggests that Lewy pathology must reach a critical burden across hippocampal circuitry to contribute to memory dysfunction beyond that related to other factors, notably coexisting Alzheimer's disease tau pathology.

We examined the extracellular vesicle (EV) and RNA composition of pooled normal cerebrospinal fluid (CSF) samples and CSF from five major neurological disorders: Alzheimer's disease (AD), Parkinson's disease (PD), low-grade glioma (LGG), glioblastoma multiforme (GBM), and subarachnoid haemorrhage (SAH), representing neurodegenerative disease, cancer, and severe acute brain injury. We evaluated: (I) size and quantity of EVs by nanoparticle tracking analysis (NTA) and vesicle flow cytometry (VFC), (II) RNA yield and purity using four RNA isolation kits, (III) replication of RNA yields within and between laboratories, and (IV) composition of total and EV RNAs by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and RNA sequencing (RNASeq). The CSF contained ~106 EVs/μL by NTA and VFC. Brain tumour and SAH CSF contained more EVs and RNA relative to normal, AD, and PD. RT-qPCR and RNASeq identified disease-related populations of microRNAs and messenger RNAs (mRNAs) relative to normal CSF, in both total and EV fractions. This work presents relevant measures selected to inform the design of subsequent replicative CSF studies. The range of neurological diseases highlights variations in total and EV RNA content due to disease or collection site, revealing critical considerations guiding the selection of appropriate approaches and controls for CSF studies.

IntroductionAlzheimer's disease (AD) and Parkinson's disease (PD) involve tau pathology. Tau is detectable in blood, but its clearance from neuronal cells and the brain is poorly understood.MethodsTau efflux from the brain to the blood was evaluated by administering radioactively labeled and unlabeled tau intracerebroventricularly in wild-type and tau knock-out mice, respectively. Central nervous system (CNS)-derived tau in L1CAM-containing exosomes was further characterized extensively in human plasma, including by single molecule array technology with 303 subjects.ResultsThe efflux of Tau, including a fraction via CNS-derived L1CAM exosomes, was observed in mice. In human plasma, tau was explicitly identified within L1CAM exosomes. In contrast to AD patients, L1CAM exosomal tau was significantly higher in PD patients than controls and correlated with cerebrospinal fluid tau.ConclusionsTau is readily transported from the brain to the blood. The mechanisms of CNS tau efflux are likely different between AD and PD.

IntroductionThe goal was to compare subgroups of dementia with Lewy Bodies (DLB) using neuropathological measures to differentiate 'pure' Lewy body (LB) dementia from 'mixed' DLB [co-occurring LB and Alzheimer's disease (AD) pathology] to facilitate diagnostic decision-making and future development of interventions based on predicted type(s) of neuropathology. Studies comparing these groups are rare relative to those differentiating 'pure' AD and all-cause DLB, and are limited by insufficient sample size, brief cognitive batteries, and/or absence of autopsy confirmation. To address these limitations, we assessed cognition and other features in a large, autopsy-confirmed DLB sample using an extensive neuropsychological battery.MethodsSubjects from an AD research center autopsy series satisfying DLB pathology criteria were divided by an AD neuropathology index into DLB-LB (Braak stage 0-3) (n = 38) and DLB-AD (Braak stage 4-6) (n = 41) and compared on baseline variables from chart reviews and standardized measures.ResultsDLB-LB subjects were more impaired on visuospatial constructions, visual conceptual reasoning, and speed of processing, but less impaired on verbal memory and confrontation naming. All-type hallucinations occurred more frequently in DLB-LB, while delusions were common in both groups. Groups were similar in education and age at onset, and in baseline age, dementia severity, and functional capacity.ConclusionSalient findings included greater impairment on visual tasks and speed of processing and more frequent reports of all-type hallucinations in DLB-LB compared to DLB-AD. Relatively intact confrontation naming in DLB-LB and no differences in reported delusions were of note. Identifying differences in phenotypic features can improve prediction of underlying neuropathology.

ObjectiveTo identify a causative variant(s) that may contribute to Alzheimer disease (AD) in African Americans (AA) in the ATP-binding cassette, subfamily A (ABC1), member 7 (ABCA7) gene, a known risk factor for late-onset AD.MethodsCustom capture sequencing was performed on ∼150 kb encompassing ABCA7 in 40 AA cases and 37 AA controls carrying the AA risk allele (rs115550680). Association testing was performed for an ABCA7 deletion identified in large AA data sets (discovery n = 1,068; replication n = 1,749) and whole exome sequencing of Caribbean Hispanic (CH) AD families.ResultsA 44-base pair deletion (rs142076058) was identified in all 77 risk genotype carriers, which shows that the deletion is in high linkage disequilibrium with the risk allele. The deletion was assessed in a large data set (531 cases and 527 controls) and, after adjustments for age, sex, and APOE status, was significantly associated with disease (p = 0.0002, odds ratio [OR] = 2.13 [95% confidence interval (CI): 1.42-3.20]). An independent data set replicated the association (447 cases and 880 controls, p = 0.0117, OR = 1.65 [95% CI: 1.12-2.44]), and joint analysis increased the significance (p = 1.414 × 10(-5), OR = 1.81 [95% CI: 1.38-2.37]). The deletion is common in AA cases (15.2%) and AA controls (9.74%), but in only 0.12% of our non-Hispanic white cohort. Whole exome sequencing of multiplex, CH families identified the deletion cosegregating with disease in a large sibship. The deleted allele produces a stable, detectable RNA strand and is predicted to result in a frameshift mutation (p.Arg578Alafs) that could interfere with protein function.ConclusionsThis common ABCA7 deletion could represent an ethnic-specific pathogenic alteration in AD.

The development of biomarkers to predict the progression of Parkinson's disease (PD) from its earliest stage through its heterogeneous course is critical for research and therapeutic development. The Parkinson's Progression Markers Initiative (PPMI) study is an ongoing international multicenter, prospective study to validate biomarkers in drug-naïve PD patients and matched healthy controls (HC). We quantified cerebrospinal fluid (CSF) alpha-synuclein (α-syn), amyloid-beta1-42 (Aβ1-42), total tau (t-tau), and tau phosphorylated at Thr181 (p-tau) in 660 PPMI subjects at baseline, and correlated these data with measures of the clinical features of these subjects. We found that CSF α-syn, t-tau and p-tau levels, but not Aβ1-42, were significantly lower in PD compared with HC, while the diagnostic value of the individual CSF biomarkers for PD diagnosis was limited due to large overlap. The level of α-syn, but not other biomarkers, was significantly lower in PD patients with non-tremor-dominant phenotype compared with tremor-dominant phenotype. In addition, in PD patients the lowest Aβ1-42, or highest t-tau/Aβ1-42 and t-tau/α-syn quintile in PD patients were associated with more severe non-motor dysfunction compared with the highest or lowest quintiles, respectively. In a multivariate regression model, lower α-syn was significantly associated with worse cognitive test performance. APOE ε4 genotype was associated with lower levels of Aβ1-42, but neither with PD diagnosis nor cognition. Our data suggest that the measurement of CSF biomarkers in early-stage PD patients may relate to disease heterogeneity seen in PD. Longitudinal observations in PPMI subjects are needed to define their prognostic performance.

Alzheimer's disease (AD) is a complex genetic disorder with no effective treatments. More than 20 common markers have been identified, which are associated with AD. Recently, several rare variants have been identified in Amyloid Precursor Protein (APP), Triggering Receptor Expressed On Myeloid Cells 2 (TREM2) and Unc-5 Netrin Receptor C (UNC5C) that affect risk for AD. Despite the many successes, the genetic architecture of AD remains unsolved. We used Genome-wide Complex Trait Analysis to (1) estimate phenotypic variance explained by genetics; (2) calculate genetic variance explained by known AD single nucleotide polymorphisms (SNPs); and (3) identify the genomic locations of variation that explain the remaining unexplained genetic variance. In total, 53.24% of phenotypic variance is explained by genetics, but known AD SNPs only explain 30.62% of the genetic variance. Of the unexplained genetic variance, approximately 41% is explained by unknown SNPs in regions adjacent to known AD SNPs, and the remaining unexplained genetic variance outside these regions.

Mild cognitive impairment (MCI) is typically diagnosed using subjective complaints, screening measures, clinical judgment, and a single memory score. Our prior work has shown that this method is highly susceptible to false-positive diagnostic errors. We examined whether the criteria also lead to "false-negative" errors by diagnostically reclassifying 520 participants using novel actuarial neuropsychological criteria. Results revealed a false-negative error rate of 7.1%. Participants' neuropsychological performance, cerebrospinal fluid biomarkers, and rate of decline provided evidence that an MCI diagnosis is warranted. The impact of "missed" cases of MCI has direct relevance to clinical practice, research studies, and clinical trials of prodromal Alzheimer's disease.

ImportanceIncreased pulse pressure associated with age-related arterial stiffening increases risk for Alzheimer dementia but the mechanism responsible for this association remains unclear.ObjectivesTo determine the relationship between pulse pressure and cerebral spinal fluid biomarker profiles of preclinical Alzheimer disease, investigate whether observed relationships are stronger in adults with more advanced arterial age (≥80 years of age), and examine the relationship between pulse pressure and progression to dementia.Design, setting, and participantsIn this retrospective cohort study, 877 participants without dementia (55-91 years of age) from the Alzheimer's Disease Neuroimaging Initiative underwent baseline health assessment, including blood pressure assessment and lumbar puncture for determination of cerebral spinal fluid phosphorylated tau (P-tau) and β-amyloid 1-42. Participants have been followed up longitudinally since 2005. The last date of examination was October 15, 2013. Clinical follow-up between 6 and 96 months tracked progression to dementia.Main outcomes and measuresRegression and analysis of covariance analyses investigated relationships between pulse pressure and distinct cerebral spinal fluid biomarker profiles. Very old participants (80 years or older) were compared with younger participants (55-79 years of age) on clinical measures and pulse pressure × age group interactions were investigated. Survival analysis examined the effect of baseline pulse pressure on progression to dementia. Covariates were age, sex, apolipoprotein E genotype, body mass index, vascular risk factors, and antihypertensive medication use.ResultsIndividuals with a P-tau-positive biomarker profile exhibited mean (SD) elevated pulse pressure regardless of age (62.0 [15.6] mm Hg for a P-tau-positive biomarker vs 57.4 [14.0] mm Hg for P-tau-negative biomarker; P = .04). In very old participants, a further increase in pulse pressure was observed in those exhibiting both P-tau elevation and β-amyloid 1-42 reduction vs either biomarkers alone (69.7 [16.0] mm Hg for both positive biomarkers vs 63.18 [13.0] mm Hg for P-tau alone vs 60.1 [16.4] mm Hg for β-amyloid 1-42 alone vs 56.6 [14.5] mm Hg for negative biomarkers; P = .003). Those with higher baseline pulse pressure progressed to dementia more rapidly (95% CI, 1.000-1.048; P = .05; hazard ratio = 1.024). Systolic pressure exhibited similar relationships with Alzheimer disease biomarkers and progression to dementia in the very old subgroup (P < .05) but showed no associations in the young old subgroup (P > .10). Diastolic pressure was reduced in young old participants with isolated phosphorylated tau elevation (P = .04).Conclusions and relevancePulse pressure, an index of vascular aging, was associated with neurodegenerative change prior to the onset of dementia across a broad age range. Among those with more advanced age, higher pulse pressure was also associated with cerebral amyloidosis in the presence of neurodegeneration and more rapid progression to dementia. Diastolic contributions to these biomarker associations were limited to young old participants whereas systolic contributions were found only in very old participants.

We examined the relationships of antemortem vascular risk factors to postmortem cerebrovascular and Alzheimer's disease (AD) pathologies. Eighty-four AD patients underwent an assessment of vascular risk (blood pressure, cholesterol, smoking, cardiovascular disease, diabetes, atrial fibrillation, transient ischemic attack [TIA], or stroke) and later underwent brain autopsy. Given our aim to examine mild cerebrovascular changes (CVCs), individuals were excluded if autopsy revealed large stroke. The most common forms of CVC were circle of Willis atherosclerosis followed by arteriosclerosis, lacunes, and microinfarcts. Excluding the history of TIA/clinical stroke, individual vascular risk factors were not associated with CVC. However, the presence of multiple vascular risk factors was associated with CVC. Furthermore, the presence of CVC was associated with lower Braak and Braak stage. These findings highlight the importance of aggregate risk in the vascular contribution to dementia. Interventions designed to maintain cerebrovascular health may represent important opportunities for preventing or delaying dementia, even when AD is the dominant pathology.

The NIA-AA criteria for "preclinical" Alzheimer's disease (AD) propose a staging method in which AD biomarkers follow an invariable temporal sequence in accordance with the amyloid cascade hypothesis. However, recent findings do not align with the proposed temporal sequence and "subtle cognitive decline," which has not been definitively operationalized, may occur earlier than suggested in preclinical AD. We aimed to define "subtle cognitive decline" using sensitive and reliable neuropsychological tests, and to examine the number and sequence of biomarker abnormalities in the Alzheimer's Disease Neuroimaging Initiative (ADNI). 570 cognitively normal ADNI participants were classified based on NIA-AA criteria and separately based on the number of abnormal biomarkers/cognitive markers associated with preclinical AD that each individual possessed. Results revealed that neurodegeneration alone was 2.5 times more common than amyloidosis alone at baseline. For those who demonstrated only one abnormal biomarker at baseline and later progressed to mild cognitive impairment/AD, neurodegeneration alone was most common, followed by amyloidosis alone or subtle cognitive decline alone, which were equally common. Findings suggest that most individuals do not follow the temporal order proposed by NIA-AA criteria. We provide an operational definition of subtle cognitive decline that captures both cognitive and functional decline. Additionally, we offer a new approach for staging preclinical AD based on number of abnormal biomarkers, without regard to their temporal order of occurrence. This method of characterizing preclinical AD is more parsimonious than the NIA-AA staging system and does not presume that all patients follow a singular invariant expression of the disease.