Clinical Alzheimer's Disease Research Articles

Differences in dynamic functional connectivity across the Alzheimer’s disease spectrum

AbstractBackgroundTo examine differences in dynamic functional connectivity (DFC) in cognitively normal subjects (CN), and patients with mild cognitive impairment (MCI) or Alzheimer’s disease (AD).MethodResting‐state functional magnetic resonance imaging (rsfMRI data of 76 participants (40 CN, 24 MCI, 11 AD) from the ADNI database (http://adni.loni.usc.edu/) was used for analysis. Groups were matched according to age, sex and education. rsfMRI data were pre‐processed using the CONN toolbox. For data reduction purposes, spatial independent and principal component analyses were performed on the normalized rsfMRI using GIFT. Resulting meaningful independent components were clustered into 13 functional resting‐state networks. Using GIFT, a sliding window approach was employed to determine dynamic functional connectivity states across the scan period of 9 minutes. Afterwards, non‐parametric t‐tests were performed comparing the groups in measures of DFC such as dwell time (i.e. staying in a state), number of transitions (i.e. switching between states), fraction time (i.e. total time spent in a state), and meta state characteristics.ResultThe DFC analysis resulted in 4 distinct functional connectivity states, which were characterized by either global connectivity patterns or distinct connectivity patterns between certain rs‐networks. Group comparisons yielded that one state was particularly more occupied by the AD group compared to the CN group (p = .02) and the MCI group (p = .001). The AD group showed a lower meta state span and number of meta states compares to the MCI and CN groups.ConclusionNetwork reorganization may influence dynamic functional connectivity patterns in pre‐ and clinical AD.

Plasma Aβ42/Aβ40 and p‐tau181 are associated with clinical progression in amnestic mild cognitive impairment: An 8‐year longitudinal study

AbstractBackgroundPrevious studies indicated that blood‐based biomarkers could predict cognitive decline in Alzheimer’s disease (AD) continuum.MethodTwo hundred and fifty‐one participants with amnestic mild cognitive impairment (aMCI) from the Shanghai Memory Study were followed up for a maximum of 8 years. Baseline blood biomarkers were measured with the single‐molecule array (Simoa) platform. Multipoint clinical diagnosis and domain‐specific cognitive functions were assessed to investigate the longitudinal relationship between blood biomarkers and clinical AD progression.ResultParticipants with high‐risk plasma Aβ42/Aβ40 (A) and p‐tau181 (T) level demonstrated the highest probability of incident AD (HR 5.54, 95% CI 2.99‐10.27), and the most dramatic decline in global cognition, attention, executive function, visuospatial function, and language. Comparing to young‐old participants, the old‐old ones with low‐ and moderate‐risk AT showed higher AD risks (HR 3.70, 95% CI 1.16‐11.81; HR 3.15, 95% CI 1.37‐7.26), and faster cognitive deterioration.ConclusionThe results supported the use of plasma Aβ42/Aβ40 and p‐tau181 as accessible and feasible indicators of AD progression and the long‐term cognitive deterioration, especially in patients with older age.

Ancestry‐Specific eQTL Associations in AA/NHW Alzheimer Disease Cohorts

AbstractBackgroundAlthough the genetic etiology of Alzheimer’s Disease (AD) has been shown to vary among ancestrally diverse populations, the influence of genetic variation on the transcriptome within these populations has not yet been extensively investigated. Multi‐ancestry AD datasets featuring both genetic information and gene expression measurements are needed to support expression quantitative trait loci (eQTl) studies in historically underrepresented populations. In this work, we have compared eQTL signals in case/control AD sample populations of both African American (AA) and non‐Hispanic white (NHW) ancestries.MethodWe analyzed cohorts of AA and NHW ancestries (Naa = 232, Nnhw = 241) with corresponding array‐based genotypes and RNA‐seq mRNA expression levels from whole blood, along with clinical AD diagnoses (Naa_case = 115, Naa_control = 117, Nnhw_case = 121, Nnhw_control = 120). Transcriptome‐wide eQTL associations between genetic variants and gene expression levels were assessed via regression across 17,638 gene units, adjusting for age, sex, experimental factors, and genetic principal components. This was repeated across all sample set combinations of ancestry‐AD pairings (ancestry = [aa, nhw, both] * AD = [case, control, both]).ResultThe number of significant (p‐value < 10e‐7) eQTL signals varied by ancestry, with the AA cohort showing 76,742 raw eQTL associations, the NHW cohort 19,734, and both ancestries combined 81,763. When further sub‐setting sample sets to AD cases only, 770 and 788 significant eQTL signals were observed for AA and NHW cohorts respectively, which impacted 135 (AA) and 130 (NHW) genes. Interestingly, these ancestry‐aware, case‐only eQTLs were remarkably distinct between the two ancestries, with only 71 (∼9.1%) of the eQTLs and only 19 (∼14.3%) of the impacted genes being shared by both ancestral cohorts. Of particular interest is the appearance of WWOX (a gene of wide neurological importance, and known AD risk loci), as differentially significant in the AA cohort (P = 8.07e‐7) as compared to the NHW cohort (P = 9.06e‐3).ConclusionWe have observed differences in eQTL signals relative to AD diagnosis status between AA and NHW sample populations, which may indicate the presence of novel ancestry‐specific effects impacting the genetic etiology of AD through changes in gene expression.

Discordance in treatment effects on clinical and imaging outcomes in recently published amyloid removing trials

AbstractBackgroundLongitudinal changes in volumetric MRI (vMRI) are correlated with longitudinal changes in cognition and function in subjects with Alzheimer’s disease (AD). In clinical trials, vMRI has been used as an exploratory outcome measure with the assumption that an effective treatment would slow down brain atrophy, in addition to slowing down cognitive decline. We have recently shown that in clinical AD trials published up to November 2020, treatment effects on clinical outcomes were associated with treatment effects on vMRI measures1. Here, we assess these relationships in three more recently published trials (Donanemab2, Lecanemab3, Lanabecestat4,5), and compared it to our previous findings.MethodTreatment effects were computed as the percent slowing in change from baseline in the active group relative to the control group for clinical (ADAS‐Cog, MMSE, CDR‐SB) and imaging (whole brain volume [WBV], ventricular volume [VV], hippocampal volume [HV]) outcomes. We assessed the concordance in directionality and magnitude of treatment effects between variables.ResultIn trials published up to November 2020, treatment effects on ADAS‐Cog and CDR‐SB were directionally concordant and significantly associated with treatment effects on WBV and VV. The trials with Donanemab and Lecanemab, amyloid‐removing antibodies, showed a clear discordance between treatment effects on all three cognitive scales and global brain atrophy (WBV and VV), with decreased cognitive decline being accompanied by an increase in atrophy (illustrated for ADAS‐Cog and WBV in Figure 1). In contrast, results from the trials with Lanabecestat, a BACE inhibitor, were more consistent with the historical relationship.ConclusionBoth Donanemab and Lecanemab, two monoclonal antibodies with amyloid‐removal properties, showed a discrepancy in treatment effects on cognition and brain atrophy. Possibly, the atrophy reflects acute reductions in brain volume related to the removal of amyloid from the brain (“pseudo‐atrophy”). Further regional analyses and follow‐up imaging studies may help elucidate the mechanism and temporal evolution.

AT(N) Biomarker profiles and Alzheimer’s Disease clinical status and memory in adults with down syndrome

AbstractBackgroundDown syndrome (DS) is seen as a genetic form of Alzheimer’s disease (AD). The National Institute on Aging and the Alzheimer’s Association proposed the AT(N) model for classifying AD biomarkers of amyloid (A), tau (T), and neurodegeneration or neuronal injury ([N]) in non‐DS populations. It is not yet known how the AT(N) classification system maps onto AD pathology and symptomology in DS. The goals of the present study were to: 1) examine AT(N) profiles in DS based on PET amyloid‐beta (Aβ) (A), tau PET (T), and hippocampal volume ([N]); and 2) evaluate potential differences in clinical AD status and memory performance by AT(N) profile in DS.MethodAnalyses included 138 adults with DS (age: M = 39.1, SD = 8.0) enrolled in the Alzheimer’s Biomarker Consortium‐ Down Syndrome study. PET Aβ and tau were assessed using [11C]PiB and [18F]AV‐1451. Structural MRI data was used to index hippocampal volume and adjusted for intracranial volume. Thresholds for elevated (+ vs. ‐) A (Aβ CL >19), T (tau composite SUVr >1.21) and (N) (hippocampal volume < 1 SD from sample mean) were based on prior studies. Clinical AD status (cognitively stable, mild cognitive impairment [MCI‐DS], dementia, and unable to determine) were based on direct measures and caregiver‐report but blind to imaging and biofluid data. The Cued Recall Test was used to assess episodic memory.ResultOverall, 66% of participants were A‐/T‐/(N)‐, 14% were A+/T‐/(N)‐, 9% were A+/T+/(N)‐, and 5% were A+/T+/(N)+. The remaining 6% had an alternative profile (e.g. A‐/T‐/(N)+). One‐way analyses of variance indicated a significant difference in age and clinical AD status by A/T/N profile. General linear models controlling for age and premorbid intellectual disability level indicated differences in memory by A/T/(N) profile.ConclusionThis study adds to the understanding of AT(N) biomarker profiles in DS and their association with AD symptomology. Clinical AD status of MCI‐DS and dementia and worse memory performance were associated with elevated T and (N), in line with non‐DS populations. The unable to determine status paralleled the MCI and dementia status groups. Findings inform models that predict the transition to AD in DS.aging after age 90.

Interaction effect of sex and diagnosis on functional connectivity within the default network in healthy controls, mild cognitive impairment and Alzheimer Disease

AbstractBackgroundAge and sex are major risk factors for late onset Alzheimer’s disease (AD). Almost 70% of AD patients are women, but reasons for sex disparities are not well understood. One potential avenue of inquiry is investigation of default network (DN) functional connectivity (FC) differences between men and women.MethodWe studied amyloid positive individuals from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), clinically diagnosed as healthy elderly controls (HCs), Mild Cognitive Impairment (MCI) and AD, with resting‐state functional Magnetic Resonance Imaging available at the diagnostic and cognitive testing visit (Table 1). We selected seven regions of interest (ROIs) in the DN (Figure 1), including bilateral angular gyrus (ANG), calcarine (CAL), precuneus (PCUN), medial orbital frontal gyrus (ORBmed) and bilateral middle occipital gyrus (MOG). Pearson’s correlation characterized FC between ROIs. Linear mixed effect models adjusted for covariates (education, handedness, presence of apolipoprotein [APOE] ε4 and intra‐subject effect), and analysis of variance (ANOVA) evaluated the effects of diagnosis, sex and their interaction, using Bonferroni correction.ResultsANOVA showed significant differences between diagnostic groups in FC of left ANG – PCUN/CAL and bilateral MOG – CAL. Significant diagnosis by interaction effects were observed in FC especially at the level of posterior‐ventral DN. Specifically, between ANG‐CAL, and PCUN‐MOG (Table 2). Post‐hoc analysis demonstrated distinct effect sizes and/or opposite direction effects in women compared to men (Figure 2). Left ANG – CAL and left ANG – PCUN connectivity had medium effect (|d| >0.5) for men in the MCI versus HC comparison, although small effect (|d| <0.2) across sexes. The discrepancies between women and men were observed in the AD versus MCI comparison, such as the left ANG – left MOG and right ANG – CAL, where they show an opposite direction of FC.ConclusionsOur study found that the sex differences in DN FC did not remain consistent across the clinical AD spectrum. Instead, significant sex by diagnosis interaction effects suggest that treating sex as a covariate overlooks sex‐specific pathological changes in brain FC.

The influence of growth and sex hormones on risk of alzheimer's disease: a mendelian randomization study.

Alzheimer's disease is more prevalent in women, possibly due to sex or growth hormones but existing evidence is inconclusive. We investigated whether genetically predicted sex and growth hormones are associated with risk of Alzheimer's disease. Genetic variants strongly and independently predicting insulin-like growth factor 1 (IGF-1), testosterone and sex hormone-binding globulin (SHBG) were obtained from large, published genome wide associations studies (GWAS) and applied to GWAS of Alzheimer's disease based on clinical diagnosis (cases = 21,982, control = 41,944) from the International Genomics of Alzheimer's Project and the UK Biobank parental (maternal cases = 27,696; paternal cases = 14,338) and siblings' diagnosis (cases = 2,171) as proxy cases. Published GWAS summary statistics were used in our analyses. Estimates were obtained from inverse variance weighting with sensitivity analysis (i.e., MR-Egger, weighted median and MR-PRESSO). Multivariable analyses adjusted for pleiotropic effects and possible sources of selection bias were also performed. Genetically predicted higher total testosterone may reduce the risk of paternal Alzheimer's disease (odds ratio (OR) 0.86, 95% confidence interval (CI) 0.76 to 0.97, per SD increase in testosterone) and in meta-analysis for women (OR 0.92, 95% CI 0.87, 0.98) with directionally similar results from other analyses. SHBG were not associated with Alzheimer's disease. IGF-1 in women was inversely associated with risk of clinical Alzheimer's disease in sensitivity analysis but not in the main analysis. These results suggest genetically predicted higher total testosterone may lower risk of Alzheimer's disease. The role of testosterone and the immune system in Alzheimer's disease could be further investigated.

Estimating Transition Probabilities Across the Alzheimer's Disease Continuum Using a Nationally Representative Real-World Database in the United States.

Clinical Alzheimer's disease (AD) begins with mild cognitive impairment (MCI) and progresses to mild, moderate, or severe dementia, constituting a disease continuum that eventually leads to death. This study aimed to estimate the probabilities of transitions across those disease states. We developed a mixed-effects multi-state Markov model to estimate the transition probabilities, adjusted for 5 baseline covariates, using the Health and Retirement Study (HRS) database. HRS surveys older adults in the United States bi-annually. Alzheimer states were defined using the modified Telephone Interview of Cognitive Status (TICS-m). A total of 11,292 AD patients were analyzed. Patients were 70.8±9.0years old, 54.9% female, and with 12.0±3.3years of education. Within 1year from the initial state, the model estimated a higher probability of transition to the next AD state in earlier disease: 12.8% from MCI to mild AD and 5.0% from mild to moderate AD, but<1% from moderate to severe AD. After 10years, the probability of transition to the next state was markedly higher for all states, but still higher in earlier disease: 29.8% from MCI to mild AD, 23.5% from mild to moderate AD, and 5.7% from moderate to severe AD. Across all AD states, the probability of transition to death was<5% after 1year and>15% after 10years. Older age, fewer years of education, unemployment, and nursing home stay were associated with a higher risk of disease progression (p<0.01). This analysis shows that the risk of progression is greater in earlier AD states, increases over time, and is higher in patients who are older, with fewer years of education, unemployed, or in a nursing home at baseline. The estimated transition probabilities can provide guidance for future disease management and clinical trial design optimization, and can be used to refine existing cost-effectiveness frameworks.

β-Amyloid Load on PET Along the Continuum of Dementia With Lewy Bodies.

β-Amyloid (Aβ) plaques can co-occur with Lewy-related pathology in patients with dementia with Lewy bodies (DLB), but Aβ load at prodromal stages of DLB still needs to be elucidated. We investigated Aβ load on PET throughout the DLB continuum, from an early prodromal stage of isolated REM sleep behavior disorder (iRBD) to a stage of mild cognitive impairment with Lewy bodies (MCI-LB), and finally DLB. We performed a cross-sectional study in patients with a diagnosis of iRBD, MCI-LB, or DLB from the Mayo Clinic Alzheimer Disease Research Center. Aβ levels were measured by Pittsburgh compound B (PiB) PET, and global cortical standardized uptake value ratio (SUVR) was calculated. Global cortical PiB SUVR values from each clinical group were compared with each other and with those of cognitively unimpaired (CU) individuals (n = 100) balanced on age and sex using analysis of covariance. We used multiple linear regression testing for interaction to study the influences of sex and APOE ε4 status on PiB SUVR along the DLB continuum. Of the 162 patients, 16 had iRBD, 64 had MCI-LB, and 82 had DLB. Compared with CU individuals, global cortical PiB SUVR was higher in those with DLB (p < 0.001) and MCI-LB (p = 0.012). The DLB group included the highest proportion of Aβ-positive patients (60%), followed by MCI-LB (41%), iRBD (25%), and finally CU (19%). Global cortical PiB SUVR was higher in APOE ε4 carriers compared with that in APOE ε4 noncarriers in MCI-LB (p < 0.001) and DLB groups (p = 0.049). Women had higher PiB SUVR with older age compared with men across the DLB continuum (β estimate = 0.014, p = 0.02). In this cross-sectional study, levels of Aβ load was higher further along the DLB continuum. Whereas Aβ levels were comparable with those in CU individuals in iRBD, a significant elevation in Aβ levels was observed in the predementia stage of MCI-LB and in DLB. Specifically, APOE ε4 carriers had higher Aβ levels than APOE ε4 noncarriers, and women tended to have higher Aβ levels than men as they got older. These findings have important implications in targeting patients within the DLB continuum for clinical trials of disease-modifying therapies.

A Call to Action to Address Sex Differences in Alzheimer Disease Clinical Trials

This Viewpoint calls for comprehensive investigations into sex differences associated with treatments in existing Alzheimer disease and integration into future Alzheimer disease and related dementia clinical trials.

Peak substrate oxidation and peak oxygen consumption are diminished in individuals with mild cognitive impairment

The number of persons with Alzheimer’s Disease (AD) is projected to double within the coming decades, placing great emphasis on identifying accessible risk factors. Prior to AD, there is an important transitional phase, called mild cognitive impairment (MCI), where individuals first display objective declines in cognitive functioning. Growing evidence suggests that the risk factors of AD and MCI adversely affect mitochondrial function, presenting a potential measure that may be useful in risk stratification. Metabolic flexibility represents the capacity of the mitochondria to oxidize a variety of fuel substrates (i.e., carbohydrates and fatty acids), and can be assessed using a graded exercise test. Thus, metabolic flexibility may be a useful index of mitochondrial health that can be evaluated prior to the development of clinical AD. OBJECTIVE: To determine whether cardiorespiratory fitness and metabolic flexibility are attenuated in older adults with MCI in response to a graded exercise test. HYPOTHESIS: We hypothesized that individuals with MCI would have similar baseline, but reduced peak oxygen consumption (VO2peak), fat oxidation (FatOx), and carbohydrate oxidation (CHOOx) compared to healthy controls. METHODS: 22 older adults with MCI and 21 sedentary healthy controls (HCs) matched for both age and sex underwent a modified Bruce Protocol treadmill test to assess VO2peak. FatOx and CHOOx were calculated based on ventilatory equivalents using the equations: FatOx = 1.67VO2 - 1.70VCO2 [L/min] and CHOOx = 4.585VO2 - 3.2255VCO2 [L/min], respectively. Unpaired t-tests were conducted to determine whether baseline or peak oxygen consumption, FatOx, and CHOOx were different between groups. RESULTS: The MCI and the HC groups were similar in age (73.5 + 8.81 vs. 71.2 + 6.33, p=0.33) and BMI (26.2 + 4.92 vs. 26.8 + 5.16, p=0.70). Baseline FatOx (0.09 + 0.03 vs. 0.10 + 0.05 g/min, p=0.47) and CHOOx (0.51 + 0.17 vs. 0.59 + 0.21 g/min, p=0.23) were not different between the MCI and HC groups. Peak FatOx (0.31 + 0.13 vs. 0.39 + 0.10 g/min, p=0.018*), and peak CHOOx (1.89 + 0.41 vs. 2.18 + 0.49 g/min, p=0.047*) were lower in the MCI group relative to HCs. Additionally, the MCI group had a lower absolute (1.32 + 0.33 vs. 1.61 + 0.47 L/min, p=0.027*), and relative (22.0 + 5.0 vs. 19.1 + 5.30 mL/kg/min, p=0.070) VO2peak, although the latter was not statistically significant. CONCLUSION: Peak FatOx, CHOOx, and absolute VO2peak are diminished in older adults with MCI, which may suggest impaired whole body mitochondrial capacity and metabolic flexibility. However, future studies are necessary to determine the exact physiological and behavioral components to these observed reductions. Supported by NIH Grants R01 AG058853 and K01 AG054731 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Plasma metabolites associated with clinically diagnosed Alzheimer’s Disease and the association is augmented using blood-based biomarkers. (P10-6.003)

<h3>Objective:</h3> Identify metabolites associated with clinical diagnosis and pathology of Alzheimer’s Disease (AD) <h3>Background:</h3> We investigated metabolites in plasma to capture systemic biochemical changes associated with AD diagnosed clinically and then using plasma biomarkers. <h3>Design/Methods:</h3> Exogenous and endogenous metabolites in plasma were measured in 300 clinical AD and 430 healthy non-demented individuals of Caribbean Hispanic ancestry using untargeted liquid-chromatography, performed on HILIC (+ ionization) and C18 (− ionization) columns, coupled to a Thermo Orbitrap HF-X mass spectrometer. Genome-wide SNP data and plasma biomarkers including Ab40, Ab42, P-tau181 and Neurofilament light chain (NfL) were obtained on all participants. Metabolite association with AD and P-tau181 levels were tested after adjustment for age and sex. Metabolites associated with P-tau181 levels (but not with NfL, a non-specific marker of neurodegeneration) were categorized as AD-specific. <h3>Results:</h3> Over 4000 metabolomic features were measured with high accuracy in the sample. 96 metabolites were associated with P-tau181 levels, but no metabolites survived multiple testing correction for association with clinical AD alone. Features putatively annotated as phosphatidylcholine (4.11E-07) and Carotamine (p=1.2e-05) were strongly associated P-tau181 levels. We observed similar results when using a diagnostic cutoff of P-tau181 levels for AD as the outcome. Metabolites associated with P-tau181 levels were enriched in amino acid metabolism, glutathione metabolism, tryrosine metabolism and hexose phosphorylation pathways. Ramipril (p=2.9e-04) and glycerophosphocholine (p=9.9e-04) were among the top associated with AD diagnosis. PLS-DA analysis identified biopterin metabolism, glycosphingolipid biosynthesis and tyrosine metabolism as the most discriminating pathways between AD and healthy controls when augmented by biomarkers. <h3>Conclusions:</h3> Metabolites specifically lipids and those involved in cardiovascular function were associated with AD and P-tau181 levels. Metabolite profiling can identify perturbed pathways in clinical and pre-clinical AD and integration with genome-wide SNP data will identify mechanisms underlying genetic association with disease. <b>Disclosure:</b> Dr. Kalia has nothing to disclose. Mrs. Reyes-Dumeyer has nothing to disclose. Mr. DUBEY has nothing to disclose. Dr. Nandakumar has nothing to disclose. Dr. Lee has nothing to disclose. Rafael Lantigua has nothing to disclose. Dr. Medrano has nothing to disclose. Dr. Rivera Mejia has nothing to disclose. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Eisai. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Honig has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Honig has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Prevail. Dr. Honig has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Cortexyme. Dr. Honig has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Legal Firms . The institution of Dr. Honig has received research support from Roche. The institution of Dr. Honig has received research support from Eisau. Dr. Honig has received research support from Alector. The institution of Dr. Honig has received research support from Transposon. Dr. Mayeux has nothing to disclose. Badri Vardarajan has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Kodikaz Therapeutics.

Identifying mixed Lewy body and Alzheimer’s disease pathologies using functional neuroimaging (P6-12.002)

<h3>Objective:</h3> To distinguish between Alzheimer’s disease, Lewy body dementia and Parkinson’s disease using functional neuroimaging. <h3>Background:</h3> Lewy body dementia (LBD) and Alzheimer’s disease (AD) are the two most common neurodegenerative causes of dementia. Autopsy studies report many cases with these clinical diagnoses having mixed pathology with alpha-synuclein, tau and amyloid proteinopathies. There is limited research in trying to distinguish these potential mixed pathology conditions prior to death. <h3>Design/Methods:</h3> 43 subjects were recruited from Ohio State University Memory Disorder and Movement Clinics. Subjects were diagnosed based on standard clinical criteria for DLB, PD and AD by fellowship trained cognitive and movement disorders faculty. Cognitive testing performed included MMSE and SAGE. We used neuroimaging methods including FDG PET, amyloid PET, and DaTscan SPECT to evaluate subjects diagnosed with dementia with Lewy bodies (DLB), AD and PD to investigate how often potential mixed pathologies could be present. The neuroimaging evaluations were blinded to clinical diagnosis. <h3>Results:</h3> 28 subjects with clinical diagnosis of Lewy body disease (15 DLB and 13 PD) and 15 subjects with clinical diagnosis AD were compared. The Lewy body subjects were 69.5 ± 7.2 years old, MMSE 26.6 ± 4, and SAGE 18.4 ± 4.7. AD subjects were 68.4 ± 9.3 years old, MMSE 16.3 ± 6.4, and SAGE 7.4 ± 6.1. 5 subjects (33%) of the clinical AD cases showed abnormal DAT scan uptake, 3 subjects (20%) of the clinical AD cases were negative for amyloid with normal DaTscan uptake, 3 subjects (20%) of the clinical DLB cases showed mixed LBD and AD features, 2 subjects (13%) of the clinical DLB cases were positive for amyloid with normal DaTscan uptake, and 1 (8%) subject with clinical PD had normal DAT scan. <h3>Conclusions:</h3> Based on functional neuroimaging, 26% of clinically diagnosed AD or DLB subjects had evidence of potential mixed pathologies and 25% were misdiagnosed. <b>Disclosure:</b> Dr. Bouchachi has nothing to disclose. Ms. Truelove has nothing to disclose. Ms. Rawson has nothing to disclose. Mrs. Icenhour has nothing to disclose. Michael Knopp has nothing to disclose. Prof. Wright has a non-compensated relationship as a Board of Directors Member with American Board of Science in Nuclear Medicine that is relevant to AAN interests or activities. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for BrainTest, Inc. Dr. Scharre has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vascular Scientific. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Acadia. Dr. Scharre has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Scharre has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for Hickman &amp; Lowder Co.. The institution of Dr. Scharre has received research support from InSightec. The institution of Dr. Scharre has received research support from Alzheimer’s Therapeutic Research Institute (ATRI). The institution of Dr. Scharre has received research support from Eisai. The institution of Dr. Scharre has received research support from vTv Therapeutics. The institution of Dr. Scharre has received research support from National Institute of Health. The institution of Dr. Scharre has received research support from Eli Lilly. The institution of Dr. Scharre has received research support from Johns Hopkins. The institution of Dr. Scharre has received research support from Biogen. The institution of Dr. Scharre has received research support from Roche. The institution of Dr. Scharre has received research support from AZ Therapies. The institution of Dr. Scharre has received research support from Biohaven. The institution of Dr. Scharre has received research support from Novartis. The institution of Dr. Scharre has received research support from Avanir. The institution of Dr. Scharre has received research support from PrecisionMed, Inc. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care. Dr. Scharre has received intellectual property interests from a discovery or technology relating to health care.

Evaluation of Plasma Biomarkers for A/T/N Classification of Alzheimer Disease Among Adults of Caribbean Hispanic Ethnicity

Cerebrospinal fluid (CSF) and plasma biomarkers can detect biological evidence of Alzheimer disease (AD), but their use in low-resource environments and among minority ethnic groups is limited. To assess validated plasma biomarkers for AD among adults of Caribbean Hispanic ethnicity. In this decision analytical modeling study, adults were recruited between January 1, 2018, and April 30, 2022, and underwent detailed clinical assessments and venipuncture. A subsample of participants also consented to lumbar puncture. Established CSF cut points were used to define AD biomarker-positive status, allowing determination of optimal cut points for plasma biomarkers in the same individuals. The performance of a panel of 6 plasma biomarkers was then assessed with respect to the entire group. Data analysis was performed in January 2023. Main outcomes were the association of plasma biomarkers amyloid-β 1-42 (Aβ42), amyloid-β 1-40 (Aβ40), total tau (T-tau), phosphorylated tau181 (P-tau181), glial fibrillary acidic protein (GFAP), and neurofilament light chain (NfL) with AD diagnosis. These biomarkers allow assessment of amyloid (A), neurofibrillary degeneration (T), and neurodegeneration (N) aspects of AD. Statistical analyses performed included receiver operating characteristics, Pearson and Spearman correlations, t tests, and Wilcoxon rank-sum, chi-square, and Fisher exact tests. Exposures included age, sex, education, country of residence, apolipoprotein-ε4 (APOE-ε4) allele number, serum creatinine, blood urea nitrogen, and body mass index. This study included 746 adults. Participants had a mean (SD) age of 71.0 (7.8) years, 480 (64.3%) were women, and 154 (20.6%) met clinical criteria for AD. Associations were observed between CSF and plasma P-tau181 (r = .47 [95% CI, 0.32-0.60]), NfL (r = 0.57 [95% CI, 0.44-0.68]), and P-tau181/Aβ42 (r = 0.44 [95% CI, 0.29-0.58]). For AD defined by CSF biomarkers, plasma P-tau181 and P-tau181/Aβ42 provided biological evidence of AD. Among individuals judged to be clinically healthy without dementia, biomarker-positive status was determined by plasma P-tau181 for 133 (22.7%) and by plasma P-tau181/Aβ42 for 104 (17.7%). Among individuals with clinically diagnosed AD, 69 (45.4%) had plasma P-tau181 levels and 89 (58.9%) had P-tau181/Aβ42 levels that were inconsistent with AD. Individuals with biomarker-negative clinical AD status tended to have lower levels of education, were less likely to carry APOE-ε4 alleles, and had lower levels of GFAP and NfL than individuals with biomarker-positive clinical AD. In this cross-sectional study, plasma P-tau181 and P-tau181/Aβ42 measurements correctly classified Caribbean Hispanic individuals with and without AD. However, plasma biomarkers identified individuals without dementia with biological evidence of AD, and a portion of those with dementia whose AD biomarker profile was negative. These results suggest that plasma biomarkers can augment detection of preclinical AD among asymptomatic individuals and improve the specificity of AD diagnosis.

Higher performance for women than men in MRI-based Alzheimer’s disease detection

IntroductionAlthough machine learning classifiers have been frequently used to detect Alzheimer’s disease (AD) based on structural brain MRI data, potential bias with respect to sex and age has not yet been addressed. Here, we examine a state-of-the-art AD classifier for potential sex and age bias even in the case of balanced training data.MethodsBased on an age- and sex-balanced cohort of 432 subjects (306 healthy controls, 126 subjects with AD) extracted from the ADNI data base, we trained a convolutional neural network to detect AD in MRI brain scans and performed ten different random training-validation-test splits to increase robustness of the results. Classifier decisions for single subjects were explained using layer-wise relevance propagation.ResultsThe classifier performed significantly better for women (balanced accuracy 87.58pm 1.14%) than for men (79.05pm 1.27%). No significant differences were found in clinical AD scores, ruling out a disparity in disease severity as a cause for the performance difference. Analysis of the explanations revealed a larger variance in regional brain areas for male subjects compared to female subjects.DiscussionThe identified sex differences cannot be attributed to an imbalanced training dataset and therefore point to the importance of examining and reporting classifier performance across population subgroups to increase transparency and algorithmic fairness. Collecting more data especially among underrepresented subgroups and balancing the dataset are important but do not always guarantee a fair outcome.

Stimulus material selection for the Dutch famous faces test for older adults.

Worldwide, approximately 22% of all individuals aged 50 years and older are currently estimated to fall somewhere on the Alzheimer's disease (AD) continuum, which can be roughly divided into preclinical AD, mild cognitive impairment (MCI), and AD dementia. While episodic memory loss (among other aspects) is typically required for a diagnosis of AD dementia, MCI is said to have occurred when cognitive impairment (including memory loss) is worse than expected for the person's age but not enough to be classified as dementia. On the other hand, preclinical AD can currently only be detected using biomarkers; clinical symptoms are not apparent using traditional neuropsychological tests. The main aim of the current paper was to explore the possibility of a test which could distinguish preclinical AD from normal aging. Recent scientific evidence suggests that the Famous Faces Test (FFT) could differentiate preclinical AD from normal aging up to 5 years before a clinical AD diagnosis. Problematic with existing FFTs is the selection of stimulus material. Faces famous in a specific country and a specific decade might not be equally famous for individuals in another country or indeed for people of different ages. The current article describes how famous faces were systematically selected and chosen for the Dutch older (60+) population using five steps. The goal was to design and develop short versions of the FFT for Dutch older adults of equivalent mean difficulty. In future work, these nine parallel versions will be necessary for (a) cross-sectional comparison as well as subsequent longitudinal assessment of cognitively normal and clinical groups and (b) creating personalized norms for the normal aged controls that could be used to compare performance within individuals with clinical diagnoses. The field needs a simple, cognitive test which can distinguish the earliest stages of the dementia continuum from normal aging.

Molecules of senescent glial cells differentiate Alzheimer’s disease from ageing

BackgroundAgeing is a major risk factor for Alzheimer’s disease (AD), which is accompanied by cellular senescence and thousands of transcriptional changes in the brain.ObjectivesTo identify the biomarkers in the cerebrospinal...

Plasma GFAP associates with secondary Alzheimer's pathology in Lewy body disease.

Within Lewy body spectrum disorders (LBSD) with α-synuclein pathology (αSyn), concomitant Alzheimer's disease (AD) pathology is common and is predictive of clinical outcomes, including cognitive impairment and decline. Plasma phosphorylated tau 181 (p-tau181 ) is sensitive to AD neuropathologic change (ADNC) in clinical AD, and plasma glial fibrillary acidic protein (GFAP) is associated with the presence of β-amyloid plaques. While these plasma biomarkers are well tested in clinical and pathological AD, their diagnostic and prognostic performance for concomitant AD in LBSD is unknown. In autopsy-confirmed αSyn-positive LBSD, we tested how plasma p-tau181 and GFAP differed across αSyn with concomitant ADNC (αSyn+AD; n = 19) and αSyn without AD (αSyn; n = 30). Severity of burden was scored on a semiquantitative scale for several pathologies (e.g., β-amyloid and tau), and scores were averaged across sampled brainstem, limbic, and neocortical regions. Linear models showed that plasma GFAP was significantly higher in αSyn+AD compared to αSyn (β = 0.31, 95% CI = 0.065-0.56, and P = 0.015), after covarying for age at plasma, plasma-to-death interval, and sex; plasma p-tau181 was not (P = 0.37). Next, linear models tested associations of AD pathological features with both plasma analytes, covarying for plasma-to-death, age at plasma, and sex. GFAP was significantly associated with brain β-amyloid (β = 15, 95% CI = 6.1-25, and P = 0.0018) and tau burden (β = 12, 95% CI = 2.5-22, and P = 0.015); plasma p-tau181 was not associated with either (both P > 0.34). Findings indicate that plasma GFAP may be sensitive to concomitant AD pathology in LBSD, especially accumulation of β-amyloid plaques.

Analysis of positron emission tomography hypometabolic patterns and neuropsychiatric symptoms in patients with dementia syndromes.

To estimate the proportions of specific hypometabolic patterns and their association with neuropsychiatric symptoms (NPS) in patients with cognitive impairment (CI). This multicenter study with 1037 consecutive patients was conducted from December 2012 to December 2019. 18 F-FDG PET and clinical/demographic information, NPS assessments were recorded and analyzed to explore the associations between hypometabolic patterns and clinical features by correlation analysis and multivariable logistic regression models. Patients with clinical Alzheimer's disease (AD, 81.6%, 605/741) and dementia with Lewy bodies (67.9%, 19/28) mostly had AD-pattern hypometabolism, and 76/137 (55.5%) of patients with frontotemporal lobar degeneration showed frontal and anterior temporal pattern (FT-P) hypometabolism. Besides corticobasal degeneration, patients with behavioral variant frontotemporal dementia (36/58), semantic dementia (7/10), progressive non-fluent aphasia (6/9), frontotemporal lobar degeneration and amyotrophic lateral sclerosis (3/5), and progressive supranuclear palsy (21/37) also mostly showed FT-P hypometabolism. The proportion of FT-P hypometabolism was associated with the presence of hallucinations (R=0.171, p=0.04), anxiety (R=0.182, p=0.03), and appetite and eating abnormalities (R=0.200, p=0.01) in AD. Specific hypometabolic patterns in FDG-PET are associated with NPS and beneficial for the early identification and management of NPS in patients with CI.

Alzheimer’s Disease from the Amyloidogenic Theory to the Puzzling Crossroads between Vascular, Metabolic and Energetic Maladaptive Plasticity

Alzheimer's disease (AD) is a progressive and degenerative disease producing the most common type of dementia worldwide. The main pathogenetic hypothesis in recent decades has been the well-known amyloidogenic hypothesis based on the involvement of two proteins in AD pathogenesis: amyloid β (Aβ) and tau. Amyloid deposition reported in all AD patients is nowadays considered an independent risk factor for cognitive decline. Vascular damage and blood-brain barrier (BBB) failure in AD is considered a pivotal mechanism for brain injury, with increased deposition of both immunoglobulins and fibrin. Furthermore, BBB dysfunction could be an early sign of cognitive decline and the early stages of clinical AD. Vascular damage generates hypoperfusion and relative hypoxia in areas with high energy demand. Long-term hypoxia and the accumulation within the brain parenchyma of neurotoxic molecules could be seeds of a self-sustaining pathological progression. Cellular dysfunction comprises all the elements of the neurovascular unit (NVU) and neuronal loss, which could be the result of energy failure and mitochondrial impairment. Brain glucose metabolism is compromised, showing a specific region distribution. This energy deficit worsens throughout aging. Mild cognitive impairment has been reported to be associated with a glucose deficit in the entorhinal cortex and in the parietal lobes. The current aim is to understand the complex interactions between amyloid β (Aβ) and tau and elements of the BBB and NVU in the brain. This new approach aimed at the study of metabolic mechanisms and energy insufficiency due to mitochondrial impairment would allow us to define therapies aimed at predicting and slowing down the progression of AD.