Sex significantly predicts medial temporal volume when controlling for the influence of ApoE4 biomarker and demographic variables: A cross-ethnic comparison.

OBJECTIVE: To explore the relationship between age, education, sex, and ApoE4 (+) status to brain volume among a cohort with amnestic mild cognitive impairment (aMCI). METHOD: One hundred and twenty-three participants were stratified into Hispanic (n = 75) and White non-Hispanic (WNH, N = 48). Multiple linear regression analyses were conducted with age, education, sex, and ApoE4 status as predictor variables and left and right combined MRI volumes of the hippocampus, parahippocampus, and entorhinal cortex as dependent variables. Variations in head sizes were corrected by normalization with a total intracranial volume measurement. RESULTS: Bonferroni-corrected results indicated that when controlling for ApoE4 status, education, and age, sex was a significant predictor of hippocampal volume among the Hispanic group (ß = .000464, R2 = .196, p < .01) and the WNH group (ß = .000455, R2 = .195, p < .05). Education (ß = .000028, R2 = .168, p < .01) and sex (ß = .000261, R2 = .168, p < .01) were significant predictors of parahippocampal volume among the Hispanic MCI group when controlling for the effects of ApoE4 status and age. One-way ANCOVAs comparing hippocampal and parahippocampal volume between males and females within groups revealed that females had significantly larger hippocampal volumes (p < .05). Hispanic females had significantly larger hippocampal (p < .001) and parahippocampal (p < .05) volume compared to males. No sex differences in parahippocampal volume were noted among WNHs. CONCLUSIONS: Biological sex, rather than ApoE4 status, was a greater predictor of hippocampal volume among Hispanic and WNH females. These findings add to the mixed literature on sex differences in dementia research and highlight continued emphasis on ethnic populations to elucidate on neurodegenerative disparities.

Association of Physical Frailty and Cognitive Function in a Population-Based Cross-Sectional Study of American Older Adults.

INTRODUCTION: Cognitive impairment and frailty are prevalent in older persons. Physical frailty is associated with cognitive decline; however, the role of effect modifiers such as age, sex, race/ethnicity, and cognitive reserve is not well understood. METHODS: Cross-sectional data from the National Health and Nutrition Examination Survey (2011-2014) were obtained for participants aged ≥60 years. Complete availability of cognitive scores was an inclusion criterion. Physical frailty was defined by the presence of exhaustion, weakness, low body mass, and/or low physical activity, and categorized into three groups: robust (0 present), pre-frail (1-2 present), or frail (3-4 present). Four cognitive test scores were converted to z-scores, and global cognition (composite z-score) was calculated by averaging the four-individual z-scores. Multivariable linear regression models were fit to estimate the associations between frailty and cognitive function. Frailty was also evaluated as a risk factor for self-reported subjective memory complaint (SMC) using logistic regression. All models were adjusted for age, sex, race/ethnicity, education, alcohol use, income, marital status, diabetes, hypertension, and history of stroke. Effect measure modification analyses were conducted by age, sex, race/ethnicity, education, and occupational cognitive demand. RESULTS: The study population comprised 2,863 participants aged ≥60 years. 50.6% of the participants were categorized into robust, 43.2% pre-frail, and 6.2% frail. After adjusting for covariates, compared to robust participants, frail and prefrail participants had lower adjusted mean global cognitive z-scores, ß^ = -0.61, 95% CI: -0.83, -0.38 and ß^ = -0.21, 95% CI: -0.30, -0.12, respectively. Both prefrail and frail participants had higher odds of SMC compared to the robust participants. We did not see strong evidence that the association between frailty and cognition was modified by the factors we studied. DISCUSSION/CONCLUSION: Both pre-frailty and frailty were associated with lower cognitive performance and were more likely to report subjective memory complaints relative to persons without frailty. These findings provide additional evidence that physical frailty may serve as a prognostic factor for cognitive deterioration or dementia, and prevention of frailty may be an important public health strategy.

Diffusion MRI relates to plasma Aß42/40 in PET negative participants without dementia.

INTRODUCTION: Magnetic resonance imaging (MRI) biomarkers are needed for indexing early biological stages of Alzheimer's disease (AD), such as plasma amyloid-ß (Aß42/40) positivity in Aß positron emission tomography (PET) negative individuals. METHODS: Diffusion free-water (FW) MRI was acquired in individuals with normal cognition (NC) and mild cognitive impairment (MCI) with Aß plasma-/PET- (NC = 22, MCI = 60), plasma+/PET- (NC = 5, MCI = 20), and plasma+/PET+ (AD dementia = 21) biomarker status. Gray and white matter FW and fractional anisotropy (FAt) were compared cross-sectionally and the relationships between imaging, plasma and PET biomarkers were assessed. RESULTS: Plasma+/PET- demonstrated increased FW (24 regions) and decreased FAt (66 regions) compared to plasma-/PET-. FW (16 regions) and FAt (51 regions) were increased in plasma+/PET+ compared to plasma+/PET-. Composite brain FW correlated with plasma Aß42/40 and p-tau181. DISCUSSION: FW imaging changes distinguish plasma Aß42/40 positive and negative groups, independent of group differences in cognitive status, Aß PET status, and other plasma biomarkers (i.e., t-tau, p-tau181, glial fibrillary acidic protein, neurofilament light). HIGHLIGHTS: Plasma Aß42/40 positivity is associated with brain microstructure decline. Plasma+/PET- demonstrated increased FW in 24 total GM and WM regions. Plasma+/PET- demonstrated decreased FAt in 66 total GM and WM regions. Whole-brain FW correlated with plasma Aß42/40 and p-tau181 measures. Plasma+/PET- demonstrated decreased cortical volume and thickness.

Plasma Alzheimer's biomarkers and brain amyloid in Hispanic and non-Hispanic older adults.

INTRODUCTION: Alzheimer's disease studies often lack ethnic diversity. METHODS: We evaluated associations between plasma biomarkers commonly studied in Alzheimer's (p-tau181, GFAP, and NfL), clinical diagnosis (clinically normal, amnestic MCI, amnestic dementia, or non-amnestic MCI/dementia), and Aß-PET in Hispanic and non-Hispanic older adults. Hispanics were predominantly of Cuban or South American ancestry. RESULTS: Three-hundred seventy nine participants underwent blood draw (71.9 ± 7.8 years old, 60.2% female, 57% Hispanic of which 88% were Cuban or South American) and 240 completed Aß-PET. P-tau181 was higher in amnestic MCI (p = 0.004, d = 0.53) and dementia (p < 0.001, d = 0.97) than in clinically normal participants and discriminated Aß-PET[+] and Aß-PET[-] (AUC = 0.86). P-tau181 outperformed GFAP and NfL. There were no significant interactions with ethnicity. Among amnestic MCI, Hispanics had lower odds of elevated p-tau181 than non-Hispanic (OR = 0.41, p = 0.006). DISCUSSION: Plasma p-tau181 informs etiological diagnosis of cognitively impaired Hispanic and non-Hispanic older adults. Hispanic ethnicity may relate to greater likelihood of non-Alzheimer's contributions to memory loss. HIGHLIGHTS: Alzheimer's biomarkers were measured in Hispanic and non-Hispanic older adults. Plasma p-tau181 related to amnestic cognitive decline and brain amyloid burden. AD biomarker associations did not differ between Hispanic and non-Hispanic ethnicity. Hispanic individuals may be more likely to have non-Alzheimer causes of memory loss.

Learning slopes in early-onset Alzheimer's disease.

OBJECTIVE: Investigation of learning slopes in early-onset dementias has been limited. The current study aimed to highlight the sensitivity of learning slopes to discriminate disease severity in cognitively normal participants and those diagnosed with early-onset dementia with and without ß-amyloid positivity METHOD: Data from 310 participants in the Longitudinal Early-Onset Alzheimer's Disease Study (aged 41 to 65) were used to calculate learning slope metrics. Learning slopes among diagnostic groups were compared, and the relationships of slopes with standard memory measures were determined RESULTS: Worse learning slopes were associated with more severe disease states, even after controlling for demographics, total learning, and cognitive severity. A particular metric-the learning ratio (LR)-outperformed other learning slope calculations across analyses CONCLUSIONS: Learning slopes appear to be sensitive to early-onset dementias, even when controlling for the effect of total learning and cognitive severity. The LR may be the learning measure of choice for such analyses. HIGHLIGHTS: Learning is impaired in amyloid-positive EOAD, beyond cognitive severity scores alone. Amyloid-positive EOAD participants perform worse on learning slopes than amyloid-negative participants. Learning ratio appears to be the learning metric of choice for EOAD participants.

Influence of amyloid and diagnostic syndrome on non-traditional memory scores in early-onset Alzheimer's disease.

INTRODUCTION: The Rey Auditory Verbal Learning Test (RAVLT) is a useful neuropsychological test for describing episodic memory impairment in dementia. However, there is limited research on its utility in early-onset Alzheimer's disease (EOAD). We assess the influence of amyloid and diagnostic syndrome on several memory scores in EOAD. METHODS: We transcribed RAVLT recordings from 303 subjects in the Longitudinal Early-Onset Alzheimer's Disease Study. Subjects were grouped by amyloid status and syndrome. Primacy, recency, J-curve, duration, stopping time, and speed score were calculated and entered into linear mixed effects models as dependent variables. RESULTS: Compared with amyloid negative subjects, positive subjects exhibited effects on raw score, primacy, recency, and stopping time. Inter-syndromic differences were noted with raw score, primacy, recency, J-curve, and stopping time. DISCUSSION: RAVLT measures are sensitive to the effects of amyloid and syndrome in EOAD. Future work is needed to quantify the predictive value of these scores. HIGHLIGHTS: RAVLT patterns characterize various presentations of EOAD and EOnonAD Amyloid impacts raw score, primacy, recency, and stopping time Timing-based scores add value over traditional count-based scores.

Sex and APOE ε4 carrier effects on atrophy, amyloid PET, and tau PET burden in early-onset Alzheimer's disease.

INTRODUCTION: We used sex and apolipoprotein E ε4 (APOE ε4) carrier status as predictors of pathologic burden in early-onset Alzheimer's disease (EOAD). METHODS: We included baseline data from 77 cognitively normal (CN), 230 EOAD, and 70 EO non-Alzheimer's disease (EOnonAD) participants from the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS). We stratified each diagnostic group by males and females, then further subdivided each sex by APOE ε4 carrier status and compared imaging biomarkers in each stratification. Voxel-wise multiple linear regressions yielded statistical brain maps of gray matter density, amyloid, and tau PET burden. RESULTS: EOAD females had greater amyloid and tau PET burdens than males. EOAD female APOE ε4 non-carriers had greater amyloid PET burdens and greater gray matter atrophy than female ε4 carriers. EOnonAD female ε4 non-carriers also had greater gray matter atrophy than female ε4 carriers. DISCUSSION: The effects of sex and APOE ε4 must be considered when studying these populations. HIGHLIGHTS: Novel analysis examining the effects of biological sex and apolipoprotein E ε4 (APOE Îµ4) carrier status on neuroimaging biomarkers among early-onset Alzheimer's disease (EOAD), early-onset non-AD (EOnonAD), and cognitively normal (CN) participants. Female sex is associated with greater pathology burden in the EOAD cohort compared to male sex. The effect of APOE ε4 carrier status on pathology burden was the most impactful in females across all cohorts.

White matter hyperintensities are higher among early-onset Alzheimer's disease participants than their cognitively normal and early-onset nonAD peers: Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We compared white matter hyperintensities (WMHs) in early-onset Alzheimer's disease (EOAD) with cognitively normal (CN) and early-onset amyloid-negative cognitively impaired (EOnonAD) groups in the Longitudinal Early-Onset Alzheimer's Disease Study. METHODS: We investigated the role of increased WMH in cognition and amyloid and tau burden. We compared WMH burden of 205 EOAD, 68 EOnonAD, and 89 CN participants in lobar regions using t-tests and analyses of covariance. Linear regression analyses were used to investigate the association between WMH and cognitive impairment and that between amyloid and tau burden. RESULTS: EOAD showed greater WMHs compared with CN and EOnonAD participants across all regions with no significant differences between CN and EOnonAD groups. Greater WMHs were associated with worse cognition. Tau burden was positively associated with WMH burden in the EOAD group. DISCUSSION: EOAD consistently showed higher WMH volumes. Overall, greater WMHs were associated with worse cognition and higher tau burden in EOAD. HIGHLIGHTS: This study represents a comprehensive characterization of WMHs in sporadic EOAD. WMH volumes are associated with tau burden from positron emission tomography (PET) in EOAD, suggesting WMHs are correlated with increasing burden of AD. Greater WMH volumes are associated with worse performance on global cognitive tests. EOAD participants have higher WMH volumes compared with CN and early-onset amyloid-negative cognitively impaired (EOnonAD) groups across all brain regions.

Cerebrospinal fluid biomarkers in the Longitudinal Early-onset Alzheimer's Disease Study.

INTRODUCTION: One goal of the Longitudinal Early Onset Alzheimer's Disease Study (LEADS) is to define the fluid biomarker characteristics of early-onset Alzheimer's disease (EOAD). METHODS: Cerebrospinal fluid (CSF) concentrations of Aß1-40, Aß1-42, total tau (tTau), pTau181, VILIP-1, SNAP-25, neurogranin (Ng), neurofilament light chain (NfL), and YKL-40 were measured by immunoassay in 165 LEADS participants. The associations of biomarker concentrations with diagnostic group and standard cognitive tests were evaluated. RESULTS: Biomarkers were correlated with one another. Levels of CSF Aß42/40, pTau181, tTau, SNAP-25, and Ng in EOAD differed significantly from cognitively normal and early-onset non-AD dementia; NfL, YKL-40, and VILIP-1 did not. Across groups, all biomarkers except SNAP-25 were correlated with cognition. Within the EOAD group, Aß42/40, NfL, Ng, and SNAP-25 were correlated with at least one cognitive measure. DISCUSSION: This study provides a comprehensive analysis of CSF biomarkers in sporadic EOAD that can inform EOAD clinical trial design.

Amyloid and tau-PET in early-onset AD: Baseline data from the Longitudinal Early-onset Alzheimer's Disease Study (LEADS).

INTRODUCTION: We aimed to describe baseline amyloid-beta (Aß) and tau-positron emission tomograrphy (PET) from Longitudinal Early-onset Alzheimer's Disease Study (LEADS), a prospective multi-site observational study of sporadic early-onset Alzheimer's disease (EOAD). METHODS: We analyzed baseline [18F]Florbetaben (Aß) and [18F]Flortaucipir (tau)-PET from cognitively impaired participants with a clinical diagnosis of mild cognitive impairment (MCI) or AD dementia aged < 65 years. Florbetaben scans were used to distinguish cognitively impaired participants with EOAD (Aß+) from EOnonAD (Aß-) based on the combination of visual read by expert reader and image quantification. RESULTS: 243/321 (75.7%) of participants were assigned to the EOAD group based on amyloid-PET; 231 (95.1%) of them were tau-PET positive (A+T+). Tau-PET signal was elevated across cortical regions with a parietal-predominant pattern, and higher burden was observed in younger and female EOAD participants. DISCUSSION: LEADS data emphasizes the importance of biomarkers to enhance diagnostic accuracy in EOAD. The advanced tau-PET binding at baseline might have implications for therapeutic strategies in patients with EOAD. HIGHLIGHTS: 72% of patients with clinical EOAD were positive on both amyloid- and tau-PET. Amyloid-positive patients with EOAD had high tau-PET signal across cortical regions. In EOAD, tau-PET mediated the relationship between amyloid-PET and MMSE. Among EOAD patients, younger onset and female sex were associated with higher tau-PET.

Baseline neuropsychiatric symptoms and psychotropic medication use midway through data collection of the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort.

INTRODUCTION: We examined neuropsychiatric symptoms (NPS) and psychotropic medication use in a large sample of individuals with early-onset Alzheimer's disease (EOAD; onset 40-64 years) at the midway point of data collection for the Longitudinal Early-onset Alzheimer's Disease Study (LEADS). METHODS: Baseline NPS (Neuropsychiatric Inventory - Questionnaire; Geriatric Depression Scale) and psychotropic medication use from 282 participants enrolled in LEADS were compared across diagnostic groups - amyloid-positive EOAD (n = 212) and amyloid negative early-onset non-Alzheimer's disease (EOnonAD; n = 70). RESULTS: Affective behaviors were the most common NPS in EOAD at similar frequencies to EOnonAD. Tension and impulse control behaviors were more common in EOnonAD. A minority of participants were using psychotropic medications, and use was higher in EOnonAD. DISCUSSION: Overall NPS burden and psychotropic medication use were higher in EOnonAD than EOAD participants. Future research will investigate moderators and etiological drivers of NPS, and NPS differences in EOAD versus late-onset AD.

Profiling baseline performance on the Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) cohort near the midpoint of data collection.

OBJECTIVE: The Longitudinal Early-Onset Alzheimer's Disease Study (LEADS) seeks to provide comprehensive understanding of early-onset Alzheimer's disease (EOAD; onset <65 years), with the current study profiling baseline clinical, cognitive, biomarker, and genetic characteristics of the cohort nearing the data-collection mid-point. METHODS: Data from 371 LEADS participants were compared based on diagnostic group classification (cognitively normal [n = 89], amyloid-positive EOAD [n = 212], and amyloid-negative early-onset non-Alzheimer's disease [EOnonAD; n = 70]). RESULTS: Cognitive performance was worse for EOAD than other groups, and EOAD participants were apolipoprotein E (APOE) ε4 homozygotes at higher rates. An amnestic presentation was common among impaired participants (81%), with several clinical phenotypes present. LEADS participants generally consented at high rates to optional trial procedures. CONCLUSIONS: We present the most comprehensive baseline characterization of sporadic EOAD in the United States to date. EOAD presents with widespread cognitive impairment within and across clinical phenotypes, with differences in APOE ε4 allele carrier status appearing to be relevant. HIGHLIGHTS: Findings represent the most comprehensive baseline characterization of sporadic early-onset Alzheimer's disease (EOAD) to date. Cognitive impairment was widespread for EOAD participants and more severe than other groups. EOAD participants were homozygous apolipoprotein E (APOE) ε4 carriers at higher rates than the EOnonAD group. Amnestic presentation predominated in EOAD and EOnonAD participants, but other clinical phenotypes were present.

Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort.

INTRODUCTION: One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. METHODS: LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. RESULTS: Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. DISCUSSION: Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. HIGHLIGHTS: Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.

The Sporadic Early-onset Alzheimer's Disease Signature Of Atrophy: Preliminary Findings From The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) Cohort.

INTRODUCTION: Magnetic resonance imaging (MRI) research has advanced our understanding of neurodegeneration in sporadic early-onset Alzheimer's disease (EOAD) but studies include small samples, mostly amnestic EOAD, and have not focused on developing an MRI biomarker. METHODS: We analyzed MRI scans to define the sporadic EOAD-signature atrophy in a small sample (n = 25) of Massachusetts General Hospital (MGH) EOAD patients, investigated its reproducibility in the large longitudinal early-onset Alzheimer's disease study (LEADS) sample (n = 211), and investigated the relationship of the magnitude of atrophy with cognitive impairment. RESULTS: The EOAD-signature atrophy was replicated across the two cohorts, with prominent atrophy in the caudal lateral temporal cortex, inferior parietal lobule, and posterior cingulate and precuneus cortices, and with relative sparing of the medial temporal lobe. The magnitude of EOAD-signature atrophy was associated with the severity of cognitive impairment. DISCUSSION: The EOAD-signature atrophy is a reliable and clinically valid biomarker of AD-related neurodegeneration that could be used in clinical trials for EOAD. HIGHLIGHTS: We developed an early-onset Alzheimer's disease (EOAD)-signature of atrophy based on magnetic resonance imaging (MRI) scans. EOAD signature was robustly reproducible across two independent patient cohorts. EOAD signature included prominent atrophy in parietal and posterior temporal cortex. The EOAD-signature atrophy was associated with the severity of cognitive impairment. EOAD signature is a reliable and clinically valid biomarker of neurodegeneration.

Semantic intrusion errors as a function of age, amyloid, and volumetric loss: a confirmatory path analysis.

OBJECTIVE: To examine the direct and indirect effects of age, APOE ϵ4 genotype, amyloid positivity, and volumetric reductions in AD-prone brain regions as it relates to semantic intrusion errors reflecting proactive semantic interference (PSI) and the failure to recover from proactive semantic interference (frPSI) on the Loewenstein-Acevedo Scales of Semantic Interference and Learning (LASSI-L), a cognitive stress test that has been consistently more predictive of preclinical and prodromal Alzheimer's disease (AD) than traditional list-learning tests. DESIGN: Cross-sectional study. SETTING: 1Florida Alzheimer's Disease Research Center baseline study. PARTICIPANTS: Two-hundred and twelve participants with Mini-Mental State Examination (MMSE) score above 16 and a broad array of cognitive diagnoses ranging from cognitively normal (CN) to dementia, of whom 58% were female, mean age of 72.1 (SD 7.9). MEASURES: Participants underwent extensive clinical and neuropsychological evaluations, MR and amyloid Positron Emission Tomography/Computer/Computer Tomography (PET/CT) imaging, and analyses of APOE ϵ4 genotype. Confirmatory path analyses were conducted in the structural equation modeling framework that estimated multiple equations simultaneously while controlling for important covariates such as sex, education, language of evaluation, and global cognitive impairment. RESULTS: Both amyloid positivity and decreased brain volumes in AD-prone regions were directly related to LASSI-L Cued B1 and Cued B2 intrusions (sensitive to PSI and frPSI effects) even after controlling for covariates. APOE ϵ4 status did not evidence direct effects on these LASSI-L cognitive markers, but rather exerted their effects on amyloid positivity, which in turn related to PSI and frPSI. Similarly, age did not have a direct relationship with LASSI-L scores, but exerted its effects indirectly through amyloid positivity and volumes of AD-prone brain regions. CONCLUSIONS: Our study provides insight into the relationships among age, APOE ϵ4, amyloid, and brain volumetric reductions as it relates to semantic intrusion errors. The investigation expands our understanding of the underpinnings of PSI and frPSI intrusions in a large cohort.

Phosphorylated tau sites that are elevated in Alzheimer's disease fluid biomarkers are visualized in early neurofibrillary tangle maturity levels in the post mortem brain.

INTRODUCTION: Alzheimer's disease (AD) biomarkers are increasingly more reliable in predicting neuropathology. To facilitate interpretation of phosphorylated tau sites as an early fluid biomarker, we sought to characterize which neurofibrillary tangle maturity levels (pretangle, intermediary 1, mature tangle, intermediary 2, and ghost tangle) are recognized. METHODS: We queried the Florida Autopsied Multi-Ethnic (FLAME) cohort for cases ranging from Braak stages I through VI, excluding non-AD neuropathologies and tauopathies. Thioflavin-S staining was compared to immunohistochemical measures of phosphorylated threonine (pT) 181, pT205, pT217, and pT231 in two hippocampal subsectors across n = 24 cases. RESULTS: Each phosphorylated tau site immunohistochemically labeled early neurofibrillary tangle maturity levels compared to advanced levels recognized by thioflavin-S. Hippocampal burden generally increased with each Braak stage. DISCUSSION: These results provide neurobiologic evidence that these phosphorylated tau fluid biomarker sites are present during early neurofibrillary tangle maturity levels and may explain why these fluid biomarker measures are observed before symptom onset. HIGHLIGHTS: Immunohistochemical evaluation of four phosphorylated tau fluid biomarker sites. Earlier neurofibrillary tangle maturity levels recognized by phosphorylated tau in proline-rich region. Advanced tangle pathology is elevated in the subiculum compared to the cornu ammonis 1 of the hippocampus. Novel semi-quantitative frequency to calculate tangle maturity frequency.

Associations Between Country where Education is Obtained and Cognitive Functioning Among South American and Caribbean Older Adults Living in the U.S.

The increasing prevalence of AD among Hispanics calls for a need for examining factors that affect cognitive functioning and risk of AD among Hispanic older adults. The current study examined cognitive functioning among older Hispanic adults living in the U.S. from two Hispanic regions, South America and the Caribbean, in relation to the country where education was obtained. Participants (n = 139) were stratified into groups based on Hispanic education region and diagnostic categories: cognitively normal and amnestic MCI (aMCI). Results of Pearson correlations showed that among Hispanic Americans in general, there were significant positive correlations between the country of education to performance on measures of episodic, verbal, and word list tests. When examined separately by region and diagnosis, only cognitively normal (CN) South Americans showed significant relationships between country of education and cognitive functioning in these areas. Results of general linear models controlling for education identified differences in neuropsychological performance between groups with the CN groups demonstrating better performance than the aMCI groups within each region. Overall, it was evident that relationships between years of education obtained outside of the U.S. and cognitive functioning were not similar among individuals from these two disparate Spanish speaking regions. This is the first study to examine the country where education was obtained among individuals from countries located in different regions with different cultures that may influence their education and cognitive development throughout life. Findings contribute to the cross-cultural neuropsychological literature in understanding factors that are unique to Hispanic older adults at risk for developing AD.

Intrusion Errors and Progression of Cognitive Deficits in Older Adults with Mild Cognitive Impairment and PreMCI States.

INTRODUCTION: Among persons with amnestic mild cognitive impairment (aMCI), intrusion errors on subscales that measure proactive semantic interference (PSI) may be among the earliest behavioral markers of elevated Alzheimer's disease brain pathology. While there has been considerable cross-sectional work in the area, it is presently unknown whether semantic intrusion errors are predictive of progression of cognitive impairment in aMCI or PreMCI (not cognitively normal but not meeting full criteria for MCI). METHODS: This study examined the extent to which the percentage of semantic intrusion errors (PIE) based on total responses on a novel cognitive stress test, the Loewenstein-Acevedo Scales for Semantic Interference and Learning (LASSI-L), could predict clinical/cognitive outcomes over an average 26-month period in older adults initially diagnosed with aMCI, PreMCI, and normal cognition. RESULTS: On the LASSI-L subscale sensitive to PSI, a PIE cut point of 44% intrusion errors distinguished between those at-risk individuals with PreMCI who progressed to MCI over time compared to individuals with PreMCI who reverted to normal on longitudinal follow-up. Importantly, PIE was able to accurately predict 83.3% of aMCI individuals who later progressed to dementia. DISCUSSION: These preliminary findings indicate that PIE on LASSI-L subscales that measure PSI may be a useful predictor of clinical progression overtime in at-risk older adults.

Mild behavioral impairment as a predictor of cognitive functioning in older adults.

OBJECTIVE: To assess the influence of mild behavioral impairment (MBI) on the cognitive performance of older adults who are cognitively healthy or have mild cognitive impairment (MCI). METHODS: Secondary data analysis of a sample (n = 497) of older adults from the Florida Alzheimer's Disease Research Center who were either cognitively healthy (n = 285) or diagnosed with MCI (n = 212). Over half of the sample (n = 255) met the operationalized diagnostic criteria for MBI. Cognitive domains of executive function, attention, short-term memory, and episodic memory were assessed using a battery of neuropsychological tests. RESULTS: Older adults with MBI performed worse on tasks of executive function, attention, and episodic memory compared to those without MBI. A significant interaction revealed that persons with MBI and MCI performed worse on tasks of episodic memory compared to individuals with only MCI, but no significant differences were found in performance in cognitively healthy older adults with or without MBI on this cognitive domain. As expected, cognitively healthy older adults performed better than individuals with MCI on every domain of cognition. CONCLUSIONS: The present study found evidence that independent of cognitive status, individuals with MBI performed worse on tests of executive function, attention, and episodic memory than individuals without MBI. Additionally, those with MCI and MBI perform significantly worse on episodic memory tasks than individuals with only MCI. These results provide support for a unique cognitive phenotype associated with MBI and highlight the necessity for assessing both cognitive and behavioral symptoms.

A distributed multitask multimodal approach for the prediction of Alzheimer's disease in a longitudinal study.

Predicting the progression of Alzheimer's Disease (AD) has been held back for decades due to the lack of sufficient longitudinal data required for the development of novel machine learning algorithms. This study proposes a novel machine learning algorithm for predicting the progression of Alzheimer's disease using a distributed multimodal, multitask learning method. More specifically, each individual task is defined as a regression model, which predicts cognitive scores at a single time point. Since the prediction tasks for multiple intervals are related to each other in chronological order, multitask regression models have been developed to track the relationship between subsequent tasks. Furthermore, since subjects have various combinations of recording modalities together with other genetic, neuropsychological and demographic risk factors, special attention is given to the fact that each modality may experience a specific sparsity pattern. The model is hence generalized by exploiting multiple individual multitask regression coefficient matrices for each modality. The outcome for each independent modality-specific learner is then integrated with complementary information, known as risk factor parameters, revealing the most prevalent trends of the multimodal data. This new feature space is then used as input to the gradient boosting kernel in search for a more accurate prediction. This proposed model not only captures the complex relationships between the different feature representations, but it also ignores any unrelated information which might skew the regression coefficients. Comparative assessments are made between the performance of the proposed method with several other well-established methods using different multimodal platforms. The results indicate that by capturing the interrelatedness between the different modalities and extracting only relevant information in the data, even in an incomplete longitudinal dataset, will yield minimized prediction errors.