Longitudinal Cognitive Changes Research Articles

The taxonomy of subjective cognitive decline: proposal and first clinical evidence from the Geneva memory clinic cohort.

Subjective Cognitive Decline (SCD) is characterized by subjective cognitive concerns without objective cognitive impairment and is considered a risk factor for cognitive decline and dementia. However, most SCD patients will not develop neurodegenerative disorders, yet they may suffer from minor psychiatric, neurological, or somatic comorbidities. The aim of the present study is to provide a taxonomy of the heterogeneous SCD entity by isolating homogenous SCD subgroups with specific clinical features and cognitive trajectoriesand to conduct a preliminary validation using data from a memory clinic sample. Participants were fifty-five SCD individuals consecutively recruited at the Geneva Memory Center. Based on clinical reports, they were classified into three clinically pre-defined subgroups: (i) those with psychological or psychiatric comorbidities (Psy), (ii) those with somatic comorbidities (SomCom), (iii) and those with no apparent cause (NAC). Baseline demographics, clinical, cognitive, and biomarker differences among the SCD subgroups were assessed. Longitudinal cognitive changes (average 3 years follow-up) were modeled using a linear mixed model. Out of the 55 SCD cases, 16 were SomCom, 18 Psy, and 21 NAC. 47% were female, mean age was 71 years. We observed higher frequency of APOE ε4 carriers in NAC (53%) compared to SomCom (14%) and Psy (0%, P=0.023) and lower level of plasma Aβ42 in NAC (6.8±1.0) compared to SomCom (8.4±1.1; P=0.031). SomCom subjects were older (74 years) than Psy (67 years, P=0.011), and had greater medial temporal lobe atrophy (1.0±1.0) than Psy (0.2±0.6) and NAC (0.4±0.5, P=0.005). SomCom have worse episodic memory performances (14.5±3.5) than Psy (15.8±0.4) and NAC (15.8±0.7, P=0.032). We observed a slightly steeper, yet not statistically significant, cognitive decline in NAC (β=-0.48) compared to Psy (β=-0.28) and SomCom (β=-0.24). NAC feature higher proportion of APOE ε4 carriers, lower plasma Aβ42 and a trend towards steeper cognitive decline than SomCom and Psy. Taken together, these findings suggest that NAC are at higher risk of cognitive decline due to AD. The proposed clinical taxonomy might be implemented in clinical practice to identify SCD at higher risk. However, such taxonomy should be tested on an independent cohort with larger sample size.

Cerebrospinal fluid α-synuclein adds the risk of cognitive decline and is associated with tau pathology among non-demented older adults

BackgroundThe role of α-synuclein in dementia has been recognized, yet its exact influence on cognitive decline in non-demented older adults is still not fully understood.MethodsA total of 331 non-demented individuals were included in the study from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). Participants were divided into two distinct groups based on their α-synuclein levels: one with lower levels (α-synuclein-L) and another with higher levels (α-synuclein-H). Measurements included neuropsychiatric scales, cerebrospinal fluid (CSF) biomarkers, and blood transcriptomics. The linear mixed-effects model investigated the longitudinal changes in cognition. Kaplan-Meier survival analysis and the Cox proportional hazards model were utilized to evaluate the effects of different levels of α-synuclein on dementia. Gene set enrichment analysis (GSEA) was utilized to investigate the biological pathways related to cognitive impairment. Pearson correlation, multiple linear regression models, and mediation analysis were employed to investigate the relationship between α-synuclein and neurodegenerative biomarkers, and their potential mechanisms affecting cognition.ResultsHigher CSF α-synuclein levels were associated with increased risk of cognitive decline and progression to dementia. Enrichment analysis highlighted the activation of tau-associated and immune response pathways in the α-synuclein-H group. Further correlation and regression analysis indicated that the CSF α-synuclein levels were positively correlated with CSF total tau (t-tau), phosphorylated tau (p-tau) 181, tumor necrosis factor receptor 1 (TNFR1) and intercellular cell adhesion molecule-1 (ICAM-1). Mediation analysis further elucidated that the detrimental effects of CSF α-synuclein on cognition were primarily mediated through CSF t-tau and p-tau. Additionally, it was observed that CSF α-synuclein influenced CSF t-tau and p-tau181 levels via inflammatory pathways involving CSF TNFR1 and ICAM-1.ConclusionsThese findings elucidate a significant connection between elevated levels of CSF α-synuclein and the progression of cognitive decline, highlighting the critical roles of activated inflammatory pathways and tau pathology in this association. They underscore the importance of monitoring CSF α-synuclein levels as a promising biomarker for identifying individuals at increased risk of cognitive deterioration and developing dementia.

Cross-sectional and Longitudinal Age-related Disintegration in Functional Connectivity: Reference Ability Neural Network Cohort.

Some theories of aging have linked age-related cognitive decline to a reduction in distinctiveness of neural processing. Observed age-related correlation increases among disparate cognitive tasks have supported the dedifferentiation hypothesis. We previously showed cross-sectional evidence for age-related correlation decreases instead, supporting an alternative disintegration hypothesis. In the current study, we extended our previous research to a longitudinal sample. We tested 135 participants (20-80 years) at two time points-baseline and 5-year follow-up-on a battery of 12 in-scanner tests, each tapping one of four reference abilities. We performed between-tasks correlations within domain (convergent) and between domain (discriminant) at both the behavioral and neural level, calculating a single measure of construct validity (convergent - discriminant). Cross-sectionally, behavioral construct validity was significantly different from chance at each time point, but longitudinal change was not significant. Analysis by median age split revealed that older adults showed higher behavioral validity, driven by higher discriminant validity (lower between-tasks correlations). Participant-level neural validity decreased over time, with convergent validity consistently greater than discriminant validity; this finding was also observed at the cross-sectional level. In addition, a disproportionate decrease in neural validity with age remained significant after controlling for demographic factors. Factors predicting longitudinal changes in global cognition (mean performance across all 12 tasks) included age, change in neural validity, education, and National Adult Reading Test (premorbid intelligence). Change in neural validity partially mediated the effect of age on change in global cognition. Our findings support the theory of age-related disintegration, linking cognitive decline to changes in neural representations over time.

Cognition and Amyloid-β in Older Veterans: Characterization and Longitudinal Outcomes of Data-Derived Phenotypes.

Within older Veterans, multiple factors may contribute to cognitive difficulties. Beyond Alzheimer's disease (AD), psychiatric (e.g., PTSD) and health comorbidities (e.g., TBI) may also impact cognition. This study aimed to derive subgroups based on objective cognition, subjective cognitive decline (SCD), and amyloid burden, and then compare subgroups on clinical characteristics, biomarkers, and longitudinal change in functioning and global cognition. Cluster analysis of neuropsychological measures, SCD, and amyloid PET was conducted on 228 predominately male Vietnam-Era Veterans from the Department of Defense-Alzheimer's Disease Neuroimaging Initiative. Cluster-derived subgroups were compared on baseline characteristics as well as 1-year changes in everyday functioning and global cognition. The cluster analysis identified 3 groups. Group 1 (n = 128) had average-to-above average cognition with low amyloid burden. Group 2 (n = 72) had the lowest memory and language, highest SCD, and average amyloid burden; they also had the most severe PTSD, pain, and worst sleep quality. Group 3 (n = 28) had the lowest attention/executive functioning, slightly low memory and language, elevated amyloid and the worst AD biomarkers, and the fastest rate of everyday functioning and cognitive decline. Psychiatric and health factors likely contributed to Group 2's low memory and language performance. Group 3 was most consistent with biological AD, yet attention/executive function was the lowest score. The complexity of older Veterans' co-morbid conditions may interact with AD pathology to show attention/executive dysfunction (rather than memory) as a prominent early symptom. These results could have important implications for the implementation of AD-modifying drugs in older Veterans.

The Mediating Effects of Education and Occupational Complexity Between Race and Longitudinal Change in Late Life Cognition in ACTIVE.

This study examined educational and occupational inequality as two aspects of social determinants of health that might mediate the longitudinal relationship between racialization and late life cognitive level and change. Participants were 2371 individuals racialized as Black and White from the ACTIVE study who provided occupational data. Data were analyzed from baseline and five assessments over 10-years using structural equation modeling. Black/White race served as the predictor, occupational complexity (OC) and years of education as mediators, and cognitive (memory, reasoning, and speed of processing) intercept, linear slope, and quadratic slope as the dependent variables. Black/White race showed significant indirect associations through education and OC on level of performance in cognition, linear change in reasoning and memory, and quadratic change in reasoning. Education and OC accounted for 11-16% of the association between race and cognitive level and represent modifiable social determinants of health that are associated with disparities in cognitive aging.

Associations of cognitive impairment and longitudinal change in cognitive function with the risk of fatal stroke in middle-aged to older Chinese

It is unclear whether cognitive impairment and the longitudinal change in cognition are associated with the risk of fatal stroke in aging populations. Based on the Guangzhou Biobank Cohort Study data a sum of 26,064 participants at baseline and all deaths caused by stroke in a mean follow-up of 14.3 years (standard deviation = 3.2) were included, and the Cox proportional hazard regression was used in this prospective cohort study. Cognitive impairment was respectively associated with an increased risk of fatal strokes (the adjusted hazard ratio (aHR) = 1.38, 95% CI1.16–1.64, P < 0.001) and fatal ischaemic stroke (aHR = 1.39, 95% CI1.10–1.77, P = 0.007), compared to median cognition; the Delayed Word Recall Test (DWRT) score was associated with a decreasing trend for the risk of fatal strokes in a restricted cubic spline analysis; the longitudinal DWRT score decline was associated with the increased risks of fatal strokes (aHR = 1.42, 95% CI 1.11–1.82, P = 0.006) and fatal haemorrhagic stroke (aHR = 1.75, 95% CI 1.10–2.78, P = 0.02), compared to the longitudinal DWRT score rise. In summary, cognitive impairment and the longitudinal decline in DWRT scores were associated with the increased risk of fatal strokes; early screening of cognitive function should be conducive to predictive intervention in fatal stroke among relatively healthy middle-aged to older populations.

Delineating cognitive resilience using fractal regulation: Cross-sectional and longitudinal evidence from the Rush Memory and Aging Project.

Degradation of fractal patterns in actigraphy independently predicts dementia risk. Such observations motivated the study to understand the role of fractal regulation in the context of neuropathologies. We examined associations of fractal regulation with neuropathologies and longitudinal cognitive changes in 533 older participants who were followed annually with actigraphy and cognitive assessments until death with brain autopsy performed. Two measures for fractal patterns were extracted from actigraphy, namely, α1 (representing the fractal regulation at time scales of <90 min) and α2 (for time scales 2 to 10h). We found that larger α1 was associated with lower burdens of Lewy body disease or cerebrovascular disease pathologies; both α1 and α2 were associated with cognitive decline. They explained an additional significant portion of the variance in the rate of cognitive decline above and beyond neuropathologies. Fractal patterns may be used as a biomarker for cognitive resilience against dementia-related neuropathologies.

Abstract 72: Association Between Stroke Subtype and Post-Stroke Cognitive Decline: A Pooled Cohort Analysis of Four Cohorts

Introduction: Associations between stroke subtype and post-stroke cognitive decline are unclear. We determined if post-stroke cognitive trajectories differed between 1) hemorrhagic vs. ischemic stroke and 2) ischemic stroke subtypes. Methods: We identified 1,150 eligible dementia-free individuals with incident stroke (93% ischemic, 7% hemorrhagic, 50% women, 31% Black, median age, 65) from 4 cohort studies from 1971-2019: Atherosclerosis Risk in Communities Study, Cardiovascular Health Study, Framingham Offspring Study, and Reasons for Geographic and Racial Differences in Stroke. Of the ischemic strokes, 22% were small-vessel occlusion, 8% large artery atherosclerosis, 21% cardioembolic, and 49% cryptogenic/other determined etiology. Linear mixed-effects models were used to estimate longitudinal changes in cognition after incident stroke. Global cognition (primary outcome), executive function, and memory were harmonized across studies and standardized as T-scores (mean [SD], 50 [10]); a 1-point difference represents a 0.1-SD difference in cognition. Median (IQR) follow-up was 5.9 (3.2, 9.2) years. Results: Survivors of ischemic stroke had significant declines in global cognition, executive function, and memory (Table). For example, global cognition declined -0.35 points/year (95%CI, -0.43, -0.26); P &lt;0.001. Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ between hemorrhagic and ischemic stroke, except for lower initial post-stroke memory scores (adjusted difference, -1.39 points; 95% CI, -2.77, -0.01; P =0.049). Survivors of small-vessel occlusions had significant declines in global cognition, executive function, and memory (Table). Initial post-stroke cognitive scores and post-stroke cognitive trajectories did not differ by ischemic stroke subtype. Conclusions: Our results suggest that stroke survivors experience long-term post-stroke cognitive decline regardless of subtype.

Validation of the brain health index in the European Prevention of Alzheimer's Dementia cohort

BackgroundBrain Health Index (BHI) assimilates various MRI sequences, giving a quantitative measure of brain health. To date, BHI validation has been cross-sectional and limited to selected populations. Further large-scale validation and assessment of temporal change is required to understand its clinical utility. AimAssess 1) relationships between variables associated with cognitive decline and BHI 2) associations between BHI and measures of cognition and 3) longitudinal changes in BHI and relationship with cognitive function. MethodsBHI computation involved Gaussian mixture-model cluster analysis of T1, T2, T2*, and T2 FLAIR MRI data from participants within the European Prevention of Alzheimer's Dementia (EPAD) cohort. Group differences (gender- and health-based) were evaluated using independent samples Welch's t-tests. Relationships between BHI, age and cognitive tests used linear regression. Longitudinal analysis (12/24 months) utilised mixed linear regression models to examine BHI changes, and paired BHI/cognition associations. ResultsData from N = 1496 predominantly Caucasian participants (50–88 years old, 43.32% male) were used. BHI scores were lower in those with diabetes (p < 0.001, d = 0.419), hypertension (p < 0.001, d = 0.375), hypercholesterolemia (p < 0.001, d = 0.193) and stroke (p < 0.05, d = 0.512). APOE was not significantly related to BHI scores. After correction for age, cross-sectional BHI scores were significantly associated with all measures of cognitive function in males, but only the Four Mountains Test (4MT) in females. Longitudinal change in BHI and cognition were not consistently related. ConclusionsBHI is a valid marker of cognitive decline and relatively stable over 1-2 year follow-up periods. Further work should assess temporal changes over a longer duration and determine relationships between BHI and cognition in more diverse populations.

Longitudinal Associations of Diet, Food Insecurity, and Supplemental Nutrition Assistance Program Use with Global Cognitive Performance in Middle-Aged and Older Adults

BackgroundDiet quality, food access, and food assistance policies may be key modifiable factors related to cognitive decline. ObjectiveWe aimed to evaluate whether diet quality, food insecurity, and Supplemental Nutrition Assistance Program (SNAP) use are associated with longitudinal changes in cognition among older adults in the United States. MethodsFood intake data from the Health Care and Nutrition Study were linked with longitudinal health information from 5 waves of the Health and Retirement Study (2012–2020). The analytic sample (n = 6968) included community-dwelling United States adults aged ≥51 y without cognitive impairment. Global cognition was measured using a telephone-based cognitive status interview (range: 0–27). Diet quality was measured with the Healthy Eating Index, using participants’ average intake of 13 dietary components. Questions regarding food access and affordability were used to determine food insecurity and use of SNAP benefits. Linear mixed-effects regression models were used to estimate longitudinal associations between diet-related factors and cognitive score changes. ResultsPoorer diets [β: −0.24; 95% confidence interval (CI): −0.33, −0.15], food insecurity (β: −1.08; 95% CI: −1.31, −0.85), and SNAP use (β: −0.57; 95% CI: −0.82, −0.32) were associated with lower baseline cognitive scores. Poorer diets (β: −0.17; 95% CI: −0.29, −0.05) and food insecurity (β: −0.23; 95% CI: −0.47, −0.01) were associated with significantly steeper declines in cognitive scores over time, after 8 and 2 y of follow-up, respectively; however, SNAP use was not significantly associated with the rate of cognitive decline over time. Estimates were qualitatively similar when restricting the sample to participants aged ≥65 y. ConclusionsResults suggest that food access and adherence to healthy diet recommendations may be important elements to maintain cognitive health in aging. SNAP benefits may be insufficient to prevent negative cognitive effects of poor diet and limited access to nutritious foods.

Blood-based biomarkers for Alzheimer's disease and cognitive function from mid- to late life.

We investigated associations of Alzheimer's disease (AD) serum biomarkers with longitudinal changes in cognitive function from mid- to late life among women. The study population included 192 women with the median age of 53.3 years at baseline, from the Study of Women's Health Across the Nation Michigan Cohort, followed up over 14 years. Associations between baseline serum amyloid β (Aβ)42, the Aβ42/40 ratio, phosphorylated tau181 (p-tau181), and total tau with longitudinal changes in cognition were evaluated using linear mixed effects models. After adjusting for confounders, lower Aβ42/40 ratios were associated with faster declines in the Digit Span Backward Test. Higher p-tau181 also showed a borderline statistically significant association with more rapid decline in the Symbol Digit Modalities Test. Our findings suggest that mid-life serum AD biomarkers could be associated with accelerated cognitive decline from mid- to late life in women. Future studies with larger samples are needed to validate and extend our findings. This study investigates midlife serum AD biomarkers on longitudinal cognitive function changes in women. Mid-life serum AD biomarkers are associated with accelerated cognitive decline. A decrease in the Aβ42/40 ratio was associated with a faster decline in the DSB score. A higher p-tau181 concentration was associated with a faster decline in the SDMT score.

Prediction of cognitive decline in healthy aging based on neuropsychiatric symptoms and PET-biomarkers of Alzheimer's disease.

Neuropsychiatric symptoms (NPS) have been associated with a risk of accelerated cognitive decline or conversion to dementia of the Alzheimer's Disease (AD) type. Moreover, the NPS were also associated with higher AD biomarkers (brain tau and amyloid burden) even in non-demented patients. But the effect of the relationship between NPS and biomarkers on cognitive decline has not yet been studied. This work aims to assess the relationship between longitudinal cognitive changes and NPS, specifically depression and anxiety, in association with AD biomarkers in healthy middle-aged to older participants. The cohort consisted of 101 healthy participants aged 50-70years, 66 of whom had neuropsychological assessments of memory, executive functions, and global cognition at a 2-year follow-up. At baseline, NPS were assessed using the Beck Depression and Anxiety Inventories while brain tau and amyloid loads were measured using positron emission topography. For tau burden, THK5351 uptake is used as a proxy of tau and neuroinflammation. Participants, declining or remaining stable at follow-up, were categorized into groups for each cognitive domain. Group classification was investigated using binary logistic regressions based on combined AD biomarkers and the two NPS. The results showed that an association between anxiety and prefrontal amyloid burden significantly classified episodic memory decline, while the classification of global cognitive decline involved temporal and occipital amyloid burden but not NPS. Moreover, depression together with prefrontal and hippocampal tau burden were associated with a decline in memory. The classification of participants based on executive decline was related to depression and mainly prefrontal tau burden. These findings suggest that the combination of NPS and brain biomarkers of AD predicts the occurrence of cognitive decline in aging.

Plasma p‐tau and brain‐derived total tau biomarkers predict longitudinal changes in Aβ, tau, and cognition across the AD continuum

AbstractBackgroundRecent studies have suggested that plasma p‐tau biomarkers are associated with cross‐sectional brain amyloid(Aβ) rather than tau tangle pathology. However, it is still unclear if plasma tau biomarkers are closely related to changes in AD pathophysiology over time. In this work, we aimed to determine if cross‐sectional measures of plasma tau biomarkers are associated with longitudinal changes in Aβ‐PET, tau‐PET, and cognition across the AD spectrum.MethodWe evaluated 157 individuals(96 cognitively unimpaired(CU) and 61 cognitively impaired (CI)) with available baseline measures of plasma Aβ42/40, p‐tau(at threonine 181, 217+, and 231), N‐terminal tau fragments(NTA, a new brain derived tau marker), and glial fibrillary acidic protein(GFAP) and with longitudinal [18F]AZD4694 Aβ‐PET, [18F]MK6340 tau‐PET and Clinical Dementia Rating sum of boxes(CDR‐SB) score from the TRIAD cohort. We also included 321(118 CU and 203 CI) individuals from the ADNI cohort with baseline plasma p‐tau181 and [18F]florbetapir Aβ‐PET and longitudinal CDR‐SB. Using linear regressions adjusted for age and sex we tested the associations between plasma biomarkers and longitudinal changes in Aβ‐PET, tau‐PET, and CDR‐SB.ResultIn CU, changes in tau‐PET were significantly associated only with plasma p‐tau217+(β = 0.331, p&lt;0.01,Figure1A). Changes in Aβ‐PET were significantly associated with p‐tau181(β = 0.594, p&lt;0.01,Figure2A), p‐tau217+(β = 0.311, p = 0.02) and NTA(β = 0.435, p&lt;0.01), while no plasma biomarker was associated with changes in cognition in CU(Figure3A). In CI, changes in tau‐PET were significantly associated with plasma p‐tau181(β = ‐0.338, p = 0.03,Figure1B) and NTA(β = ‐0.379, p = 0.03), while no plasma biomarker was significantly associated with changes in Aβ‐PET. Changes in cognition were significantly associated with plasma p‐tau181(β = 0.340, p = 0.01, Figure3B), p‐tau217+(β = 0.54, p&lt;0.01), and NTA(β = 0.530, p&lt;0.01). Similarly, in the ADNI cohort, plasma p‐tau181 was associated with longitudinal changes in cognition in CI (β = 0.247, p&lt;0.01,Figure3D).ConclusionWe demonstrate that cross‐sectional measures of plasma p‐tau and NTA biomarkers were associated with longitudinal Aβ deposition and tau accumulation in CU, while in CI they were only associated with tau accumulation. Interestingly, plasma tau biomarkers were also associated with changes in cognition in CI individuals. The fact that abnormal levels of plasma tau biomarkers are associated with longitudinal changes in AD pathophysiology has implications for the use of these markers in clinical trials and practice.

Life course neighborhood social determinants of health and longitudinal changes in cognition in three Alzheimer’s Disease Research Center cohorts

AbstractBackgroundSeminal studies on exposure to life course social determinants of health, such as neighborhood racial segregation and neighborhood poverty, suggest detrimental associations with poorer cognitive function. We aimed to test the opposite by examining the relationship between self‐reported exposure to health‐promoting neighborhood environments over the life course and cognitive function among older adults.MethodParticipants were persons living without dementia at three US Alzheimer’s Disease Research Centers (University of California, Davis in Sacramento (UCD); Washington University in Saint Louis (WU); and Wake Forest University in Winston‐Salem (WFU)). An ancillary study (K01AG063895, PI: Besser) included the Life Course Sociodemographics and Neighborhood Questionnaire (LSNEQ) comprised of indices like neighborhood measures of socioeconomic status (NSES), walking and biking frequency, and greenness from childhood, midlife, and late life. LSNEQ data were linked with late‐life cognitive test z‐scores (Animals and Vegetables Category Fluency, Trail Making Parts A and B) from the National Alzheimer’s Coordinating Center Uniform Data Set. Multivariable linear mixed effects models tested associations between the LSNEQ index scores (composite values over childhood and mid‐ and late‐life) and baseline and longitudinal change in cognitive function controlling for demographics, Center, and baseline global Clinical Dementia Rating (0 or 0.5).ResultThe sample (n = 322) included 65% women, 17% Black, 76% White, and 7% other/mixed racialized group participants and was, on average, 70±7 years old and followed for 2.5±3.2 years. Life Course NSES was lower for UCD (mean = 12.7, SD = 3.5) versus WU (mean = 13.9, SD = 3.2) and WFU (mean = 14.3, SD = 3.2). Life Course Neighborhood Walking and Biking frequency did not differ by Center. Life Course Neighborhood Greenness differed across Centers, and was lowest for WU (mean = 4.8, SD = 1.3) and highest for WFU (mean = 5.6; SD = 1.2). In multivariable analyses, greater Life Course Neighborhood Walking and Biking was associated with higher baseline Trail A scores (estimate = 0.83, 95% CI = 0.08‐1.58) and slower decline on Animals over time (estimate = 0.024, 95% CI = 0.002‐0.045). Greater Life Course Neighborhood Greenness was associated with slower decline on Vegetables over time (estimate = 0.035, 95% CI = 0.001‐0.069).ConclusionThese preliminary findings suggest self‐reported, life course neighborhood exposures and behaviors (i.e., greenness and neighborhood walking/biking) may be associated with better cognition and slower decline in later life.

Exploring biomarker profiles of the cognitively unimpaired individuals in early tau PET Braak stage

AbstractBackgroundIn this study, we evaluated the association between tau PET and fluid biomarkers and explored biological mechanisms associated with elevated tau in cognitively unimpaired(CU) individuals.MethodSeventy‐nine CU individuals from the ALFA+ cohort had [18F]RO‐948 and [18F]flutemetamol PET, T1‐weighted MRI, CSF and plasma biomarkers. Longitudinal changes in cognition were measured using cognition composites(Table1). Participants were categorized into AT stages using CSF biomarkers and pre‐established cut‐offs(Table 1). [18F]RO‐948 SUVR was measured in entorhinal(BraakI/II), limbic(BraakIII/IV), and neocortical(BraakV/VI) regions using the inferior cerebellum as reference. Regional positivity thresholds per Braak region were calculated as mean+2SD of the A‐T‐ group. [18F]flutemetamol PET scans were quantified in Centiloids(CL). Associations between [18F]RO‐948 SUVRs and AD biomarkers (Figure1) were assessed using Pearson correlations. Receiver Operating Curve(ROC) analyses were conducted to determine the capacity of biomarkers to predict BraakI/II positivity. In those with CL&gt;cut‐off for tau‐PET positivity, differences in non‐core AD fluid biomarkers(Figure2) and longitudinal cognition were sought between tau BraakI/II positive and negative individuals. The mediating effect of non‐core AD biomarkers on the AD pathophysiological cascade were sought. FDR‐corrected p‐values&lt;0.05 were considered significant.ResultNine cases(11.4%) were positive in BraakI/II. Following a hierarchical pattern, four of them were also positive for BraakIII/IV and one for BraakV/VI. Fluid biomarkers presented correlations with tau PET SUVR in all Braak stages (Figure1) and predictive capacity for tau‐PET positivity in BraakI/II(Table2). In individuals with CL&gt;32.53, BraakI/II positives had higher levels of CSF‐GFAP(p&lt;0.01) and CSF‐NFL(p = 0.03), and presented declines in PACC and in visual, attention, and memory composites (Figure1). CSF‐GFAP partially mediated the association between CL and tau‐PET (16%) and between tau‐PET and CSF‐NfL (30%).ConclusionEarly in the AD continuum, [18F]RO‐948 PET conformed to the Braak hierarchical model. CSF and plasma biomarkers showed moderate associations with tau PET SUVR but good capacity to predict tau PET positivity in BraakI/II. Tau‐PET positivity in this region was associated with higher astrogliosis, neurodegeneration and cognitive decline as compared to tau‐PET negatives with similar levels of amyloid deposition. Astrogliosis partially explained the observed associations between amyloid deposition and the presence of tau tangles in medial temporal regions and, even strongly, between the latter and neurodegeneration.

Relationships between sleep apnea and insomnia with cognition among Latinos in the National Alzheimer’s Coordinating Center (NACC)

AbstractBackgroundSleep difficulties (e.g., sleep apnea, insomnia) have been associated with worse late life cognitive health and increased risk for dementia. However, the role of sleep, a potentially modifiable factor, in cognitive aging is understudied among Hispanics/Latinos/Latinxs (henceforth Latinos)—a group that faces dementia disparities. Therefore, we examined the relationships between sleep difficulties and cognition in this population using data from the National Alzheimer’s Coordinating Center (NACC).MethodParticipants included 1,633 Latinos (64% females) ages 21 to 98 years old from the NACC (funded by NIA/NIH Grant U24 AG072122). This analysis used data collected at 35 ADRCs from 2015‐2022. Exposures included history of self‐reported and/or clinically assessed sleep apnea (n = 261) and hyposomnia/insomnia (n = 384). Outcomes were concurrent cognitive scores from tests of learning, memory, semantic fluency, processing speed, confrontation naming, and executive functioning. Covariates included age, sex, education, heritage (e.g., Cuban), cognitive status, and body mass index. General linear models separately tested the associations between sleep difficulties with cognition in crude and fully‐adjusted models. Additionally, we examined whether sex, age, or heritage modified these associations.ResultsSleep apnea was associated with faster processing speed, and insomnia was associated with worse confrontation naming in crude but not fully‐adjusted models. In fully adjusted models, sex modified the associations of both sleep apnea and insomnia with semantic fluency. Specifically, men without sleep apnea had worse semantic fluency than all other groups; no other group differences emerged. Females in either insomnia group had better semantic fluency than men in either insomnia group, and women without insomnia had marginally better semantic fluency than women with insomnia. Older age (continuous) was associated with worse executive functioning, specifically working memory, among individuals with insomnia to a greater extent than those without insomnia. Heritage did not modify associations between sleep difficulties with cognition.ConclusionConsistent with previous, we found that sleep measures were associated with cognition in this group of Latinos from a wide age‐range. Our findings were specific to semantic fluency and varied based on demographic factors (e.g., sex). Future studies should examine the relationships between sleep with longitudinal change in cognition in this underserved community.

Good plumbing for a healthy brain: new insights into the relationship between cerebral blood flow and tissue microstructural integrity

AbstractAlzheimer’s disease (AD) has historically been regarded as a gray matter disease, with cortical atrophy on the macroscopic scale and development of amyloid‐β plaques and neurofibrillary tau tangles on the microscopic scale. However, this paradigm has been challenged mainly due to the continuous failure of anti‐amyloid interventions to stop cognitive decline. Researchers are now wondering whether these proteins aggregations are simply byproducts of other primary drivers of neurodegeneration. Based on these observations, a new paradigm put the myelination at the center of the pathophysiology of AD suggesting that alterations in myelin may lead to progressive disconnections of neural networks that could underlie age‐related cognitive decline and AD. Recent advances in quantitative MRI methodology have enabled probing tissue microstructure with exquisite sensitivity, particularly using diffusion tensor imaging and relaxation times, and has revealed nonlinear age‐related trajectories of cerebral tissues during aging. However, although sensitive to myelin, these MRI metrics are not specific precluding specific interpretation of the underlying mechanisms involved in these microstructural changes. To address this challenge, we have developed an advanced method, called BMC‐mcDESPOT, to measure myelin water fraction (MWF), a specific surrogate of myelin content, and provided the first in‐vivo evidence of myelin breakdown in mild cognitive impairment and dementias. Further, this method has opened the way to provide novel insights into the impact of vascular, genetic, and metabolic risk factors on myelination, as well as on the role of myelin in cognition and physical functioning. In this talk, we will present an overview of some of our recent improvements to further accelerate MWF imaging. We will also present results relating reversible risk factors, including cerebral blood flow, obesity and hypertension, to myelin integrity. Finally, we will discuss new results of the implication of cerebral myelination in longitudinal changes in cognition, including memory, executive function, attention, verbal fluency and processing speed, as well as in changes in gait speeds. Understanding the role of myelination in cognitive and physical functioning has the potential to provide a window into the underlying biology of age‐related brain diseases, and to nominate new MR imaging biomarkers for longitudinal assessment and targets for intervention.

Serum biomarkers for prognosis and monitoring in asymptomatic Alzheimer’s Disease

AbstractBackgroundPrognostic and monitoring capabilities of blood‐based biomarkers for early cognitive decline, amyloid‐β (Aβ) accumulation and grey matter (GM) loss in the asymptomatic phase of Alzheimer disease require further investigation over extended time periods. This longitudinal study investigated serum glial fibrillary acidic protein (GFAP), neurofilament light (NfL) and Aβ1‐42/Aβ1‐40 as potential prognostic and monitoring biomarkers in cognitively unimpaired (CU) elderly.MethodWe included 184 CU older adults (Table 1) who underwent baseline serum sampling and 2‐yearly neuropsychological assessment for up to 10 years (median: 6 years, Figure 1). A subset (N = 109) underwent serial blood sampling, Aβ‐PET and structural MRI at 2 (N = 73), 3 (N = 34), or 4 (N = 2) time points (time interval: 2‐10 years, median: 6 years). Cognition was evaluated in memory, language and executive functioning domains through conversion of neuropsychological tests scores to standardised z‐scores and subsequent averaging per domain. Aβ‐accumulation and GM loss were analysed in a voxelwise manner using Voxelstats with cluster‐level p RFT&lt;.05 and voxel‐level puncorrected&lt;.001 significance thresholds.[1] Aβ1‐42/Aβ1‐40 was inverted to facilitate biomarker comparison. Linear‐mixed effects models were used to (i) identify the predictive value of serum biomarkers for longitudinal cognitive decline, Aβ‐accumulation and GM loss, (ii) calculate annual serum biomarker rates of change and (iii) investigate associations between longitudinal biomarker changes and longitudinal changes in cognition, Aβ‐PET and GM volume.ResultHigh baseline GFAP and NfL predicted a longitudinal decline in memory (βGFAP*time = ‐0.020, pFDR = 0.03; βNfL*time = ‐0.031, pFDR = 0.002) and language (βGFAP*time = ‐0.025, pFDR&lt;0.001, βNfL*time = ‐0.017, pFDR = 0.04), and longitudinal GM loss within the hippocampus. Low Aβ1‐42/Aβ1‐40 predicted memory decline (βAβ1‐42/Aβ1‐40*time = ‐0.022, pFDR = 0.03) as well as Aβ accumulation within Aβ‐vulnerable regions (Figure 1). Serum GFAP (βtime = 0.022, pFDR&lt;.001) and NfL (βtime = 0.040, pFDR&lt;.001) increased over time. Longitudinal serum NfL increases were associated with a concomitant decline in memory (β∆NfL*time = ‐0.031, pFDR= .004), language (β∆NfL*time = ‐0.022, pFDR= .01) and GM volume (Figure 2). Serum GFAP increases were associated with precuneal Aβ accumulation. Aβ1‐42/Aβ1‐40 decreases were stronger in Aβ‐ subjects (pFDR&lt;.001) and did not associate with Aβ accumulation, nor any other longitudinal marker.ConclusionSerum GFAP, NfL and Aβ1‐42/Aβ1‐40 are prognostic and/or monitoring biomarkers providing complementary information by reflecting different Aβ‐dependent or ‐independent pathophysiological processes.REFERENCE[1] Mathotaarachchi et al. Front Neuroinform 2016.

Neurophysiological activity linked to Alzheimer’s disease pathology relates to longitudinal cognition and progression to mild cognitive impairment

AbstractBackgroundAlzheimer’s Disease (AD) is defined by the pathological accumulation of amyloid‐beta (Aß) and tau in the brain. Regional deposition of these proteins is associated with changes in frequency‐defined neurophysiological activity that can be detected using non‐invasive magnetoencephalography (MEG). Here we examined whether these neurophysiological alterations were associated with participants’ demographics and longitudinal changes in cognition. Additionally, we addressed the clinical utility of MEG to predict progression to mild cognitive impairment (MCI), as compared to other established AD imaging biomarkers.MethodWe used Positron Emission Tomography (PET) to measure the deposition of whole‐brain Aß ([18F]NAV4694) and tau ([18F] Flortaucipir), Magnetic Resonance Imaging (MRI) to measure hippocampal volume and resting‐state MEG to capture neurophysiological activity in a group of clinically unimpaired older adults with family history of AD (PREVENT‐AD cohort; n = 103). We implemented a multivariate partial least squares (PLS) analysis to test the association between imaging markers (i.e., neurophysiological activity and AD proteinopathy) and participants’ clinical profiles (i.e., demographic‐clinical variables and longitudinal cognition data). For the second analysis we used logistic regression models to assess the added value of neurophysiological activity to predict MCI progression compared to established MRI/PET imaging markers (n = 100; 14 MCI progressors).ResultThe PLS analysis identified significant latent variables that linked proteinopathy‐related neurophysiological activity slowing to older age, lower education, positive APOE e4 status and longitudinal deficits in cognition across multiple domains (Figure 1). The initial logistic regression model included demographic and clinical variables and had an AUC = 0.772, which increased to 0.794 after adding the MRI hippocampal volume. Incorporating MEG spectral power from temporal regions where tau accumulates resulted in a considerable increase in accuracy with an AUC = 0.873. The model including Aß and tau PET on top of MRI and MEG markers reached an AUC = 0.905 (Figure 2).ConclusionOur results show that the neurophysiological changes linked to AD pathology are associated with longitudinal cognitive impairment across multiple domains. MEG spectral power from early tau accumulating regions improved the accuracy for predicting MCI progression, contributing information beyond traditional demographic/clinical variables and structural MRI and representing a more accessible and less invasive alternative compared to PET imaging.

White matter changes in the cholinergic system in Alzheimer’s disease and dementia with Lewy bodies

AbstractBackgroundThe early degeneration of the cholinergic nucleus basalis of Meynert (NBM) and its cortical projections is a hallmark of both dementia with Lewy bodies (DLB) and Alzheimer’s disease (AD). In addition to the NBM, the other major cholinergic projection system originates in the pedunculopontine nucleus (PPN) and provides innervation to the thalamus. Given that visual hallucinations are a hallmark of DLB, but not AD, and have recently been attributed to thalamic degeneration, we tested whether the PPN projection system is differentially altered in DLB compared to AD.MethodsNBM‐cortical and PPN‐thalamus white matter pathways were tracked using diffusion‐weighted imaging data from 46 patients with AD, 48 with DLB, 35 with mild cognitive impairment (MCI) with AD, 38 with MCI with Lewy bodies, and 71 control participants. A free‐water corrected DTI model was estimated. Free water fraction along the cholinergic pathways was compared between groups controlling for age, sex, and free water fraction from a white matter control mask. Multiple linear regression was applied to test associations with cognitive function, core Lewy body symptoms with a focus on visual hallucinations, and changes in cognition using longitudinal follow‐up data.ResultsFree water fraction in the NBM lateral pathway was increased in both dementia and MCI groups compared to controls and this was associated with performance on overall cognition and phonemic fluency tests as well as with longitudinal changes in cognition (Figure 1). Free water fraction along the PPN‐thalamus tract was increased only in DLB patients while it appeared relatively spared in AD and this increase in the Lewy body patients was related to the presence of visual hallucinations (Figure 2). These results were largely replicated in an independent validation cohort (34 AD, 34 DLB, 35 controls).ConclusionOur cross‐validated findings show that the cholinergic input to the thalamus from the PPN is selectively affected in DLB and contributes to visual hallucinations.