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White matter hyperintensities (WMHs) are brain white matter lesions that are hyperintense on fluid attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) scans. Larger WMH volumes have been associated with Alzheimer’s disease (AD) and with cognitive decline. However, the relationship between WMH volumes and cross-sectional cognitive measures has been inconsistent. We hypothesize that this inconsistency may arise from 1) the presence of AD-specific neuropathology that may obscure any WMH effects on cognition, and 2) varying criteria for creating a WMH segmentation. Manual and automated programs are typically used to determine segmentation boundaries, but criteria for those boundaries can differ. It remains unclear whether WMH volumes are associated with cognitive deficits, and which segmentation criteria influence the relationships between WMH volumes and clinical outcomes. In a sample of 260 non-demented participants (ages 55–90, 141 males, 119 females) from the Alzheimer’s Disease Neuroimaging Initiative (ADNI), we compared the performance of five WMH segmentation methods, by relating the WMH volumes derived using each method to both clinical diagnosis and composite measures of executive function and memory. To separate WMH effects on cognition from effects related to AD-specific processes, we performed analyses separately in people with and without abnormal cerebrospinal fluid amyloid levels. WMH volume estimates that excluded more diffuse, lower-intensity lesions were more strongly correlated with clinical diagnosis and cognitive performance, and only in those without abnormal amyloid levels. These findings may inform best practices for WMH segmentation, and suggest that AD neuropathology may mask WMH effects on clinical diagnosis and cognition. •WMH boundary selection modifies the relationship between WMH volume and cognition.•When less hyperintense voxels were excluded, WMH volume related best to cognition.•In Aβ- participants, greater WMH volume was associated with worse clinical measures.•Alzheimer’s disease-related processes may mask the effect of WMHs on cognition.•Larger total, frontal, parietal and periventricular WMH volumes were related to worse cognition.

With dementia cases rising globally, identifying modifiable psychological factors that support cognitive resilience is crucial. Hopefulness, an optimistic emotional state, may serve as a protective factor against cognitive decline. However, its role in cognitively normal (CN) individuals remains underexplored. We aim to investigate the association between self-reported hopefulness and overall cognitive function in CN older adults and to examine the moderating effect of physical activity on this relationship. A total of 152 CN adults aged 65-90 years were included in the General Lifestyle and Alzheimer's Disease (AD) study. Hopefulness was assessed by the Geriatric Depression Scale item \"Are you hopeful about the future?,\" with \"Yes\" and \"No\" responses defining the hopefulness and non-hopefulness groups. Cognitive function was measured using the total score (TS) of the Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuropsychological battery. Physical activity was evaluated using the Physical Activity Scale for the Elderly. Participants in the hopefulness group showed significantly higher TS scores compared to the non-hopefulness group (B = 5.009,  = 0.003). Physical activity moderated this relationship, with a stronger positive association observed in individuals with high-to-moderate activity levels (B = 7.409,  < 0.001). Self-reported hopefulness, defined as optimism about the future, is positively associated with cognitive function in CN older adults, particularly among those with high-to-moderate physical activity levels. Interventions promoting both emotional well-being and physical activity may offer synergistic benefits for cognitive health.

Aging is accompanied by changes in multiple cognitive domains, which can impact older adults’ ability to maintain independence. The ability to manage one’s personal finances is an activity of daily living most often studied in the context of Mild Cognitive Impairment and dementia. However, it is critical that we also understand the nature and sources of variation in financial capacity in cognitively unimpaired populations. This study aimed to establish meaningful individual differences in financial capacity in this population and to define those primary behavioral predictors of individual differences. Applying a partial least squares correlation approach, we found significant associations between financial capacity, as assessed by the Financial Capacity-Short Form, and a battery of neuropsychological and self-report measures in normal aging ( r  = .56, p  < .001). Key predictors of financial capacity included fluid reasoning, crystallized intelligence, working memory updating, visual memory, and self-reported sleep duration (| r s| = 0.29−0.56, p s = 0.02− 0.001). These findings indicate that financial capacity is supported by multiple cognitive domains in aging. Further, associations with fluid reasoning and crystallized intelligence suggest some individuals may be more protected against clinically-relevant impairment in financial capacity through cognitive reserve mechanisms.

Subjective cognitive decline (SCD) is considered an early risk stage for dementia due to Alzheimer's disease (AD) and the development of pathological brain changes, such as the aggregation of amyloid-beta (amyloid-β) plaques. This study evaluates the association between specific features of SCD and cerebral amyloid-β load measured by positron emission tomography (PET) with 18 F-florbetaben in 40 cognitively normal older individuals. Global amyloid-β, as well as regional amyloid-β load for the frontal, temporal, parietal, and cingulate cortex, was quantified. Specific features of SCD, such as subjective cognitive complaints and worry, were assessed using the 39-item Everyday Cognition Scales and the 16-item Penn State Worry Questionnaire. Spearman's rank partial correlation analyses, adjusted for age and apolipoprotein E ε4 status, were conducted to test the associations between specific features of SCD and cerebral amyloid-β load. The severity of subjective cognitive complaints in everyday memory and organization was positively correlated with amyloid-β load in the frontal cortex. In addition, the severity of subjective cognitive complaints in everyday planning was positively correlated with amyloid-β load in the parietal cortex. Higher levels of worry were associated with higher amyloid-β load in the frontal cortex. After correction of the PET data for partial volume effects, these associations were reduced to trend level. In conclusion, the severity of subjective cognitive complaints and the level of trait worry were positively associated with cortical amyloid-β burden, particularly in the frontal and parietal cortex. Further studies are required to elucidate the direction of these associations in order to develop strategies to prevent amyloid deposition and cognitive decline.

Tau pathology, a hallmark of Alzheimer's disease, is observed in the brains of virtually all individuals over 70 years. Using 18F-AV-1451 (18F-flortaucipir) positron emission tomography, we evaluated tau pathology in 54 cognitively normal participants (mean age: 77.5 years, SD: 8.9) from the Baltimore Longitudinal Study of Aging. We assessed associations between positron emission tomography signal and age, sex, race, and amyloid positivity. We investigated relationships between regional signal and retrospective rates of change in regional volumes and cognitive function adjusting for age, sex, and amyloid status. Greater age, male sex, black race, and amyloid positivity were associated with higher 18F-AV-1451 retention in distinct brain regions. Retention in the entorhinal cortex was associated with lower entorhinal volume (β = −1.124, SE = 0.485, P = .025) and a steeper decline in memory performance (β = −0.086, SE = 0.039, P = .029). Assessment of medial temporal tau pathology will provide insights into early structural brain changes associated with later cognitive impairment and Alzheimer's disease. •Age and amyloid-associated tau positron emission tomography (PET) differences in frontal, temporal, and occipital areas.•Entorhinal tau PET associated with lower volume in the same region.•Medial temporal tau PET related to memory decline in older cognitively normals.

BACKGROUND The apolipoprotein E (APOE) gene includes the strongest protective (ε2) and risk (ε4) variants for sporadic Alzheimer's disease (AD), but underlying mechanisms remain unclear. We studied APOE genotype effects on the cerebrospinal fluid (CSF) proteome. METHODS Using untargeted tandem mass tag mass spectrometry, we analyzed CSF from 227 cognitively normal (CN) controls (A–T–), 165 CN A+, and 177 individuals with mild cognitive impairment (MCI A+) from two large cohorts. We compared protein levels across APOE genotypes using linear regression and characterized biological pathways. RESULTS Five hundred forty‐nine of 978 proteins (56%) differed between ε2/ε3 (n = 32 individuals) or ε4 carriers (n = 181 individuals) and ε3/ε3 controls. ε2/ε3 controls showed the most differences, with higher levels of 280 proteins enriched for neuronal plasticity. ε4 carrier controls showed increased proteins linked to blood–brain barrier dysfunction, and A+ ε4 carriers were related to glucose metabolism. DISCUSSION Combining two cohorts enabled analysis of the rare APOE ε2 genotype, suggesting protective effects may occur through improved neuronal plasticity. Highlights Apolipoprotein E (APOE) genotypes show distinct cerebrospinal fluid proteomic mechanisms in early Alzheimer's disease (AD). Combining cohorts enabled analysis of rare APOE ε2–associated protection in AD. The rare ε2 genotype may confer protection through improved neuronal plasticity. APOE ε4 carriers show increased blood–brain barrier dysfunction and glucose metabolism. These findings offer new insights into genotype‐specific mechanisms in early AD.

INTRODUCTION Amyloid beta (Aβ) can be detected in vivo years before Alzheimer's disease (AD) symptom onset and, according to recent criteria, is sufficient for a biological diagnosis. This study evaluates emotional responses to Aβ status disclosure in cognitively normal individuals. METHODS Questionnaires were given before and 6 months after Aβ positron emission tomography results disclosure to assess anxiety and depression related to the possibility of an elevated result, subjective memory complaints, and motivation for risk‐reduction behavior. RESULTS One hundred ninety‐nine cognitively normal adults were included. Non‐elevated Aβ status disclosure was associated with reductions in all emotional parameters compared to baseline (p < 0.001). Elevated Aβ disclosure was associated with no changes in depression or memory complaints and a modest decrease in anxiety and motivation to change lifestyle (p < 0.048). DISCUSSION No negative psychological effects were observed after Aβ status disclosure. Decreased motivation for lifestyle changes was seen after disclosure of both elevated and non‐elevated amyloid status and should be targeted. Highlights No negative psychological effects were observed after amyloid beta (Aβ) status disclosure. Motivation for lifestyle changes decreased after Aβ disclosure. Lower education may predict “unfavorable” response to non‐elevated Aβ disclosure. Results support personalized communication strategies for Aβ disclosure.

Alzheimer's disease (AD) is characterized by amyloid-beta plaques, tau tangles, and neuroinflammation. C-X3-C motif chemokine ligand 1 (CX3CL1, also known as fractalkine), a neuroimmune chemokine implicated in AD pathogenesis, shows inconsistent alterations in plasma/serum across studies. Specifically examining age-dependency and diagnostic utility, we investigated plasma CX3CL1 levels across the cognitive continuum (cognitively normal [CN], amnestic mild cognitive impairment [aMCI], AD) in a Chinese cohort. A total of 443 participants, including 130 patients with AD, 72 patients with aMCI, and 99 age-and sex-matched CN controls, as well as a cohort of 142 CN subjects of different ages, were enrolled from Chongqing General Hospital. Plasma CX3CL1 levels were determined using Enzyme-Linked Immunosorbent Assay (ELISA). Apolipoprotein E genotypes (APOE) were performed. The correlations between Plasma CX3CL1 levels and cognition test scores or age were analyzed. The optimal diagnostic sensitivity and specificity were determined using receiver operating characteristic curve analysis. Plasma CX3CL1 levels significantly increased with age in CN individuals. No significant sex difference was found. Plasma CX3CL1 levels did not differ significantly between APOE ε4 carriers and non-carriers. Stepwise elevation across continuum: CX3CL1 levels showed a significant stepwise increase: CN controls (1.73 ± 0.51 ng/mL) < aMCI (2.40 ± 1.06 ng/mL) < AD (4.15 ± 1.24 ng/mL) (p < 0.001 between all groups). This pattern persisted in both male and female subgroups, between the AD group and the aMCI group, between the AD group and the CN control group (p < 0.001), between the aMCI group and the CN control group, and between the male and female subgroups (p < 0.05). CX3CL1 levels negatively correlated with Mini-Mental State Examination (MMSE) scores and positively correlated with age. Plasma CX3CL1 levels exhibit a significant age-dependent increase in cognitively normal individuals, peak in midlife (40-49 years), and demonstrate a stepwise elevation across the AD continuum (CN → aMCI → AD). Strong inverse correlations with cognitive scores in disease groups and high diagnostic accuracy for AD, particularly against CN, support its role as a biomarker reflecting both physiological aging and AD-related pathological decline. Its regulation appears independent of APOE ε4 status. The midlife peak suggests potential relevance for preclinical processes, warranting further investigation of CX3CL1 as a biomarker and therapeutic target.

Little is known about the association of cortical Aβ with depression and anxiety among cognitively normal (CN) elderly persons. We conducted a cross-sectional study derived from the population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota; involving CN persons aged ≥ 60 years that underwent PiB-PET scans and completed Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI). Cognitive diagnosis was made by an expert consensus panel. Participants were classified as having abnormal (≥1.4; PiB+) or normal PiB-PET (<1.4; PiB−) using a global cortical to cerebellar ratio. Multi-variable logistic regression analyses were performed to calculate odds ratios (OR) and 95% confidence intervals (95% CI) after adjusting for age and sex. Of 1,038 CN participants (53.1% males), 379 were PiB+. Each one point symptom increase in the BDI (OR = 1.03; 1.00–1.06) and BAI (OR = 1.04; 1.01–1.08) was associated with increased odds of PiB-PET+. The number of participants with BDI > 13 (clinical depression) was greater in the PiB-PET+ than PiB-PET- group but the difference was not significant (OR = 1.42; 0.83–2.43). Similarly, the number of participants with BAI > 10 (clinical anxiety) was greater in the PiB-PET+ than PiB-PET− group but the difference was not significant (OR = 1.77; 0.97–3.22). As expected, depression and anxiety levels were low in this community-dwelling sample, which likely reduced our statistical power. However, we observed an informative albeit weak association between increased BDI and BAI scores and elevated cortical amyloid deposition. This observation needs to be tested in a longitudinal cohort study.

Background Amyloid pathology is the pathological hallmark in Alzheimer’s disease (AD) and can precede clinical dementia by decades. So far it remains unclear how amyloid pathology leads to cognitive impairment and dementia. To design AD prevention trials it is key to include cognitively normal subjects at high risk for amyloid pathology and to find predictors of cognitive decline in these subjects. These goals can be accomplished by targeting twins, with additional benefits to identify genetic and environmental pathways for amyloid pathology, other AD biomarkers, and cognitive decline. Methods From December 2014 to October 2017 we enrolled cognitively normal participants aged 60 years and older from the ongoing Manchester and Newcastle Age and Cognitive Performance Research Cohort and the Netherlands Twins Register. In Manchester we included single individuals, and in Amsterdam monozygotic twin pairs. At baseline, participants completed neuropsychological tests and questionnaires, and underwent physical examination, blood sampling, ultrasound of the carotid arteries, structural and resting state functional brain magnetic resonance imaging, and dynamic amyloid positron emission tomography (PET) scanning with [ 18 F]flutemetamol. In addition, the twin cohort underwent lumbar puncture for cerebrospinal fluid collection, buccal cell collection, magnetoencephalography, optical coherence tomography, and retinal imaging. Results We included 285 participants, who were on average 74.8 ± 9.7 years old, 64% female. Fifty-eight participants (22%) had an abnormal amyloid PET scan. Conclusions A rich baseline dataset of cognitively normal elderly individuals has been established to estimate risk factors and biomarkers for amyloid pathology and future cognitive decline.